Outcomes of patients with exomphalos and associated congenital heart diseases.

INTRODUCTION: Exomphalos is an anterior abdominal wall defect resulting in herniation of contents into the umbilical cord. Severe associated chromosomal anomalies and congenital heart disease (CHD) are known to influence mortality, but it is not clear which cardiac anomalies have the greatest impact on survival. METHODS: We performed a retrospective review of the treatment and outcome of patients with exomphalos over a 30-year period (1990-2020), with a focus on those with the combination of exomphalos major and major CHD (EMCHD). RESULTS: There were 123 patients with exomphalos identified, 59 (48%) had exomphalos major (ExoMaj) (defect > 5 cm or containing liver), and 64 (52%) exomphalos minor (ExoMin). In the ExoMaj group; 17% had major CHD (10/59), M:F 28:31, 29% premature (< 37 weeks, 17/59) and 14% had low birth-weight (< 2.5 kg, 8/59). In the ExoMin group; 9% had major CHD (6/64), M:F 42:22, 18% premature and 10% had low birth-weight. The 5-year survival was 20% in the EMCHD group versus 90% in the ExoMaj with minor or no CHD [p < 0.0001]. Deaths in the EMCHD had mainly right heart anomalies and all of them required mechanical ventilation (MV) for pulmonary hypoplasia prior to cardiac intervention. In contrast, survivors did not require mechanical ventilation prior to cardiac intervention. CONCLUSION: EMCHD is associated with high mortality. The most significant finding was high mortality in those with right heart anomalies in combination with pulmonary hypoplasia, especially if pre-intervention mechanical ventilation is required.

Non-invasive cardiac output monitoring with electrical velocimetry after cardiac surgery in infants.

INTRODUCTION: Low cardiac output following cardiac surgery is a major determinant of outcome that may be improved by early detection, yet there are no widely accepted methods for its measurement in young children. We evaluated the feasibility of the routine use of electrical velocimetry, a non-invasive technique providing continuous measurement of cardiac output, in infants in the early postoperative period. METHODS: With ethical approval and parental consent, infants undergoing cardiac surgery were recruited. The ICON electrical velocimetry monitor was attached on admission to the intensive care unit (ICU) and remained for up to 24h. RESULTS: A total of 15 infants were recruited, median age 3 months (interquartile range (IQR) 0.5-7.5) and weight 4.8kg (IQR 3.9-7.1), undergoing various operations. Cardiac index had a weak correlation with arterial lactate (r=-0.24, p=0.02) and no correlation with blood pressure, central venous pressure or arteriovenous oxygen difference. Data were recorded for a median of 19h (range 5-24), with lead detachment or movement artefact the most common causes of data loss. There was marked minute-to-minute variability, with 25% of consecutive measurements having >5% variability. CONCLUSION: Cardiac index measured by electrical velocimetry in infants in the early postoperative period is impaired by frequent data loss and marked intrapatient variability. Our feasibility study suggests that it is unsuitable for use as a routine monitoring tool in the setting of postsurgical ICU care.

Fluid dynamic induced break-up during volcanic eruptions.

Determining whether magma fragments during eruption remains a seminal challenge in volcanology. There is a robust paradigm for fragmentation of high viscosity, silicic magmas, however little is known about the fragmentation behaviour of lower viscosity systems-the most abundant form of volcanism on Earth and on other planetary bodies and satellites. Here we provide a quantitative model, based on experiments, for the non-brittle, fluid dynamic induced fragmentation of low viscosity melts. We define the conditions under which extensional thinning or liquid break-up can be expected. We show that break-up, both in our experiments and natural eruptions, occurs by both viscous and capillary instabilities operating on contrasting timescales. These timescales are used to produce a universal break-up criterion valid for low viscosity melts such as basalt, kimberlite and carbonatite. Lastly, we relate these break-up instabilities to changes in eruptive behaviour, the associated natural hazard and ultimately the deposits formed.

The fingerprint of a flow: wrinkle patterns in nonuniform coatings on pre-stretched soft foundations.

We study the wrinkle patterns obtained when applying a thin polymeric film on a uniaxially prestretched soft foundation. The film is coated onto a substrate where it drains under the action of gravity, thereby introducing a continuous variation in its thickness. We first study the fluid mechanics component of the problem and derive the coating profile as a function of the curing properties of the polymeric solution. Upon polymerization, the prestretch is released and yields the formation of wrinkles, which are arranged in organized patterns, including fractals. We study a variety of scenarios depending on the relative orientation of the gradient of film thickness and the stretching direction. In particular, we characterize and rationalize the distribution of singular events in our problem where wrinkles merge to allow a variation of the average value of the wrinkle wavelength across the sample.

Spatter matters - distinguishing primary (eruptive) and secondary (non-eruptive) spatter deposits.

Spatter is a common pyroclastic product of hawaiian fountaining, which typically forms vent-proximal ramparts or cones. Based on textural characteristics and field relations of spatter from the 1969 Mauna Ulu eruption of Kilauea, Hawai'i, three spatter types were identified: (1) Primary spatter deposited as spatter ramparts and isolated cones during the peak of episode 1; (2) Late-stage spatter comprising dense, small volume, vent proximal deposits, formed at the end of episode 1; (3) Secondary spatter preserved in isolated mounds around tectonic ground cracks that we interpret to have formed by the disruption of overlying lava. We propose that not all spatter deposits are evidence of primary magmatic fountaining. Rather, deposits can be "secondary" in nature and associated with lava drain-back, disruption, and subsequent ejection from tectonic cracks. Importantly, these secondary pyroclastic deposits are difficult to distinguish from primary eruptive features based on field relations and bulk clast vesicularity alone, allowing for the potential misinterpretation of eruption vents, on Earth and in remotely sensed planetary data, thereby misinforming hazard maps and probabilistic assessments. Here, we show that vesicle number density provides a statistically-robust metric by which to discriminate primary and secondary spatter, supporting accurate identification of eruptive vents.

Precision medicine for suicidality: from universality to subtypes and personalization.

Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a 'liquid biopsy' approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies. Such markers may reflect and/or be a proxy for the core biology of suicide. We were successful in this endeavor, using a comprehensive stepwise approach, leading to a wealth of findings. Steps 1, 2 and 3 were discovery, prioritization and validation for tracking suicidality, resulting in a Top Dozen list of candidate biomarkers comprising the top biomarkers from each step, as well as a larger list of 148 candidate biomarkers that survived Bonferroni correction in the validation step. Step 4 was testing the Top Dozen list and Bonferroni biomarker list for predictive ability for suicidal ideation (SI) and for future hospitalizations for suicidality in independent cohorts, leading to the identification of completely novel predictive biomarkers (such as CLN5 and AK2), as well as reinforcement of ours and others previous findings in the field (such as SLC4A4 and SKA2). Additionally, we examined whether subtypes of suicidality can be identified based on mental state at the time of high SI and identified four potential subtypes: high anxiety, low mood, combined and non-affective (psychotic). Such subtypes may delineate groups of individuals that are more homogenous in terms of suicidality biology and behavior. We also studied a more personalized approach, by psychiatric diagnosis and gender, with a focus on bipolar males, the highest risk group. Such a personalized approach may be more sensitive to gender differences and to the impact of psychiatric co-morbidities and medications. We compared testing the universal biomarkers in everybody versus testing by subtypes versus personalized by gender and diagnosis, and show that the subtype and personalized approaches permit enhanced precision of predictions for different universal biomarkers. In particular, LHFP appears to be a strong predictor for suicidality in males with depression. We also directly examined whether biomarkers discovered using male bipolars only are better predictors in a male bipolar independent cohort than universal biomarkers and show evidence for a possible advantage of personalization. We identified completely novel biomarkers (such as SPTBN1 and C7orf73), and reinforced previously known biomarkers (such as PTEN and SAT1). For diagnostic ability testing purposes, we also examined as predictors phenotypic measures as apps (for suicide risk (CFI-S, Convergent Functional Information for Suicidality) and for anxiety and mood (SASS, Simplified Affective State Scale)) by themselves, as well as in combination with the top biomarkers (the combination being our a priori primary endpoint), to provide context and enhance precision of predictions. We obtained area under the curves of 90% for SI and 77% for future hospitalizations in independent cohorts. Step 5 was to look for mechanistic understanding, starting with examining evidence for the Top Dozen and Bonferroni biomarkers for involvement in other psychiatric and non-psychiatric disorders, as a mechanism for biological predisposition and vulnerability. The biomarkers we identified also provide a window towards understanding the biology of suicide, implicating biological pathways related to neurogenesis, programmed cell death and insulin signaling from the universal biomarkers, as well as mTOR signaling from the male bipolar biomarkers. In particular, HTR2A increase coupled with ARRB1 and GSK3B decreases in expression in suicidality may provide a synergistic mechanistical corrective target, as do SLC4A4 increase coupled with AHCYL1 and AHCYL2 decrease. Step 6 was to move beyond diagnostics and mechanistical risk assessment, towards providing a foundation for personalized therapeutics. Items scored positive in the CFI-S and subtypes identified by SASS in different individuals provide targets for personalized (psycho)therapy. Some individual biomarkers are targets of existing drugs used to treat mood disorders and suicidality (lithium, clozapine and omega-3 fatty acids), providing a means toward pharmacogenomics stratification of patients and monitoring of response to treatment. Such biomarkers merit evaluation in clinical trials. Bioinformatics drug repurposing analyses with the gene expression biosignatures of the Top Dozen and Bonferroni-validated universal biomarkers identified novel potential therapeutics for suicidality, such as ebselen (a lithium mimetic), piracetam (a nootropic), chlorogenic acid (a polyphenol) and metformin (an antidiabetic and possible longevity promoting drug). Finally, based on the totality of our data and of the evidence in the field to date, a convergent functional evidence score prioritizing biomarkers that have all around evidence (track suicidality, predict it, are reflective of biological predisposition and are potential drug targets) brought to the fore APOE and IL6 from among the universal biomarkers, suggesting an inflammatory/accelerated aging component that may be a targetable common denominator.

Ash production by attrition in volcanic conduits and plumes.

Tephra deposits result from explosive volcanic eruption and serve as indirect probes into fragmentation processes operating in subsurface volcanic conduits. Primary magmatic fragmentation creates a population of pyroclasts through volatile-driven decompression during conduit ascent. In this study, we explore the role that secondary fragmentation, specifically attrition, has in transforming primary pyroclasts upon transport in volcanic conduits and plumes. We utilize total grain size distributions from a suite of natural and experimentally produced tephra to show that attrition is likely to occur in all explosive volcanic eruptions. Our experimental results indicate that fine ash production and surface area generation is fast (<15 min) thereby rapidly raising the fractal dimension of tephra deposits. Furthermore, a new metric, the Entropy of Information, is introduced to quantify the degree of attrition (secondary fragmentation) from grain size data. Attrition elevates fine ash production which, in turn, has consequences for eruption column stability, tephra dispersal, aggregation, volcanic lightening generation, and has concomitant effects on aviation safety and Earth's climate.

Early-life risk factors identified for owner-reported feline overweight and obesity at around two years of age.

Obesity is considered the second most common health problem in pet cats in developed countries. This study used prospective data from a longitudinal study of pet cats ('C.L.A.W.S.', www.bristol.ac.uk/vetscience/claws) to identify early-life risk factors for feline overweight/obesity occurring at around two years of age. Data were collected via five owner-completed questionnaires (for cats aged two-six months, six months, 12 months, 18 months and two years respectively) completed between May 2011 and April 2015. Owner-reported body condition scores (BCS) of cats at age two years, assessed using images from the 9-point BCS system (Laflamme, 1997), were categorised into a dichotomous variable: overweight/obese (BCS 6-9) and not overweight (BCS 1-5) and used as the dependent variable. Of the 375 cats with owner-reported BCS, 25.3% were overweight or obese at two years of age. Multivariable logistic regression models were built using stepwise forward-selection. To account for potential hierarchical clustering due to multi-cat households two-level random intercept models were considered but clustering had no impact on the analysis. Models were compared using Wald tests. Six factors were significantly associated with overweight/obesity at two years of age: being overweight or obese at one year of age (OR=10.6, 95%CI 4.4-25.3); owner belief that BCS 7 was the ideal weight (OR=33.2, 95%CI 8.5-129.4), or that BCS represented overweight cats but they would not be concerned if their cat were classified in this category (OR=2.7, 95%CI 1.2-6.2), at questionnaire five completion; vets advising owners that the cat should lose weight, or making no comment on their weight, between one and two years of age (OR=12.1, 95%CI 3.2-44.9 and OR=3.9, 95%CI 1.5-10.3 respectively); owners giving their cat treats when they "felt happy" with them at 18 months of age (OR=2.7, 95%CI 1.0 - 7.3); feeding ≥250g wet food daily between two and six months of age (OR=2.7, 95%CI 1.2-5.9), and feeding dry food as the only or major part (>50%) of the diet at two years of age (OR=2.1, 95%CI 1.0-4.2). These findings have the potential to reduce the current high prevalence of a widespread problem by informing preventive advice, and as such improving the health and welfare of pet cats.

Risk factors for road traffic accidents in cats up to age 12†months that were registered between 2010 and 2013 with the UK pet cat cohort ('Bristol Cats').

Road traffic accidents (RTAs) are a common cause of death and injury in domestic cats, and a concern to many owners. This study assessed potential risk factors for RTAs in cats up to 12 months of age within a UK cat cohort known as 'The Bristol Cats study'. Data were obtained from three questionnaires, completed by cat owners when their cats were approximately 8-16 weeks old, 6 months old and 12 months old. Information was gathered regarding environmental conditions, cat characteristics and owner management factors. Univariable and multivariable logistic regression models were used to assess associations between these factors and RTAs. Of 1264 eligible study cats, 49 (3.9 per cent) had been involved in an RTA, of which 71.4 per cent (35/49) were known to result in fatal injuries. Rural locations were associated with a higher odds of RTAs than towns, cities or suburban locations. An increased odds of an RTA was also associated with cats that were reported by their owners to hunt at the roadside, as well as cats whose owners classified the road by their house as being a 'long straight section of road'. No significant associations were found between coat colour, breed, sex or neuter status and the odds of an RTA.

Foot-and-Mouth Disease Impact on Smallholders - What Do We Know, What Don't We Know and How Can We Find Out More?

Foot-and-mouth disease (FMD) endemic regions contain three-quarters of the world's FMD susceptible livestock and most of the world's poor livestock keepers. Yet FMD impact on smallholders in these regions is poorly understood. Diseases of low mortality can exert a large impact if incidence is high. Modelling and field studies commonly find high FMD incidence in endemic countries. Sero-surveys typically find a third of young cattle are sero-positive, however, the proportion of sero-positive animals that developed disease, and resulting impact, are unknown. The few smallholder FMD impact studies that have been performed assessed different aspects of impact, using different approaches. They find that FMD impact can be high (>10% of annual household income). However, impact is highly variable, being a function of FMD incidence and dependency on activities affected by FMD. FMD restricts investment in productive but less FMD-resilient farming methods, however, other barriers to efficient production may exist, reducing the benefits of FMD control. Applying control measures is costly and can have wide-reaching negative impacts; veterinary-cordon-fences may damage wildlife populations, and livestock movement restrictions and trade bans damage farmer profits and the wider economy. When control measures are ineffective, farmers, society and wildlife may experience the burden of control without reducing disease burden. Foot-and-mouth disease control has benefitted smallholders in South America and elsewhere. Success takes decades of regional cooperation with effective veterinary services and widespread farmer participation. However, both the likelihood of success and the full cost of control measures must be considered. Controlling FMD in smallholder systems is challenging, particularly when movement restrictions are hard to enforce. In parts of Africa this is compounded by endemically infected wildlife and limited vaccine performance. This paper reviews FMD impact on smallholders in endemic countries. Significant evidence gaps exist and guidance on the design of FMD impact studies is provided.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 2 - Epidemiology, Wildlife and Economics.

We assessed knowledge gaps in foot-and-mouth disease (FMD) research, and in this study, we consider (i) epidemiology, (ii) wildlife and (iii) economics. The study took the form of a literature review (2011-2015) combined with research updates collected in 2014 from 33 institutes from across the world. Findings were used to identify priority areas for future FMD research. During 2011-2015, modelling studies were dominant in the broad field of epidemiology; however, continued efforts are required to develop robust models for use during outbreaks in FMD-free countries, linking epidemiologic and economics models. More guidance is needed for both the evaluation and the setting of targets for vaccine coverage, population immunity and vaccine field efficacy. Similarly, methods for seroprevalence studies need to be improved to obtain more meaningful outputs that allow comparison across studies. To inform control programmes in endemic countries, field trials assessing the effectiveness of vaccination in extensive smallholder systems should be performed to determine whether FMD can be controlled with quality vaccines in settings where implementing effective biosecurity is challenging. Studies need to go beyond measuring only vaccine effects and should extend our knowledge of the impact of FMD and increase our understanding of how to maximize farmer participation in disease control. Where wildlife reservoirs of virus exist, particularly African Buffalo, we need to better understand when and under what circumstances transmission to domestic animals occurs in order to manage this risk appropriately, considering the impact of control measures on livelihoods and wildlife. For settings where FMD eradication is unfeasible, further ground testing of commodity-based trade is recommended. A thorough review of global FMD control programmes, covering successes and failures, would be extremely valuable and could be used to guide other control programmes.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 1 - Overview of Global Status and Research Needs.

The Global Foot-and-mouth disease (FMD) Research Alliance periodically reviews the state of FMD research to assess progress and to identify new priorities. In this supplement we provide an update of global FMD research, comprising (i) this overview paper, which includes background information with key findings, and papers covering (ii) epidemiology, wildlife and economics, (iii) vaccines, (iv) diagnostics, (v) biotherapeutics and disinfectants, (vi) immunology and (vii) pathogenesis and molecular biology. FMD research publications were reviewed (2011-2015) and activity updates were obtained from 33 FMD research institutes from around the world. Although a continual threat, FMD has been effectively controlled in much of the world using existing tools. However, control remains a challenge in most developing countries, where little has been done to understand the ongoing burden of FMD. More research is needed to support control in endemically infected countries, particularly robust field studies. Traditional FMD vaccines have several limitations including short duration and spectrum of protection, cold chain requirements, and the costs and biosecurity risks associated with vaccine production. Significant progress has been made in the development of novel vaccine candidates, particularly in the use of recombinant vaccines and virus-like particles as an alternative to traditional inactivated whole virus vaccines. Continued investment is needed to turn these developments into improved vaccines produced at scale. Increased knowledge of cellular and mucosal immunity would benefit vaccine development, as would further advances in our ability to enhance vaccine capsid stability. Developments in molecular biology and phylogenetics underlie many of the recent advances in FMD research, including improved vaccines and diagnostics, and improved understanding of FMD epidemiology. Tools for genetic analyses continue to become both more powerful and more affordable enabling them to be used to address an ever-expanding range of questions. This rapidly advancing field potentiates many areas of FMD research and should be prioritized.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 5 - Biotherapeutics and Disinfectants.

We assessed knowledge gaps in foot-and-mouth disease (FMD) research. Findings are reported in a series of papers, and in this article, we consider biotherapeutics and disinfectants. The study took the form of a literature review (2011-2015) combined with research updates collected in 2014 from 33 institutes from across the world. Findings were used to identify priority areas for future FMD research. While vaccines will remain the key immunological intervention used against FMD virus (FMDV) for the foreseeable future, it takes a few days for the immune system to respond to vaccination. In an outbreak situation, protection could potentially be provided during this period by the application of rapid, short-acting biotherapeutics, aiming either to stimulate a non-specific antiviral state in the animal or to specifically inhibit a part of the viral life cycle. Certain antiviral cytokines have been shown to promote rapid protection against FMD; however, the effects of different immune-modulators appear to vary across species in ways and for reasons that are not yet understood. Major barriers to the effective incorporation of biotherapeutics into control strategies are cost, limited understanding of their effect on subsequent immune responses to vaccines and uncertainty about their potential impact if used for disease containment. Recent research has highlighted the importance of environmental contamination in FMDV transmission. Effective disinfectants for FMDV have long been available, but research is being conducted to further develop methods for quantitatively evaluating their performance under field, or near-field, conditions. During outbreaks in South Korea in 2010 there was public concern about potential environmental contamination after the mass use of disinfectant and mass burial of culled stock; this should be considered during outbreak contingency planning.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 3 - Vaccines.

This study assessed research knowledge gaps in the field of FMDV (foot-and-mouth disease virus) vaccines. The study took the form of a literature review (2011-15) combined with research updates collected in 2014 from 33 institutes from across the world. Findings were used to identify priority areas for future FMD vaccine research. Vaccines play a vital role in FMD control, used both to limit the spread of the virus during epidemics in FMD-free countries and as the mainstay of disease management in endemic regions, particularly where sanitary controls are difficult to apply. Improvements in the performance or cost-effectiveness of FMD vaccines will allow more widespread and efficient disease control. FMD vaccines have changed little in recent decades, typically produced by inactivation of whole virus, the quantity and stability of the intact viral capsids in the final preparation being key for immunogenicity. However, these are exciting times and several promising novel FMD vaccine candidates have recently been developed. This includes the first FMD vaccine licensed for manufacture and use in the USA; this adenovirus-vectored FMD vaccine causes in vivo expression of viral capsids in vaccinated animals. Another promising vaccine candidate comprises stabilized empty FMDV capsids produced in vitro in a baculovirus expression system. Recombinant technologies are also being developed to improve otherwise conventionally produced inactivated vaccines, for example, by creating a chimeric vaccine virus to increase capsid stability and by inserting sequences into the vaccine virus for desired antigen expression. Other important areas of ongoing research include enhanced adjuvants, vaccine quality control procedures and predicting vaccine protection from immune correlates, thus reducing dependency on animal challenge studies. Globally, the degree of independent vaccine evaluation is highly variable, and this is essential for vaccine quality. Previously neglected, the importance of evaluating vaccination programme effectiveness and impact is increasingly being recognized.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 6 - Immunology.

This study assessed gaps and priorities for FMDV (foot-and-mouth disease virus) research in the field of immunology. The study took the form of a literature review (2011-15) combined with research updates collected in 2014 from 33 institutes from across the world. Findings were used to identify priority areas for future FMD research. Improved understanding of FMDV immunology facilitates the development of vaccines, adjuvants and diagnostic tests, and will allow better assessment and prediction of vaccine potency and match, with reduced use of animals, particularly large animals, in experimental studies. Continued characterization of the immune systems of several FMD host species has underpinned substantial advances in knowledge of their interaction with FMDV. Recent studies have shed light on the mechanisms underlying formation of the bovine B- and T-cell response; there is also a greater understanding of the significance of non-neutralizing antibodies during FMDV infection and the interactions of antibody-bound virus with immune cells. This knowledge is directly relevant to vaccine development, as well as understanding protection and cross-protection. Despite ongoing research, significant knowledge gaps remain in the areas of neonatal and mucosal immunity. The impact of maternally derived antibody upon the neonate's ability to respond to FMD vaccination has received some attention, but few firm conclusions can be drawn at this stage, and little is known of the cellular response of young animals in general. The mucosal immune system of FMDV-susceptible species requires continued characterization, especially if the potential of mucosal vaccine-delivery systems is to be realized for FMD immunization.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 4 - Diagnostics.

This study assessed knowledge gaps in foot-and-mouth disease (FMD) research in the field of diagnostics. The study took the form of a literature review (2011-15) combined with research updates collected in 2014 from 33 institutes from around the world. Findings were used to identify priority areas for future FMD research. Molecular and genetic technologies, including sequencing, are developing at an increasing rate both in terms of capability and affordability. These advances potentiate progress in many other fields of research, from vaccine development to epidemiology. The development of RT-LAMP represents an important breakthrough allowing greater use and access to molecular diagnostics. It is now possible to determine virus serotype using PCR, although only for certain virus pools, continued progress is needed to cover the global spectrum of FMD viruses. Progress has also been made in the development of pen-side rapid diagnostics, some with the ability to determine serotype. However, further advances in pen-side serotype or strain determination would benefit both FMD-free countries and endemic countries with limited access to well-resourced laboratories. Novel sampling methods that show promise include air sampling and baited ropes, the latter may aid sampling in wildlife and swine. Studies of infrared thermography for the early detection of FMD have not been encouraging, although investigations are ongoing. Multiplex tests have been developed that are able to simultaneously screen for multiple pathogens with similar clinical signs. Crucial for assessing FMDV freedom, tests exist to detect animals that have been infected with FMDV regardless of vaccination status; however, limitations exist, particularly when testing previously vaccinated animals. Novel vaccines are being developed with complementary DIVA tests for this purpose. Research is also needed to improve the current imprecise approaches to FMD vaccine matching. The development of simple, affordable tests increases access to FMD diagnostics, greatly benefiting regions with limited laboratory capacity.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 7 - Pathogenesis and Molecular Biology.

We assessed research knowledge gaps in the fields of FMDV (foot-and-mouth disease virus) pathogenesis and molecular biology by performing a literature review (2011-15) and collecting research updates (2014) from 33 institutes from across the world. Findings were used to identify priority areas for future research. There have been important advances in FMDV pathogenesis; FMDV remains in lymph nodes of many recovered animals that otherwise do not appear persistently infected, even in species previously not associated with the carrier state. Whether virus retention helps maintain host immunity and/or virus survival is not known. Studies of FMDV pathogenesis in wildlife have provided insights into disease epidemiology, in endemic and epidemic settings. Many aspects of FMDV infection and virus entry remain unknown; however, at the cellular level, we know that expression level and availability of integrins (that permit viral entry), rate of clearance of infected cells and strength of anti-viral type I IFN (interferon) response are key determinants of tissue tropism. Extending findings to improved understanding of transmission requires a standardized approach and adoption of natural routes of infection during experimental study. There has been recognition of the importance of autophagosomes for FMDV entry into the cytoplasm following cell surface receptor binding, and that distinct internal cellular membranes are exploited for viral replication and immune evasion. New roles for viral proteins in blocking type I IFN production and downstream signalling have been identified facilitating research in anti-viral therapeutics. We know more about how infection affects cell protein expression, and research into molecular determinants of capsid stability has aided the development of stable vaccines. We have an expanding knowledge of viral and host molecular determinates of virulence and infectiousness, and of how phylogenetics may be used to estimate vaccine match and strain distribution. With ongoing advances, these areas could translate into significantly improved disease control.

Mass vaccination, immunity and coverage: modelling population protection against foot-and-mouth disease in Turkish cattle.

Foot-and-mouth disease (FMD) in Turkey is controlled using biannual mass vaccination of cattle. However, vaccine protection is undermined by population turnover and declining immunity. A dynamic model of the Turkish cattle population was created. Assuming biannual mass vaccination with a single-dose primary course, vaccine history was calculated for the simulated population (number of doses and time since last vaccination). This was used to estimate population immunity. Six months after the last round of vaccination almost half the cattle aged < 24 months remain unvaccinated. Only 50% of all cattle would have received > 1 vaccine dose in their life with the last dose given ≤ 6 months ago. Five months after the last round of vaccination two-thirds of cattle would have low antibody titres (< 70% protection threshold). Giving a two-dose primary vaccination course reduces the proportion of 6-12 month old cattle with low titres by 20-30%. Biannual mass vaccination of cattle leaves significant immunity gaps and over-reliance on vaccine protection should be avoided. Using more effective vaccines and vaccination strategies will increase population immunity, however, the extent to which FMD can be controlled by vaccination alone without effective biosecurity remains uncertain.