West Nile virus spread in Europe: Phylogeographic pattern analysis and key drivers.

BACKGROUND: West Nile virus (WNV) outbreaks in birds, humans, and livestock have occurred in multiple areas in Europe and have had a significant impact on animal and human health. The patterns of emergence and spread of WNV in Europe are very different from those in the US and understanding these are important for guiding preparedness activities. METHODS: We mapped the evolution and spread history of WNV in Europe by incorporating viral genome sequences and epidemiological data into phylodynamic models. Spatially explicit phylogeographic models were developed to explore the possible contribution of different drivers to viral dispersal direction and velocity. A "skygrid-GLM" approach was used to identify how changes in environments would predict viral genetic diversity variations over time. FINDINGS: Among the six lineages found in Europe, WNV-2a (a sub-lineage of WNV-2) has been predominant (accounting for 73% of all sequences obtained in Europe that have been shared in the public domain) and has spread to at least 14 countries. In the past two decades, WNV-2a has evolved into two major co-circulating clusters, both originating from Central Europe, but with distinct dynamic history and transmission patterns. WNV-2a spreads at a high dispersal velocity (88km/yr-215 km/yr) which is correlated to bird movements. Notably, amongst multiple drivers that could affect the spread of WNV, factors related to land use were found to strongly influence the spread of WNV. Specifically, the intensity of agricultural activities (defined by factors related to crops and livestock production, such as coverage of cropland, pasture, cultivated and managed vegetation, livestock density) were positively associated with both spread direction and velocity. In addition, WNV spread direction was associated with high coverage of wetlands and migratory bird flyways. CONCLUSION: Our results suggest that-in addition to ecological conditions favouring bird- and mosquito- presence-agricultural land use may be a significant driver of WNV emergence and spread. Our study also identified significant gaps in data and the need to strengthen virological surveillance in countries of Central Europe from where WNV outbreaks are likely seeded. Enhanced monitoring for early detection of further dispersal could be targeted to areas with high agricultural activities and habitats of migratory birds.

Nonutility of Diagnostic Testing in Ambulatory Patients With Supraventricular Tachycardia.

BACKGROUND: Supraventricular tachycardia (SVT) is the most common arrhythmia in the pediatric population. Patients often present to the emergency department and undergo extensive diagnostic assessment. The objective of this study is to determine the frequency of diagnostic studies obtained in such patients and to assess clinical significance of these results. METHODS: A retrospective study was performed from 2011 to 2018 in a single-center ED, including patients 21 years of age or younger presenting with SVT without shock. RESULTS: A total of 40 patients with 92 encounters were included for analysis. The mean age was 8.58 (±5.51) years; 55% female. A total of 67.4% underwent serologic laboratory evaluation, of which 8 (12.9%) had any abnormality. Only one was deemed clinically significant to warrant intervention. Nearly 30% of patients underwent chest radiography, with no clinically significant findings. CONCLUSIONS: Patients undergoing ED management of uncomplicated SVT are likely to undergo laboratory investigation and unlikely to have abnormal studies impacting their care. Given the associated risk of false-positive studies, the discomfort to the patient and parent, and cost of these studies, routine laboratory or radiographic investigation in this population may be unwarranted.

The effect of seasonal strength and abruptness on predator-prey dynamics.

Coupled dynamical systems in ecology are known to respond to the seasonal forcing of their parameters with multiple dynamical behaviours, ranging from seasonal cycles to chaos. Seasonal forcing is predominantly modelled as a sine wave. However, the transition between seasons is often more sudden as illustrated by the effect of snow cover on predation success. A handful of studies have mentioned the robustness of their results to the shape of the forcing signal but did not report any detailed analyses. Therefore, whether and how the shape of seasonal forcing could affect the dynamics of coupled dynamical systems remains unclear, while abrupt seasonal transitions are widespread in ecological systems. To provide some answers, we conduct a numerical analysis of the dynamical response of predator-prey communities to the shape of the forcing signal by exploring the joint effect of two features of seasonal forcing: the magnitude of the signal, which is classically the only one studied, and the shape of the signal, abrupt or sinusoidal. We consider both linear and saturating functional responses, and focus on seasonal forcing of the predator's discovery rate, which fluctuates with changing environmental conditions and prey's ability to escape predation. Our numerical results highlight that a more abrupt seasonal forcing mostly alters the magnitude of population fluctuations and triggers period-doubling bifurcations, as well as the emergence of chaos, at lower forcing strength than for sine waves. Controlling the variance of the forcing signal mitigates this trend but does not fully suppress it, which suggests that the variance is not the only feature of the shape of seasonal forcing that acts on community dynamics. Although theoretical studies may predict correctly the sequence of bifurcations using sine waves as a representation of seasonality, there is a rationale for applied studies to implement as realistic seasonal forcing as possible to make precise predictions of community dynamics.

Association of IL6ST (gp130) Polymorphism with Functional Outcome Following Spontaneous Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Genes associated with the inflammatory response and cytostructural integrity may influence recovery following a brain injury. To examine this in the setting of spontaneous intracerebral hemorrhage (ICH), selected single nucleotide polymorphisms (SNPs) were assessed for associations with patient outcome. METHODS: A cohort of 54 patients with supratentorial ICH were enrolled. Based on known involvement with neuroinflammation and cytostructural integrity, 10 preselected SNPs from 6 candidate genes were tested for associations with 6-month functional outcome (modified Rankin Scale [mRS] ≥ 3), mortality, and in-hospital deterioration (Glasgow Coma Scale decrease by >2 within 7 days of admission) following ICH. Fisher's exact test and logistic regression with adjustment for race and ICH score were performed. RESULTS: SNP rs10940495 (gp130 G/A) within the gp130 gene was the only SNP significantly associated with lower odds of an unfavorable 6-month functional outcome (odds ratio = .16 for mRS ≥ 3; 95% confidence interval, .03-.87, P = .03). Compared with major allele (A) homozygotes, minor allele (G) carriers in the IL6 signal transducer gene (gp130) locus were 84% less likely to have a poor outcome (mRS ≥ 3) at 6 months following spontaneous ICH. The SNP rs10940495 (gp130 G/A) and SNP rs3219119 (PARP-1 A/T) were associated with 6-month mortality (P = .02 and .04, respectively) only on univariate analysis. None of the SNPs examined were associated with in-hospital deterioration. CONCLUSION: In this exploratory study, SNP rs10940495 in the gp130 locus was associated with functional outcome at 6 months following spontaneous ICH. These findings, which should be validated through a larger study, suggest that inflammation plays an important role in mediating outcomes after ICH.

Moving forward in circles: challenges and opportunities in modelling population cycles.

Population cycling is a widespread phenomenon, observed across a multitude of taxa in both laboratory and natural conditions. Historically, the theory associated with population cycles was tightly linked to pairwise consumer-resource interactions and studied via deterministic models, but current empirical and theoretical research reveals a much richer basis for ecological cycles. Stochasticity and seasonality can modulate or create cyclic behaviour in non-intuitive ways, the high-dimensionality in ecological systems can profoundly influence cycling, and so can demographic structure and eco-evolutionary dynamics. An inclusive theory for population cycles, ranging from ecosystem-level to demographic modelling, grounded in observational or experimental data, is therefore necessary to better understand observed cyclical patterns. In turn, by gaining better insight into the drivers of population cycles, we can begin to understand the causes of cycle gain and loss, how biodiversity interacts with population cycling, and how to effectively manage wildly fluctuating populations, all of which are growing domains of ecological research.

Student-derived solutions to address barriers hindering reports of unprofessional behaviour.

BACKGROUND: Barriers hinder medical students from reporting breaches in professional behaviour, which can adversely impact institutional culture. No studies have reported student perspectives on how to address these barriers successfully. Our study (i) evaluated the likelihood of reporting based on violation severity, (ii) assessed barriers to reporting and (iii) elicited students' proposed solutions. METHODS: Four medical students designed a cross-sectional study in 2015. In response to seven scenarios, students rated the likelihood of reporting the violation, indicated perceived barriers and identified solutions. Additional questions investigated the perceived importance of professionalism, confidence in understanding professionalism and trust in administrative protection from negative consequences. RESULTS: Two hundred and seventy-two students in their clinical years (MS2-4) responded to the survey (RR = 50%). Students were 70-90% likely to report major violations, but < 30% likely to report minor or moderate violations. Barriers included concerns about an uncomfortable relationship (41%), potential negative repercussions on grades or opportunities (23%), and addressing by direct discussion rather than reporting (23%). Solutions included simplified reporting, control over report release date, improved feedback to reporters, training for real-time resolution of concerns and a neutral resource to help students triage concerns. No differences existed between classes regarding the importance or understanding of professionalism. In linear regression, only importance of professionalism predicted likelihood of reporting and this did not change with training. CONCLUSIONS: Hindered by common barriers, students are unlikely to report a violation unless it is a serious breach of professionalism. Student-derived solutions should be explored by medical school administrators to encourage reporting of violation of professionalism.

Hunting, food subsidies, and mesopredator release: the dynamics of crop-raiding baboons in a managed landscape.

The establishment of protected areas or parks has become an important tool for wildlife conservation. However, frequent occurrences of human-wildlife conflict at the edges of these parks can undermine their conservation goals. Many African protected areas have experienced concurrent declines of apex predators alongside increases in both baboon abundance and the density of humans living near the park boundary. Baboons then take excursions outside of the park to raid crops for food, conflicting with the human population. We model the interactions of mesopredators (baboons), apex predators, and shared prey in the park to analyze how four components affect the proportion of time that mesopredators choose to crop-raid: (1) the presence of apex predators; (2) nutritional quality of the crops; (3) mesopredator "shyness" about leaving the park; and (4) human hunting of mesopredators. We predict that the presence of apex predators in the park is the most effective method for controlling mesopredator abundance, and hence significantly reduces their impact on crops. Human hunting of mesopredators is less effective as it only occurs during crop-raiding excursions. Furthermore, making crops less attractive, for instance by planting crops further from the park boundary or farming less nutritional crops, can reduce the amount of time mesopredators crop-raid.

Seasonal forcing in a host-macroparasite system.

Seasonal forcing represents a pervasive source of environmental variability in natural systems. Whilst it is reasonably well understood in interacting populations and host-microparasite systems, it has not been studied in detail for host-macroparasite systems. In this paper we analyse the effect of seasonal forcing in a general host-macroparasite system with explicit inclusion of the parasite larval stage and seasonal forcing applied to the birth rate of the host. We emphasise the importance of the period of the limit cycles in the unforced system on the resulting dynamics in the forced system. In particular, when subject to seasonal forcing host-macroparasite systems are capable of multi-year cycles, multiple solution behaviour, quasi-periodicity and chaos. The host-macroparasite systems show a larger potential for multiple solution behaviour and a wider range of periodic solutions compared to similar interacting population and microparasite systems. By examining the system for parameters that represent red grouse and the macroparasite nematode Trichostrongylus tenuis we highlight how seasonality could be an important factor in explaining the wide range of seemingly uncorrelated cycle periods observed in grouse abundance in England and Scotland.

How do variations in seasonality affect population cycles?

Seasonality is an important component in many population systems, and factors such as latitude, altitude and proximity to the coastline affect the extent of the seasonal fluctuations. In this paper, we ask how changes in seasonal fluctuations impact on the population cycles. We use the Fennoscandian vole system as a case study, focusing on variations in the length of the breeding season. We use a predator-prey model that includes generalist and specialist predation alongside seasonal forcing. Using a combination of bifurcation analysis and direct simulations, we consider the effects of varying both the level of generalist predation and the length of the breeding season; these are the main changes that occur over a latitudinal gradient in Fennoscandia. We predict that varying the breeding season length leads to changes in the period of the multi-year cycles, with a higher period for shorter breeding season lengths. This concurs with the gradient of periodicity found in Fennoscandia. The Fennoscandian vole system is only one of many populations that are affected by geographical and temporal changes in seasonality; thus our results highlight the importance of considering these changes in other population systems.

Seasonal forcing and multi-year cycles in interacting populations: lessons from a predator-prey model.

Many natural systems are subject to seasonal environmental change. As a consequence many species exhibit seasonal changes in their life history parameters--such as a peak in the birth rate in spring. It is important to understand how this seasonal forcing affects the population dynamics. The main way in which seasonal models have been studied is through a two dimensional bifurcation approach. We augment this bifurcation approach with extensive simulation in order to understand the potential solution behaviours for a predator-prey system with a seasonally forced prey growth rate. We consider separately how forcing influences the system when the unforced dynamics have either monotonic decay to the coexistence steady state, or oscillatory decay, or stable limit cycles. The range of behaviour the system can exhibit includes multi-year cycles of different periodicities, parameter ranges with coexisting multi-year cycles of the same or different period as well as quasi-periodicity and chaos. We show that the level of oscillation in the unforced system has a large effect on the range of behaviour when the system is seasonally forced. We discuss how the methods could be extended to understand the dynamics of a wide range of ecological and epidemiological systems that are subject to seasonal changes.

Modelling the temperature suitability for the risk of West Nile Virus establishment in European Culex pipiens populations.

Increases in temperature and extreme weather events due to global warming can create an environment that is beneficial to mosquito populations, changing and possibly increasing the suitable geographical range for many vector-borne diseases. West Nile Virus (WNV) is a flavivirus, maintained in a mosquito-avian host cycle that is usually asymptomatic but can cause primarily flu-like symptoms in human and equid accidental hosts. In rare circumstances, serious disease and death are possible outcomes for both humans and horses. The main European vector of WNV is the Culex pipiens mosquito. This study examines the effect of environmental temperature on WNV establishment in Europe via Culex pipiens populations through use of a basic reproduction number ( R 0 ${R_0}$ ) model. A metric of thermal suitability derived from R 0 ${R_0}$ was developed by collating thermal responses of different Culex pipiens traits and combining them through use of a next-generation matrix. WNV establishment was determined to be possible between 14°C and 34.3°C, with the optimal temperature at 23.7°C. The suitability measure was plotted against monthly average temperatures in 2020 and the number of months with high suitability mapped across Europe. The average number of suitable months for each year from 2013 to 2019 was also calculated and validated with reported equine West Nile fever cases from 2013 to 2019. The widespread thermal suitability for WNV establishment highlights the importance of European surveillance for this disease and the need for increased research into mosquito and bird distribution.

Interventions to prevent hypothermia in extremely preterm low-weight infants undergoing cardiac catheterisation.

BACKGROUND: In January 2019, a new device called the Amplatzer Piccolo Occluder was approved by the US Food and Drug Administration for percutaneous closure of patent ductus arteriosus in infants weighing more than 700 g and of postnatal age more than 3 days. Premature low-weight infants are predisposed to hypothermia when transported outside of the thermo-neutral environment. At our institution, 90% of extremely preterm low-weight infants developed transient moderate hypothermia in the cardiac catheterisation suite. METHODS: We conducted a study testing multiple hypotheses aimed at preventing hypothermia in the cardiac catheterisation suite. Interventions included increasing ambient room temperature, reducing exposure to cold environment and reducing overall time spent in the remote location. The primary outcome was the proportion of patients who developed transient hypothermia at the start of the procedure in the cardiac catheterisation suite. The secondary measures included mean core body temperature at four different instances, as well as anaesthesia time, procedure time and radiation exposure. RESULTS: During the study period, 10 patients were enrolled in each group. The postintervention group saw a reduction in transient hypothermia from 90% to 40% (absolute risk reduction 50%, p=0.02). Data analysis showed an improvement in mean core body temperature (35.4°C vs 36.4°C, p<0.01) as well as a smaller percentage drop in temperature (4% vs 1.3%, p<0.01) between the two groups, both of which were statistically significant. The anaesthesia time, procedure time and radiation exposure reduced between the two groups. CONCLUSION: The application of the interventions reduced hypothermia in this high-risk population. The implementation of a protocol with collaboration of a multidisciplinary team is indispensable in providing optimal care to extremely preterm infants.

Percutaneous Closure of Patent Ductus Arteriosus.

Percutaneous-based patent ductus arteriosus closure is technically feasible among infants less than 1.5 kg. However, marked heterogeneity in the type and nature of adverse events obscures current safety profile assessments. Although data on the risks of postdevice closure syndrome remain promising, a lack of comparative trials of surgical ductal ligation and inconsistent surveillance across published studies obscure confidence in present estimates of safety and efficacy. To minimize risk and yield the greatest benefits, clinical studies of patent ductus arteriosus treatment should consider incorporating more robust assessments to ensure that infants at greatest risk for adverse ductal consequences are included.

A user-friendly decision support tool to assist one-health risk assessors.

One-Health risk assessments are integral to developing efficient responses to disease threats, including global pandemics. However, short timeframes, inadequate disease-specific information and an insufficient skill-base make it hard for inexperienced assessors to distinguish between a large portfolio of approaches. The wrong choice can detract from the disease response. Here, we present an interactive decision support tool to help with this choice. A workshop with participants from diverse professional backgrounds provided six themes that should be considered when deciding on the best approach. Questions based on these themes were then developed to populate a decision tree which guides users to their most appropriate approach. One-Health risk assessment tools and literature were used as examples of the different approaches. The tool provides links to these examples and short descriptions of the approaches. Answers are easily changed, facilitating exploration though different approaches. The simple data structure of the tool means it is easy to update with more resources and approaches. It provides a valuable source of guidance and information for less experienced risk assessors.

Predicting spread and effective control measures for African swine fever-Should we blame the boars?

An ongoing, continually spreading, outbreak of African swine fever (ASF), following its identification in Georgia in 2007, has resulted in 17 European and 12 Asian countries reporting cases by April 2020, with cases occurring in both wild boar and domestic pigs. Curtailing further spread of ASF requires understanding of the transmission pathways of the disease. ASF is self-sustaining in the wild boar population, and they have been implicated as one of the main drivers of transmission within Europe. We developed a spatially explicit model to estimate the risk of infection with ASF in wild boar and pigs due to natural movement of wild boar that is applicable across the whole of Europe. We demonstrate the model by using it to predict the probability that early cases of ASF in Poland were caused by wild boar dispersion. The risk of infection in 2015 is computed due to wild boar cases in Poland in 2014, compared against reported cases in 2015, and then the procedure is repeated for 2015-2016. We find that long- and medium-distance spread of ASF (i.e. >30 km) is unlikely to have occurred due to wild boar dispersal, due in part to the generally short distances wild boar will travel (<20 km on average). We also predict the relative success of different control strategies in 2015, if they were implemented in 2014. Results suggest that hunting of wild boar reduces the number of new cases, but a larger region is at risk of ASF compared with no control measure. Alternatively, introducing wild boar-proof fencing reduces the size of the region at risk in 2015, but not the total number of cases. Overall, our model suggests wild boar movement is only responsible for local transmission of disease; thus, other pathways are more dominant in medium- and long-distance spread of the disease.

Livestock Health and Food Chain Risk Assessment.

The EUropean FOod Risk Assessment (EU-FORA) Fellowship work programme 'Livestock Health and Food Chain Risk Assessment', funded by EFSA was proposed by the Animal and Plant Health Agency (APHA), UK. A scientist with a PhD in Food Science was selected to work within the Biomathematics and Risk Research group, under the guidance of a senior risk assessor. The programme consisted of four different modules that covered a wide range of aspects related to risk assessment (RA). The aims, activities and conclusions obtained during the year are described in this article. The learning-by-doing approach in RA allowed the fellow to discover a broad pool of methodologies, tools and applications while developing his own knowledge in RA, as well as gaining scientific network for future collaborations in the field.

Cross-Validation of Generic Risk Assessment Tools for Animal Disease Incursion Based on a Case Study for African Swine Fever.

In recent years, several generic risk assessment (RA) tools have been developed that can be applied to assess the incursion risk of multiple infectious animal diseases allowing for a rapid response to a variety of newly emerging or re-emerging diseases. Although these tools were originally developed for different purposes, they can be used to answer similar or even identical risk questions. To explore the opportunities for cross-validation, seven generic RA tools were used to assess the incursion risk of African swine fever (ASF) to the Netherlands and Finland for the 2017 situation and for two hypothetical scenarios in which ASF cases were reported in wild boar and/or domestic pigs in Germany. The generic tools ranged from qualitative risk assessment tools to stochastic spatial risk models but were all parameterized using the same global databases for disease occurrence and trade in live animals and animal products. A comparison of absolute results was not possible, because output parameters represented different endpoints, varied from qualitative probability levels to quantitative numbers, and were expressed in different units. Therefore, relative risks across countries and scenarios were calculated for each tool, for the three pathways most in common (trade in live animals, trade in animal products, and wild boar movements) and compared. For the 2017 situation, all tools evaluated the risk to the Netherlands to be higher than Finland for the live animal trade pathway, the risk to Finland the same or higher as the Netherlands for the wild boar pathway, while the tools were inconclusive on the animal products pathway. All tools agreed that the hypothetical presence of ASF in Germany increased the risk to the Netherlands, but not to Finland. The ultimate aim of generic RA tools is to provide risk-based evidence to support risk managers in making informed decisions to mitigate the incursion risk of infectious animal diseases. The case study illustrated that conclusions on the ASF risk were similar across the generic RA tools, despite differences observed in calculated risks. Hence, it was concluded that the cross-validation contributed to the credibility of their results.

Livestock, food chain and public health risk assessment.

The EUropean FOod Risk Assessment (EU-FORA) Fellowship work programme 'Livestock, food chain and public health risk assessment', founded by EFSA was proposed by the Animal and Plant Health Agency (APHA), United Kingdom (UK). A scientist working in the field of food safety was selected to work within the Department of Epidemiological Sciences, under the guidance of an experienced risk assessor. The programme was structured in four different modules that covered a wide range of aspects related to risk assessment (RA). Taken together, all modules ensured a broad overview of the various methodologies, tools and applications of RA. Thus, the learning-by-doing working programme in RA allowed the fellow to develop her knowledge in RA, to diversify her competencies and to extend her scientific network for future collaborations in the field of RA.

The Risk of Infection by African Swine Fever Virus in European Swine Through Boar Movement and Legal Trade of Pigs and Pig Meat.

African swine fever (ASF) is currently spreading westwards throughout Europe and eastwards into China, with cases occurring in both wild boar and domestic pigs. A generic risk assessment framework is used to determine the probability of first infection with ASF virus (ASFV) at a fine spatial scale across European Union Member States. The framework aims to assist risk managers across Europe with their ASF surveillance and intervention activities. Performing the risk assessment at a fine spatial scale allows for hot-spot surveillance, which can aid risk managers by directing surveillance or intervention resources at those areas or pathways deemed most at risk, and hence enables prioritization of limited resources. We use 2018 cases of ASF to estimate prevalence of the disease in both wild boar and pig populations and compute the risk of initial infection for 2019 at a 100 km2 cell resolution via three potential pathways: legal trade in live pigs, natural movement of wild boar, and legal trade in pig meat products. We consider the number of pigs, boar and amount of pig meat entering our area of interest, the prevalence of the disease in the origin country, the probability of exposure of susceptible pigs or boar in the area of interest to introduced infected pigs, boar, or meat from an infected pig, and the probability of transmission to susceptible animals. We provide maps across Europe indicating regions at highest risk of initial infection. Results indicate that the risk of ASF in 2019 was predominantly focused on those regions which already had numerous cases in 2018 (Poland, Lithuania, Hungary, Romania, and Latvia). The riskiest pathway for ASFV transmission to pigs was the movement of wild boar for Eastern European countries and legal trade of pigs for Western European countries. New infections are more likely to occur in wild boar rather than pigs, for both the pig meat and wild boar movement pathways. Our results provide an opportunity to focus surveillance activities and thus increase our ability to detect ASF introductions earlier, a necessary requirement if we are to successfully control the spread of this devastating disease for the pig industry.

Plasmodium vivax readiness to transmit: implication for malaria eradication.

BACKGROUND: The lack of a continuous long-term in vitro culture system for Plasmodium vivax severely limits our knowledge of pathophysiology of the most widespread malaria parasite. To gain direct understanding of P. vivax human infections, we used Next Generation Sequencing data mining to unravel parasite in vivo expression profiles for P. vivax, and P. falciparum as comparison. RESULTS: We performed cloud and local computing to extract parasite transcriptomes from publicly available raw data of human blood samples. We developed a Poisson Modelling (PM) method to confidently identify parasite derived transcripts in mixed RNAseq signals of infected host tissues. We successfully retrieved and reconstructed parasite transcriptomes from infected patient blood as early as the first blood stage cycle; and the same methodology did not recover any significant signal from controls. Surprisingly, these first generation blood parasites already show strong signature of transmission, which indicates the commitment from asexual-to-sexual stages. Further, we place the results within the context of P. vivax's complex life cycle, by developing mathematical models for P. vivax and P. falciparum and using sensitivity analysis assess the relative epidemiological impact of possible early stage transmission. CONCLUSION: The study uncovers the earliest onset of P. vivax blood pathogenesis and highlights the challenges of P. vivax eradication programs.