Corrigendum: Control and Eradication Programs for Six Cattle Diseases in the Netherlands.

[This corrects the article DOI: 10.3389/fvets.2021.670419.].

Control and Eradication Programs for Six Cattle Diseases in the Netherlands.

Within the European Union, infectious cattle diseases are categorized in the Animal Health Law. No strict EU regulations exist for control, evidence of disease freedom, and surveillance of diseases listed other than categories A and B. Consequently, EU member states follow their own varying strategies for disease control. The aim of this study was to provide an overview of the control and eradication programs (CPs) for six cattle diseases in the Netherlands between 2009 and 2019 and to highlight characteristics specific to the Dutch situation. All of these diseases were listed as C,D or E in the New Animal Health Law. In the Netherlands, CPs are in place for six endemic cattle diseases: bovine viral diarrhea, infectious bovine rhinotracheitis, salmonellosis, paratuberculosis, leptospirosis, and neosporosis. These CPs have been tailored to the specific situation in the Netherlands: a country with a high cattle density, a high rate of animal movements, a strong dependence on export of dairy products, and a high-quality data-infrastructure. The latter specifically applies to the dairy sector, which is the leading cattle sector in the Netherlands. When a herd enters a CP, generally the within-herd prevalence of infection is estimated in an initial assessment. The outcome creates awareness of the infection status of a herd and also provides an indication of the costs and time to achieve the preferred herd status. Subsequently, the herd enrolls in the control phase of the CP to, if present, eliminate the infection from a herd and a surveillance phase to substantiate the free or low prevalence status over time. The high-quality data infrastructure that results in complete and centrally registered census data on cattle movements provides the opportunity to design CPs while minimizing administrative efforts for the farmer. In the CPs, mostly routinely collected samples are used for surveillance. Where possible, requests for proof of the herd status are sent automatically. Automated detection of risk factors for introduction of new animals originating from a herd without the preferred herd status i.e., free or unsuspected, is in place using centrally registered data. The presented overview may inspire countries that want to develop cost-effective CPs for endemic diseases that are not (yet) regulated at EU level.

A description and qualitative comparison of the elements of heterogeneous bovine viral diarrhea control programs that influence confidence of freedom.

For endemic infections in cattle that are not regulated at the European Union level, such as bovine viral diarrhea virus (BVDV), European Member States have implemented control or eradication programs (CEP) tailored to their specific situations. Different methods are used to assign infection-free status in CEP; therefore, the confidence of freedom associated with the "free" status generated by different CEP are difficult to compare, creating problems for the safe trade of cattle between territories. Safe trade would be facilitated with an output-based framework that enables a transparent and standardized comparison of confidence of freedom for CEP across herds, regions, or countries. The current paper represents the first step toward development of such a framework by seeking to describe and qualitatively compare elements of CEP that contribute to confidence of freedom. For this work, BVDV was used as a case study. We qualitatively compared heterogeneous BVDV CEP in 6 European countries: Germany, France, Ireland, the Netherlands, Sweden, and Scotland. Information about BVDV CEP that were in place in 2017 and factors influencing the risk of introduction and transmission of BVDV (the context) were collected using an existing tool, with modifications to collect information about aspects of control and context. For the 6 participating countries, we ranked all individual elements of the CEP and their contexts that could influence the probability that cattle from a herd categorized as BVDV-free are truly free from infection. Many differences in the context and design of BVDV CEP were found. As examples, CEP were either mandatory or voluntary, resulting in variation in risks from neighboring herds, and risk factors such as cattle density and the number of imported cattle varied greatly between territories. Differences were also found in both testing protocols and definitions of freedom from disease. The observed heterogeneity in both the context and CEP design will create difficulties when comparing different CEP in terms of confidence of freedom from infection. These results highlight the need for a standardized practical methodology to objectively and quantitatively determine confidence of freedom resulting from different CEP around the world.

Efficacy of a voluntary BVDV control programme: Experiences from the Netherlands.

The outcomes of a voluntary bovine viral diarrhoea virus (BVDV) control programme that has been in place in the Netherlands since 1997 were analysed. This 'BVDV-free' programme was studied in dairy herds in the period 1 August 2007 to 1 August 2013. The programme was based on a test and cull approach at the herd level, after which the BVDV status was monitored by testing young stock for antibodies against BVDV or by antigen testing of newborn calves. One of the challenges of the programme was that, without any legislation or subsidies, farmers had to be motivated to pay all costs involved, with eradication of BVDV from their farm as the only incentive. During the study period, the percentage of dairy farms with a 'BVDV-free' status in the Netherlands increased from 13% to 24%, while the prevalence of active BVDV infections in Dutch dairy herds decreased. This may be related to the increasing number of participants in the 'BVDV-free' programme.

A compromised maternal vitamin D status is associated with congenital heart defects in offspring.

BACKGROUND: Interactions between genetic and environmental factors, including modifiable maternal nutrition and lifestyle, play a significant role in the pathogenesis of most congenital heart defects (CHD). The aim of this study was to investigate associations between periconceptional maternal vitamin D status and the prevalence of CHD in offspring. METHODS: A case-control study was performed in 345 mothers of a child with CHD and 432 mothers of a child without CHD from four tertiary hospitals in the Netherlands between 2003 and 2005. Approximately 15months after pregnancy mothers filled out questionnaires regarding general characteristics and periconceptional lifestyle. Maternal blood was obtained to determine serum 25-hydroxyvitamin D and lipid concentrations. The 25-hydroxyvitamin D concentration was stratified into a deficient <50nmol/l, moderate 50-75nmol/l and adequate >75nmol/l status. Logistic regression was performed to study associations between vitamin D status and CHD risk, adjusted for maternal age, body mass index, ethnicity, smoking and total cholesterol concentration. RESULTS: Case mothers less often had an adequate vitamin D status compared with controls (27% vs. 38%; p=0.002). The use of multivitamin supplements, ethnicity, season and body mass index were associated with vitamin D concentrations. A moderate (odds ratio 1.58, [95%CI 1.08, 2.32]) and deficient (odds ratio 2.15, [95%CI 1.44-3.19]) vitamin D status were associated with CHD in offspring. CONCLUSION: A compromised maternal vitamin D status is associated with an approximately two-fold increased prevalence of CHD in offspring. Therefore, improvement of the periconceptional maternal vitamin D status is recommended.

Quantification of the probability of reintroduction of IBR in the Netherlands through cattle imports.

In the Netherlands, the feasibility of a national control program for infectious bovine rhinotracheitis (IBR) is discussed. The aim of this program would be to achieve freedom from BoHV1 circulation (the causal agent of IBR), in the Dutch cattle population. When IBR would be eradicated, maintaining the free status is essential and insight in the probability of introduction of IBR through cattle imports is crucial. Values for input parameters such as the number of imports per country of origin, herd level prevalence and probability that a random imported animal per age category was either acutely or latently infected with IBR were quantified. A stochastic simulation model was built to predict the basic risk and the efficacy of four risk mitigating scenarios were evaluated. These scenarios involved testing prior to import, import restrictions and vaccination. The model output predicted that IBR infected animals are imported regularly. In an IBR free situation, 571 (5th and 95th percentile: 431-781) cattle herds will be newly infected. Latent infections account for most newly infected herds (77%). When the virus in the imported latently infected animal does not reactivate, subsequent impact of such infections remains limited. The model predicted that most of the herds infected by introduction of acutely infected animals would be veal herds. The scenario in which imports were only allowed from status 9 or 10 countries combined with testing cattle that originated from status 9 countries was most effective in reduction of the import risk to 70 herds per year. The scenario in which vaccination of calves was combined with testing of older cattle was estimated to reduce the number of newly infected herds to 82 per year. The stakeholders classified the latter scenario as most realistic because this scenario was deemed both feasible and rather effective. This study did not evaluate the impact of introduction of IBR in the cattle population, which might differ depending on the type of infection (acute vs. latent) and the herd type in which the virus is introduced. Moreover, when making the final decision about the optimal intervention, the economic perspective should also be taken into account. This study predicted that introduction of IBR will remain a risk for the Dutch cattle population after virus circulation is eliminated from the Netherlands. The import risk is reduced most in scenarios in which testing and vaccination are combined.

A quantitative risk-analysis for introduction of Bovine Viral Diarrhoea Virus in the Netherlands through cattle imports.

Many countries have implemented control programmes aiming to eradicate Bovine Viral Diarrhoea Virus (BVDV). After obtaining the free status, a risk of re-introduction of the virus through import may remain. Therefore the risk of introduction of BVDV through cattle imports in the Netherlands was quantified and the effectiveness of subsequent intervention measures was assessed. Data, literature and expert opinion were used to estimate values for input parameters to feed a stochastic simulation model. The probability that BVDV was imported was differentiated into persistently infected (PI) cattle, trojan cows that transmitted the virus vertically resulting in a PI foetus (TR) and transient infected cattle (TI). The import risk was stratified to beef, dairy, small scale, suckler, trade, veal and young stock herds. The intervention scenarios that were evaluated consisted of virus testing, a combination of virus testing and antibody testing in pregnant cows, abolishment of imports from high risk countries (i.e. countries with a BVDV prevalence >15%) and a combination of import restrictions and testing prior to import. Each year, 334 (5th and 95th percentile: 65-902) Dutch cattle herds were estimated to be infected with BVDV through import. Veal herds account for most infections associated with import (87%), whereas in the other herd types, only 9 beef, 6 dairy, 2 small scale, 16 suckler, 10 trade and 2 young stock herds are infected through imports per year. Import of PI cattle is the most important risk for introduction in veal herds, while import of TR cows is the main source of BVDV introduction in dairy, small scale and suckler herds. With the intervention scenarios, the number of BVDV infected herds in the Netherlands could be reduced to 81 and 58 herds per year when respectively virus testing or a combination of virus and antibody testing was applied or to 108 herds when import from high risk countries was abolished. With the scenario in which both import from high risk countries was abolished combined with virus and antibody testing, the number of BVDV infected herds could be reduced to 17 herds per year. The risk assessment showed that BVDV is regularly imported in the Netherlands. The import risk can effectively be reduced by implementing diagnostic testing prior to import and only import cattle with a favourable result, eventually combined with certain trade restrictions.

Evaluation of the epidemiological and economic consequences of control scenarios for bovine viral diarrhea virus in dairy herds.

Bovine viral diarrhea virus (BVDV) is an important endemic infection. However, no information was available on whether it would be economically beneficial to implement a national control program in the Netherlands. Therefore, a stochastic simulation model was developed in which control scenarios were added to compare the epidemiological and economic consequences of BVDV control in Dutch dairy herds in the next 10 yr. In the epidemiological part of the model, herds could be classified as susceptible, infectious, recovered, or vaccinated. The outputs of the epidemiological module served as input for the economic module. Net costs that could be attributed to bovine viral diarrhea consisted of production losses, costs for testing, and culling persistently infected cattle in the present voluntary Dutch BVDV control program and costs for vaccination. Four different control scenarios were simulated, involving testing and culling of persistently infected (based on serum or ear-notch testing), and monitoring BVDV statuses and vaccination and were derived from BVDV control programs that are currently executed in Europe. The costs and benefits of BVDV control in the current situation and in each of the simulated control scenarios were evaluated assuming an annual discount rate of 2%. The model estimated a mean BVDV herd prevalence of 18.0% in 2014 and showed a slightly decreasing prevalence over time. The outputs seemed realistic for the present situation in the Netherlands when compared with actual survey data. The average annual net costs associated with bovine viral diarrhea were estimated at €27.8 million for the dairy industry. Two control scenarios were beneficial in controlling BVDV during the study period (between 2015 and 2025). In the scenario where tracing and removing of PI animals and monitoring of the subsequent status was obligatory, the benefit to cost (B/C) ratio was 1.5 (€1.5 benefit for each invested euro). In the scenario in which the BVDV status of all herds was determined, followed by voluntary measures before control measures became obligatory, the B/C ratio was 1.1. The B/C ratio of the scenarios included could be even higher when it was assumed that nondairy herds participated in the control program as well. The model provided the opportunity to compare the effect of voluntary and mandatory control scenarios on the BVDV prevalence and costs and benefits relative to the current situation in the Netherlands. The model was used to support policy makers in their decisions about a BVDV control program.

Secondary structure and expression in vivo and in vitro of messenger RNAs into which upstream AUG codons have been inserted.

We wanted to discover whether the conformation of the mRNA leader sequence is involved in translational fidelity. For this purpose we constructed several mutants of Semliki Forest virus 26S mRNA and inserted AUG codons into the leader sequence. We then analyzed the results of in vitro and in vivo translation of these mRNAs, probed enzymatically the secondary structure and performed minimal energy folding of the transcripts. Our results indicate that the position of a hairpin in the leader sequence determines at which AUG codon downstream from that hairpin translation is initiated.

Minimal energy foldings of eukaryotic mRNAs form a separate leader domain.

We have investigated the minimal energy foldings of 38 mature mRNAs, including the globin family, the insulins, the growth hormones and interleukin-2, and have compared these foldings with those of fully and partly randomised sequences. The mRNAs differ from the random sequences in that they form a separate leader hairpin of 40-60 nucleotides, with the initiation codon typically located downstream of this hairpin, followed by a main fold in which a region flanking the initiation codon is basepaired with the trailer: resulting in a close proximity of the 5' and 3' end of the mRNA. The formation of this conformation depends not only--or primarily--on the structure of the leader, but on both the leader and trailer sequence and their interaction with the coding sequence. Thus if, as the frequent occurrence of this pattern suggests, the secondary structure of the leader regions plays a role in the initiation of translation, possibly accounting for the specificity of initiation and the different translational efficiencies of various mRNAs, we expect that these features may be influenced both by leader and trailer mutants.

Additional methylation at the N(2)-position of the cap of 26S Semliki Forest virus late mRNA and initiation of translation.

Cap analysis of the late 26S Semliki Forest viral mRNA reveals that almost 30% of the caps possess both a methyl group at the N(7)-position and one at the N(2)-position. We have compared the degree of methylation of the caps of polysomal and non-polysomal 26S mRNA in order to check whether this feature is responsible for its translation late in infection. It was found that extra methyl groups on the caps cause a lower rate of initiation. Polysomal 26S mRNA contained less m2,7G- and m2,2,7G-caps than free 26S. The cap analog m2,2,7Gp was slightly less inhibitory than m7Gp in an in vitro translation system.

Impaired maturation of mouse mammary tumor virus precursor polypeptides in lymphoid leukemia cells, producing intracytoplasmic A particles and no extracellular B-type virions.

Processing of polypeptides of the mouse mammary tumor virus, a type B retrovirus, was investigated in a transplanted thymic lymphoma cell line of the GR strain (GRSL). This cell line was maintained in vivo in ascites form and in vitro as a suspension culture. GRSL cells produce clusters of intracytoplasmic A particles and are virtually deficient in the production of mature extracellular B-type particles. As control, a mammary tumor cell line of the same mouse strain capable of complete virion synthesis was used. The kinetics of viral polypeptide synthesis were studied by pulse labeling with various isotopes (including (35)S and (32)P), followed by immunoprecipitation of cell lysates with monospecific antisera to the major mouse mammary tumor virus gag and env proteins, p27 and gp52, respectively. Both the primary gag and env precursor polypeptides were synthesized in the GRSL cells, but their conversion into viral proteins was impaired. The major gag precursor, Pr73(gag), was stable over a period of 8 h, and mature viral core polypeptides could not be detected. Also, the highly phosphorylated intermediates in the proteolytic processing of Pr73(gag) in virus-producing cells were absent in GRSL cells. By immunoprecipitation, Pr73(gag) was detected in a GRSL particle fraction with the density of intracytoplasmic A particles. The precursor for envelope proteins, Pr73(env), was turned over without the generation of mature viral envelope components gp52 and gp36. The in vivo-transplanted ascites GRSL cells, however, were shown to express gp52 on the cell surface together with a 73,000-dalton polypeptide, as indicated by cell surface iodination and immunoprecipitation.