Expert opinion on the identification, risk assessment, and mitigation of microorganisms and parasites relevant to xenotransplantation products from pigs.

Xenotransplantation has the potential to address shortages of organs available for clinical transplantation, but concerns exist regarding potential risks posed by porcine microorganisms and parasites (MP) to the health of human recipients. In this study, a risk-based framework was developed, and expert opinion was elicited to evaluate porcine MP based on swine exposure and risk to human health. Experts identified 255 MP to include in the risk assessment. These were rated by experts for five criteria regarding potential swine exposure in the USA and human health risks. MP were subsequently categorized into three risk mitigation groups according to pre-defined rules: disqualifying porcine MP (due to their pathogenic potential, n = 130); non-disqualifying porcine MP (still relevant to consider for biosecurity or monitoring efforts, n = 40); and alert/watch list (not reported in the USA or MP not in swine, n = 85). Most disqualifying (n = 126) and non-disqualifying (n = 36) porcine MP can effectively be eliminated with high biosecurity programs. This approach supports surveillance and risk mitigation strategies for porcine MP in swine produced for xenotransplantation, such as documentation of freedom from porcine MP, or use of porcine MP screening, monitoring, or elimination options. To the authors' knowledge, this is the first effort to comprehensively identify all relevant porcine MP systematically and transparently evaluate the risk of infection of both donor animals and immunosuppressed human recipients, and the potential health impacts for immunosuppressed human recipients from infected xenotransplantation products from pigs.

Sleeping with the enemy: Maintaining ASF-free farms in affected areas.

African Swine Fever (ASF) continues to spread worldwide, with very limited eradication success in countries where the disease affects domestic pig populations. Various biosecurity tools exist to reduce the on-farm risk incursion of ASF and other diseases. However, their focus on overall biosecurity scores and benchmarking results in recommendations that are not always cost-effective. We propose to apply a risk analysis approach that actively involves farmers and farmworkers in identifying their weakest links in biosecurity and corresponding mitigation efforts. Furthermore, the approach's focus on describing and understanding pathways of introduction and/or spread specific to individual farms creates buy-in from producers for investing in biosecurity measures and improving compliance.

Partitioning, a Novel Approach to Mitigate the Risk and Impact of African Swine Fever in Affected Areas.

As African swine fever (ASF) continues to expand geographically, supplementary control strategies are needed to reduce disease risk and impact in affected areas. Full depopulation is central to current ASF control efforts, and its efficacy depends on surveillance and timely disease reporting, while resulting in large losses regardless of the producers' efforts to promptly detect, report, and contain the disease. This disconnect between prompt detection and reporting, and subsequent farm losses, can deter producers to invest in ASF detection and control. Alternative approaches are needed to incentivize individual producers to invest in early detection and reporting. We postulate that commercial swine farms may be effectively partitioned in separate units, or subpopulations, to which biosecurity, surveillance and control can be applied. The suggested Partitioning framework relies on three main components: 1. external and internal biosecurity to reduce the risk of ASF introduction and maintain separate subpopulations; 2. cost-effective on-farm ASF surveillance to enhance early detection; 3. response plans at the unit level, including culling of affected subpopulations, and demonstration of freedom from disease on the remaining ones. With such Partitioning approach, individual producers may reduce ASF risk on a farm and in the region, while also reducing ASF outbreak losses via targeted depopulation of affected units. It requires relevant legislation to incorporate the notion of within-farm subpopulations and provide a regulatory framework for targeted depopulation and substantiation of disease freedom. Its design should be tailored to fit individual farms. Partitioning can be an effective public-private partnership approach for ASF risk reduction. It should be driven by industry, as its benefits are accrued mainly by individual producers, but regulatory oversight is key to ensure proper implementation and avoid further disease spread. Partitioning's value is greatest for producers in ASF-affected regions, but ASF-free areas could also benefit from it for preparedness and early detection. It could also be adapted to other transboundary animal diseases and can be implemented as a stand-alone program or in conjunction with other efforts such as zoning and compartmentalization. Partitioning would contribute to the improved resilience and sustainability of the global pork industry and will benefit consumers and society through improved food security and animal welfare.

Outbreak-Related Disease Burden Associated with Consumption of Unpasteurized Cow's Milk and Cheese, United States, 2009-2014.

The growing popularity of unpasteurized milk in the United States raises public health concerns. We estimated outbreak-related illnesses and hospitalizations caused by the consumption of cow's milk and cheese contaminated with Shiga toxin-producing Escherichia coli, Salmonella spp., Listeria monocytogenes, and Campylobacter spp. using a model relying on publicly available outbreak data. In the United States, outbreaks associated with dairy consumption cause, on average, 760 illnesses/year and 22 hospitalizations/year, mostly from Salmonella spp. and Campylobacter spp. Unpasteurized milk, consumed by only 3.2% of the population, and cheese, consumed by only 1.6% of the population, caused 96% of illnesses caused by contaminated dairy products. Unpasteurized dairy products thus cause 840 (95% CrI 611-1,158) times more illnesses and 45 (95% CrI 34-59) times more hospitalizations than pasteurized products. As consumption of unpasteurized dairy products grows, illnesses will increase steadily; a doubling in the consumption of unpasteurized milk or cheese could increase outbreak-related illnesses by 96%.

Cost-benefit analysis of vaccination against Mycobacterium avium ssp. paratuberculosis in dairy cattle, given its cross-reactivity with tuberculosis tests.

Johne's disease (JD), or paratuberculosis, is a chronic enteric disease of ruminants, caused by infection with Mycobacterium avium ssp. paratuberculosis (MAP). Johne's disease causes considerable economic losses to the US dairy industry, estimated to be over $200 million annually. Available control strategies include management measures to improve calf hygiene, test-and-cull strategies, and vaccination. Although the first 2 strategies have shown to reduce the prevalence of MAP, they require dedicated and long-term efforts from dairy producers, with often relatively slow progress. As a result, uptake of both strategies has not been as wide as expected given the economic benefits especially of improved hygiene. Vaccination has also been found to reduce the prevalence and economic losses of JD, but most economic estimates have been based on simulation of hypothetical vaccines. In addition, if an animal is vaccinated, cross-reactivity between MAP antibodies and bovine tuberculosis (BTB) antigens may occur, decreasing the specificity of BTB tests. Therefore, MAP vaccination would cause additional indirect costs to the BTB surveillance and control program. The objective of the present study was to use data from a MAP vaccine trial together with an epidemiologic and economic model to estimate the direct on-farm benefits of MAP vaccination and to estimate the indirect costs of MAP vaccination due to the cross-reactivity with BTB tests. Direct economic benefits of MAP vaccination were estimated at $8.03 (90% predictive interval: -$25.97 to $41.36) per adult animal per year, all accruing to the dairy producers. This estimate is likely an underestimation of the true direct benefits of MAP vaccination. In addition, indirect economic costs due to cross-reactivity were $2.14 per adult animal per year, making MAP vaccination economically attractive. Only in regions or states with a high frequency of BTB testing (because of, for example, Mycobacterium bovis outbreaks in a wild deer population) and areas where typically small groups of animals are BTB tested would MAP vaccination not be economically attractive.

Treatment of advanced Parkinson's disease in the United States: a cost-utility model.

BACKGROUND: As Parkinson's disease (PD) progresses, patients and their families experience substantial health and economic burdens. Because motor fluctuations (also called 'off-time') are linked to poor quality of life and higher healthcare costs, minimizing off-time is an effective strategy for reducing costs associated with PD. OBJECTIVE: To assess the cost utility of rasagiline or entacapone as adjunctive therapies to levodopa versus levodopa/carbidopa/entacapone (LCE) versus standard levodopa monotherapy in patients with advanced PD and motor fluctuations in the US. METHODS: A 2-year stochastic Markov model was utilized to examine the cost effectiveness of treatments of advanced PD. The model assumed that patients transition health status every 4 months. Transition probabilities, including uncertainties, were estimated from clinical trial data. Medical costs, daily drug costs and utility weights were obtained from published literature. RESULTS: Over 2 years, all therapy options showed greater effectiveness than levodopa alone. Rasagiline+levodopa and LCE were cost saving from a payor perspective, while entacapone+levodopa was cost saving from a societal perspective. Mean benefits over 2 years were 0.12 (90% credibility interval [CI] 0.07, 0.18) additional quality-adjusted life-years (QALYs) for rasagiline+levodopa, entacapone+levodopa and LCE, 5.08 (90% CI 3.87, 6.28) additional months with

Farm-level economic analysis of the US National Johne's Disease Demonstration Herd Project.

OBJECTIVE: To evaluate farm-level economic costs and benefits related to control of paratuberculosis (Johne's disease) in dairy herds in the National Johne's Disease Demonstration Herd Project (NJDDHP). DESIGN: Economic analysis. SAMPLE POPULATION: 40 dairy herds enrolled in the NJDDHP. PROCEDURES: A farm-level economic analysis of the US NJDDHP was performed. Costs and benefits of management-related practices to control Johne's disease were estimated on the basis of results for 40 dairy operations enrolled in the project. From these costs and benefits, the net present value (NPV) for control of Johne's disease was estimated. Results-Analysis revealed a mean NPV of $34/animal (equivalent to approx $3/animal/y) when there were no testing costs for producers and a mean NPV of -$14/animal when testing costs were borne by the producers. CONCLUSIONS AND CLINICAL RELEVANCE: Management-related practices to control Johne's disease were typically found to be of marginal economic benefit when the costs of testing were not borne by producers. The continuation of the NJDDHP for another 2 to 4 years would allow more precise estimation of the economic benefits of a control program for Johne's disease.

Simulation of alternatives for the Dutch Johne's disease certification-and-monitoring program.

To identify optimal method(s) for certification and subsequent monitoring of Mycobacterium avium subsp. paratuberculosis (Map)-unsuspected herds, certification-and-monitoring schemes were studied using a stochastic simulation model ("JohneSSim"). JohneSSim simulated the within-herd transmission and economic aspects of Map in closed Dutch dairy herds. The model was validated with field observations on Map-unsuspected herds. The current Dutch certification-and-monitoring schemes were compared with 11 alternative schemes in which individual and pooled fecal culture, ELISA, Johnin-intradermal test and gamma-IFN ELISA were used, varying the test frequency, tested age group and number of tested animals. On reaching the 'Map-free' status with the standard certification scheme, 11% of the simulated herds were not truly Map-free. Therefore, the designation 'Map-free' should be changed into, for instance, 'low-risk Map'. In the most-attractive alternative certification scheme, the 'Map-free' status was reached after four herd examinations (at 2-year intervals) consisting of serial testing of all cattle > or = 2 years of age with a pooled fecal culture and individual fecal culture of positive pools. This scheme resulted in lower total and annual discounted costs and a lower animal-level prevalence at reaching the 'Map-free' status compared to the standard scheme, assuming that there was no new introduction of the infection. Schemes to monitor the 'Map-free' status were compared, assuming that this status was reached with the standard certification scheme. In comparison to the standard monitoring scheme, none of the alternative monitoring schemes resulted in both a lower animal-level prevalence of undetected pre-existing Map infections in closed herds, and lower median annual discounted costs. Results of the model were very sensitive to the assumed sensitivity of the fecal culture test and to management measures that prevent within-herd transmission of Map. If these preventive measures were taken, the probability of undetected Map infections in closed 'Map-free' herds was decreased substantially.

Economic consequences of control programs for paratuberculosis in midsize dairy farms in the United States.

OBJECTIVE: To evaluate the epidemiologic efficacy and economic efficiency of current and potential future control programs for paratuberculosis (Johne's disease) on midsize dairy herds in the United States. DESIGN: Stochastic dynamic computer simulation model. SAMPLE POPULATION: Data on prices and other input variables collected from various sources were used to represent a population of midsize US dairy herds infected with paratuberculosis. PROCEDURE: The simulation model was modified to reflect management and production characteristics of midsize dairy herds in the United States. The model was validated by use of field data and expert opinion. Various control strategies then were simulated and compared on an epidemiologic basis and on the basis of economic efficiency. RESULTS: Test-and-cull strategies and vaccination against paratuberculosis were not able to decrease the mean prevalence of disease in the United States. Typically, only vaccination was economically attractive. Improved management strategies decreased the prevalence of paratuberculosis considerably and had high economic benefits. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of results of this study suggests that test-and-cull strategies alone do not reduce the prevalence of paratuberculosis in cattle and are costly for producers to pursue. Vaccination did not reduce the prevalence but was economically attractive. Finally, improved calf-hygiene strategies were found to be critically important in every paratuberculosis control program and most were economically attractive programs for midsize US dairy farms with the disease.

Development of the Dutch Johne's disease control program supported by a simulation model.

The development of a simulation model, "JohneSSim", was part of a research program aimed at designing a national Johne's disease control program for The Netherlands. Initially, the focus was mainly directed towards different compulsory "test-and-cull" strategies. However, the results from the JohneSSim model showed that eradication of Johne's disease based on such strategies would not be possible within 20 years and that it was also economically unattractive. However, improved calf management seemed to be more effective in reducing the prevalence within the same time period. Simulation of a strategy using an "ideal test" (80% sensitivity in all infected animals) showed a considerably faster decrease in prevalence. However, this strategy proved to be economically unattractive because of the high culling rate of (young) test-positive animals. The simulation model was also adapted to study beef cow herds. However, the results indicated that none of the strategies were able to reduce the mean true prevalence to almost zero for such herds. Only strategies based on "separation of calves and adult animals" proved to significantly reduce the prevalence but such a strategy is unpractical and uneconomic for Dutch beef cow herds. Due to this finding and the relative low number of Dutch beef cow farms, first priority has been given to the development of a Johne's disease control program for dairy farms. Based on the results of the "JohneSSim" model, the new national voluntary Johne's disease control program for dairy, Paratuberculosis Program Netherlands (PPN), started in September 2000. The PPN is based on a stepwise improvement of calf hygiene, with little dependency on "test and culling". The model results indicated that, if dairy farmers consistently carried out the necessary management adaptations, PPN considerably decreased prevalence and that it was economically more attractive than any previous plans.

A simulation of Johne's disease control.

A dynamic and stochastic simulation model (the "JohneSSim model") was developed to evaluate the economic and epidemiological effects of different strategies for control of paratuberculosis in dairy herds. Animals occupy one of the six defined infection states; the spread of Johne's disease is modeled with five infection routes. Many different dairy farm situations can be simulated. Control strategies that can be simulated are: (1) test-and-cull; (2) calf hygiene management; (3) vaccination and (4) grouping of animals. Losses are caused by: (1) reduced milk production; (2) diagnosis and treatment costs; (3) lower slaughter value of cows and (4) sub-optimal culling. The benefits were calculated as reduction in the losses caused by Johne's disease; the costs of each strategy were calculated on the basis of actual costs of each item; and net present value (NPV) was calculated as benefits minus costs. Herd and prevalence data from The Netherlands and Pennsylvania, USA were used. In both situations, a low true mean prevalence within 20 years could be reached only when all calf management tools were applied. The Dutch control program (PPN) was on average economically attractive (with or without labor costs, the average NPV was Euro 1183 and 12,397, respectively). In Pennsylvania, contract heifer rearing and improved calf hygiene reduced the prevalence effectively and had large economic benefits (US$ 43,917 for 20-year period) if the calves were sent to the heifer facility while very young. Validation with data from 21 infected Dutch dairy farms (as well as face-validation: comparison of the results of the JohneSSim model with experiences of Johne's experts) supported the basic assumptions in the model.