Development and application of an interactive generic physiologically based pharmacokinetic (igPBPK) model for adult beef cattle and lactating dairy cows to estimate tissue distribution and edible tissue and milk withdrawal intervals for per- and polyfluoroalkyl substances (PFAS).

Humans can be exposed to per- and polyfluoroalkyl substances (PFAS) through dietary intake from milk and edible tissues from food animals. This study developed a physiologically based pharmacokinetic (PBPK) model to predict tissue and milk residues and estimate withdrawal intervals (WDIs) for multiple PFAS including PFOA, PFOS and PFHxS in beef cattle and lactating dairy cows. Results showed that model predictions were mostly within a two-fold factor of experimental data for plasma, tissues, and milk with an estimated coefficient of determination (R2) of >0.95. The predicted muscle WDIs for beef cattle were <1 day for PFOA, 449 days for PFOS, and 69 days for PFHxS, while the predicted milk WDIs in dairy cows were <1 day for PFOA, 1345 days for PFOS, and zero day for PFHxS following a high environmental exposure scenario (e.g., 49.3, 193, and 161 ng/kg/day for PFOA, PFOS, and PFHxS, respectively, for beef cattle for 2 years). The model was converted to a web-based interactive generic PBPK (igPBPK) platform to provide a user-friendly dashboard for predictions of tissue and milk WDIs for PFAS in cattle. This model serves as a foundation for extrapolation to other PFAS compounds to improve safety assessment of cattle-derived food products.

Development of machine learning algorithms to estimate maximum residue limits for veterinary medicines.

Establishing maximum-residue limits (MRLs) for veterinary medicine helps to protect the human food supply. Guidelines for establishing MRLs are outlined by regulatory authorities that drug sponsors follow in each country. During the drug approval process, residue limits are targeted for specific animal species and matrices. Therefore, MRLs are commonly not established for other species. This study demonstrates unestablished MRLs can be reliably predicted for under-represented food commodity groups using machine learning (ML). Classification methods with imbalanced data were used to analyze MRL data from multiple countries by implementing resampling techniques in different ML classifiers. Afterward, we developed and evaluated a data-mining method for predicting unestablished MRLs. Seven different ML classifiers such as support vector classifier, multi-layer perceptron (MLP), random forest, decision tree, k-neighbors, Gaussian NB, and AdaBoost have been selected in this baseline study. Among these, the neural network MLP classifier reliably scored the highest average-weighted F1 score (accuracy >99% with markers and ≈88% without markets) in predicting unestablished MRLs. This provides the first study to apply ML algorithms in regulatory food animal medicine. By predicting and estimating MRLs, we can potentially decrease the use and cost of live animals and the overall research burden of determining new MRLs.

A systematic review of economic assessments for brucellosis control interventions in livestock populations.

Brucellosis in livestock is a disease of paramount importance to animal and human health authorities due to its socio-economic and public health consequences. Benefit cost analyses can help policymakers decide whether allocation of resources is economically beneficial to cover the costs of brucellosis control interventions in populations. One broad question of interest is: what are the consequences of acting, or failing to act, on policy options of selected intervention scenarios (e.g., vaccination, test-and-slaughter, vaccination combined with test-and-slaughter, versus a status-quo scenario). The objective of the systematic review reported here was to conduct a critical appraisal of published research reports of economic assessments of brucellosis control interventions in livestock populations. The systematic review followed standard guidelines using a Population, Intervention, Comparison, Outcome, and Context framework and Preferred Reporting Items for Systematic Review and Meta-Analysis. The review targeted research reports focused on brucellosis control interventions in livestock populations at the national or regional level. Economic outcomes of interest were benefit-cost ratio (BCR), net present value, internal rate of return, or payback period. Eleven studies conducted in Brazil, China, India, Iraq, Mexico, Mongolia, Spain, Turkey, or the USA met the inclusion criteria and were included. The baseline prevalence of brucellosis in selected study populations ranged from 1.4% in cattle in Turkey to 20% in goats in Mexico. In six studies, selected intervention scenarios of vaccination alone produced BCRs that ranged from 3.2 in yaks in China or in cattle, sheep and goats in Mongolia, to 21.3 in cattle and/or buffalo in India. In three studies, interventions of test-and-slaughter produced BCRs that ranged from - 1.2 in goats in Mexico to 0.6 in cattle in Spain. In four studies, vaccination in combination with test-and-slaughter produced BCRs that ranged from 0.2 in yaks in China to 3.7 in cattle and buffalo in India. In seven studies, using sensitivity analysis, different input parameters (prevalence of brucellosis, meat price, cashmere price, vaccination coverage, test-and-slaughter coverage, milk price, vaccination protection, abortion cost, abortion rate, or price of lamb) had an impact on economic outcomes. Vaccination alone was cost-effective, but test-and-slaughter was not, for brucellosis control in selected livestock populations in focus countries. Vaccination in combination with test-and-slaughter produced profitable or nonprofitable economic outcomes. While most studies reported the cost and benefits of implementing brucellosis control interventions, only one study explained socio-economic consequences of economic outcomes, when acting, or failing to act, on selected interventions in livestock populations.

Early-life heat stress exposure impacts dairy calf feeding and thermoregulatory behavior.

Heat stress has well-known influences on dairy calf physiology, but less is understood about calf behavioral responses to heat stress. Herein, we evaluated milk replacer intake, standing activity, and lying behaviors of calves exposed to prenatal or postnatal heat stress or both. Holstein calves were born to dams experiencing heat stress (HT; shade of a freestall barn) or cooling (CL; shade, fans, and soakers) during late gestation [~44 d before calving, prenatal; mean daily temperature-humidity index (THI) = 78]. They were then subsequently exposed to postnatal heat stress (shade and natural ventilation of an open-sided barn) or cooling (shade of the barn and forced ventilation by fans) from birth to weaning (56 d; mean daily THI = 77; n = 12 per prenatal × postnatal treatment). Heat stress was confirmed by elevated respiration rate and rectal temperature of the prenatal dam and the postnatal calf. Calves were group-housed with automatic milk feeders, from which milk replacer (MR) intake was assessed. Calf behavior was monitored using loggers and video. Postnatal-HT calves tended to consume less MR per hour in the late morning and drank less MR per visit relative to postnatal-CL calves. Postnatal-HT calves spent more time lying laterally and less time lying sternally in a tucked position during overnight hours. Prenatal-HT calves stood longer across the day, particularly overnight, compared with prenatal-CL calves. This study characterized behavioral responses of preweaning dairy calves exposed to chronic heat stress or active cooling during early-life developmental windows.

Burden of anemia and intestinal parasites in farmers and family members and owned livestock in two geographic locations in Senegal before and during the rainy seasons.

Different environmental conditions can impact the burden of anemia and intestinal parasite infections in human and livestock populations. The objective of this study was to compare the prevalence of anemia and intestinal parasite infections in farmers, family members, and owned sheep in two geographic locations along the Senegal River in June (end of the dry season) and September (rainy season). In Diawara, the prevalence of anemia in humans was high in June (74%) and remained high in September (75%) (p = 0.91). The prevalence of intestinal parasite infections increased from 7% in June to 54% in September (p < 0.05). Anemia was associated with age (children) and sex (women) (p < 0.05); but not with a positive diagnosis of intestinal parasite infection (p = 0.73). In sheep, the prevalence of anemia increased from 43% in June to 73% in September (p < 0.05), and the prevalence of intestinal parasite infections increased from 75% in June to 100% in September (p < 0.05). A positive diagnosis of Haemonchus contortus was associated with anemia (p = 0.05) and loss of body weight (2.4 kg) (p = 0.08). In Mpal, similar anemia and parasite infection trends were observed in children and sheep. The persistent high prevalence of anemia, and the impact of the rainy season on the burden of intestinal parasite infections in farmers, family members, and owned sheep can justify a One Health approach, where Senegal's ministries of health and of agriculture share resources for implementation and evaluation of government program efforts to reduce anemia in children and women, as well as morbidity and mortality in owned livestock; particularly in remote areas where public health services and veterinary services are very limited.

An Interactive Generic Physiologically Based Pharmacokinetic (igPBPK) Modeling Platform to Predict Drug Withdrawal Intervals in Cattle and Swine: A Case Study on Flunixin, Florfenicol, and Penicillin G.

Violative chemical residues in edible tissues from food-producing animals are of global public health concern. Great efforts have been made to develop physiologically based pharmacokinetic (PBPK) models for estimating withdrawal intervals (WDIs) for extralabel prescribed drugs in food animals. Existing models are insufficient to address the food safety concern as these models are either limited to 1 specific drug or difficult to be used by non-modelers. This study aimed to develop a user-friendly generic PBPK platform that can predict tissue residues and estimate WDIs for multiple drugs including flunixin, florfenicol, and penicillin G in cattle and swine. Mechanism-based in silico methods were used to predict tissue/plasma partition coefficients and the models were calibrated and evaluated with pharmacokinetic data from Food Animal Residue Avoidance Databank (FARAD). Results showed that model predictions were, in general, within a 2-fold factor of experimental data for all 3 drugs in both species. Following extralabel administration and respective U.S. FDA-approved tolerances, predicted WDIs for both cattle and swine were close to or slightly longer than FDA-approved label withdrawal times (eg, predicted 8, 28, and 7 days vs labeled 4, 28, and 4 days for flunixin, florfenicol, and penicillin G in cattle, respectively). The final model was converted to a web-based interactive generic PBPK platform. This PBPK platform serves as a user-friendly quantitative tool for real-time predictions of WDIs for flunixin, florfenicol, and penicillin G following FDA-approved label or extralabel use in both cattle and swine, and provides a basis for extrapolating to other drugs and species.

Large-Scale Data Mining of Rapid Residue Detection Assay Data From HTML and PDF Documents: Improving Data Access and Visualization for Veterinarians.

Extra-label drug use in food animal medicine is authorized by the US Animal Medicinal Drug Use Clarification Act (AMDUCA), and estimated withdrawal intervals are based on published scientific pharmacokinetic data. Occasionally there is a paucity of scientific data on which to base a withdrawal interval or a large number of animals being treated, driving the need to test for drug residues. Rapid assay commercial farm-side tests are essential for monitoring drug residues in animal products to protect human health. Active ingredients, sensitivity, matrices, and species that have been evaluated for commercial rapid assay tests are typically reported on manufacturers' websites or in PDF documents that are available to consumers but may require a special access request. Additionally, this information is not always correlated with FDA-approved tolerances. Furthermore, parameter changes for these tests can be very challenging to regularly identify, especially those listed on websites or in documents that are not publicly available. Therefore, artificial intelligence plays a critical role in efficiently extracting the data and ensure current information. Extracting tables from PDF and HTML documents has been investigated both by academia and commercial tool builders. Research in text mining of such documents has become a widespread yet challenging arena in implementing natural language programming. However, techniques of extracting tables are still in their infancy and being investigated and improved by researchers. In this study, we developed and evaluated a data-mining method for automatically extracting rapid assay data from electronic documents. Our automatic electronic data extraction method includes a software package module, a developed pattern recognition tool, and a data mining engine. Assay details were provided by several commercial entities that produce these rapid drug residue assay tests. During this study, we developed a real-time conversion system and method for reflowing contents in these files for accessibility practice and research data mining. Embedded information was extracted using an AI technology for text extraction and text mining to convert to structured formats. These data were then made available to veterinarians and producers via an online interface, allowing interactive searching and also presenting the commercial test assay parameters in reference to FDA-approved tolerances.

Anemia and intestinal parasites in farmers and family members and sheep in two agro-ecological zones in Senegal.

The burden of anemia in Senegal is high, particularly in children and women in rural households. The main objectives of the study reported here were (i) to measure and compare the prevalence of anemia and intestinal parasitic infections in farmers and family members and sheep in two agro-ecological zones in Senegal and (ii) to examine the association between anemia and age or sex in farmers and family members. The study was conducted in Mpal (250 km from Dakar, the capital city) and Diawara (700 km from Dakar, a remote location near the Malian border). In humans, the prevalence of anemia was higher in Diawara (64/86 = 74%), compared to Mpal (13/29 = 45%) (p < 0.01). Using logistic regression, the odds of anemia were 20.3, 5.7, and 3.2 times higher in children 1-4 years old, children 5-12 years-old, and teenagers 13-19 years old, respectively, compared to adults 20-60 years old, after controlling for study site and sex (p < 0.05). In Diawara, the odds of anemia were 2.9 times higher in women, compared to men, after controlling for age (p = 0.06). The prevalence of intestinal parasites (Giardia sp.) was the same (7%) at both locations. In sheep, the prevalence of low packed cell volume (PCV) and low body condition was higher in Diawara (48/60 = 60% and 11/60 = 18%, respectively), compared to Mpal (23/46 = 50% and 0/46 = 0%, respectively) (p < 0.05). Clinical anemia was associated (p < 0.01) with low PCV and a positive diagnosis of H. contortus. Overall, the prevalence of anemia was higher in farmers and family members and owned sheep in Diawara. In addition, anemia was more common in children and women, an indication that intra-household food allocation may be regulated in favor of men and older age groups. The consequences of livestock affected with anemia and undernutrition can be significant. High morbidity and mortality in livestock can lead to low household income, inadequate household access to and individual consumption of animal source foods, and subsequent risk of anemia in children and women in rural households in Senegal.

Development and Application of an Interactive Physiologically Based Pharmacokinetic (iPBPK) Model to Predict Oxytetracycline Tissue Distribution and Withdrawal Intervals in Market-Age Sheep and Goats.

Oxytetracycline (OTC) is a widely used antibiotic in food-producing animals. Extralabel use of OTC is common and may lead to violative residues in edible tissues. It is important to have a quantitative tool to predict scientifically based withdrawal intervals (WDIs) after extralabel use in food animals to ensure human food safety. This study focuses on developing a physiologically based pharmacokinetic (PBPK) model for OTC in sheep and goats. The model included 7 compartments: plasma, lung, liver, kidneys, muscle, fat, and rest of the body. The model was calibrated with serum and tissue (liver, muscle, kidney, and fat) concentration data following a single intramuscular (IM, 20 mg/kg) and/or intravenous (IV, 10 mg/kg) administration of a long-acting formulation in sheep and goats. The model was evaluated with independent datasets from Food Animal Residue Avoidance Databank (FARAD). Results showed that the model adequately simulated the calibration datasets with an overall estimated coefficient of determination (R2) of 0.95 and 0.92, respectively, for sheep and goat models and had acceptable accuracy for the evaluation datasets. Monte Carlo sampling technique was applied to predict the time needed for drug concentrations in edible tissues to fall below tolerances for the 99th percentiles of the population. The model was converted to a web-based interactive PBPK (iPBPK) interface to facilitate model applications. This iPBPK model provides a useful tool to estimate WDIs for OTC after extralabel use in small ruminants to ensure food safety and serves as a basis for extrapolation to other tetracycline drugs and other food animals.

Physiological parameter values for physiologically based pharmacokinetic models in food-producing animals. Part III: Sheep and goat.

This report is the third in a series of studies that aimed to compile physiological parameters related to develop physiologically based pharmacokinetic (PBPK) models for drugs and environmental chemicals in food-producing animals including swine and cattle (Part I), chickens and turkeys (Part II), and finally sheep and goats (the focus of this manuscript). Literature searches were conducted in multiple databases (PubMed, Google Scholar, ScienceDirect, and ProQuest), with data on relevant parameters including body weight, relative organ weight (% of body weight), cardiac output, relative organ blood flow (% of cardiac output), residual blood volume (% of organ weight), and hematocrit reviewed and statistically summarized. The mean and standard deviation of each parameter are presented in tables. Equations describing the growth curves of sheep and goats are presented in figures. When data are sufficient, parameter values are reported for different ages or production classes of sheep, including fetal sheep, lambs, and market-age sheep (mature sheep). These data provide a reference database for developing standardized PBPK models to predict drug withdrawal intervals in sheep and goats, and also provide a basis for extrapolating PBPK models from major species such as cattle to minor species such as sheep and goats.

Combined effect of mastitis and parity on pregnancy loss in lactating Holstein cows.

The main objective of this study was to examine the combined effect of mastitis and parity on pregnancy loss (PL) in lactating Holstein cows. A secondary objective was to estimate the cost of mastitis including that of PL attributable to mastitis. A total of 1,774 lactation periods from 1,047 Holstein cows with different parities from one dairy farm were included in a matched case-control study. All study cows were diagnosed pregnant by transrectal ultrasonography on day 33 after timed artificial insemination (TAI). Case cows (n = 222 lactations) were those later diagnosed non-pregnant by transrectal palpation on day 47 or 75 after TAI. Control cows (n = 1,552 lactations) were those confirmed pregnant by transrectal palpation on day 75 after TAI. Case cows were matched with eligible controls according to year of calving and calving-to-conception interval (CCI) ± 3 days. Cows with different parities were classified as exposed to subclinical mastitis (somatic cell score (SCS) > 4.5 in at least one Dairy Herd Improvement Association (DHIA) test day) or clinical mastitis (with or without evidence of subclinical mastitis) during two exposure periods: 1-42 days before breeding or 1-75 days during gestation (1 to PL diagnosis day in case cows, or 1-75 day in control cows). Conditional logistic regression was used to model the odds of PL as a function of previous exposure to mastitis in different parities. Cost of PL attributable to mastitis ($/case) among cows with mastitis was estimated based on attributable risk calculated in the epidemiologic analysis. We observed a higher than expected combined effect between exposure to mastitis (subclinical or clinical) before breeding and parity 3 or ≥ 4, and during gestation and parity ≥ 4 on PL. The cost of PL attributable to mastitis was highest ($196/case) in cows in parity ≥ 4 affected with clinical mastitis during gestation. Overall, study results indicate the impact of mastitis on PL is higher in older cows (parity ≥ 3). Dairy farmers and attending veterinarians can consider the combined effect of mastitis and parity when evaluating causes for PL and strategies for optimizing reproductive performance in dairy cows.

Mycoplasma bovis: Interactions with the Immune System and Failure to Generate an Effective Immune Response.

Host responses are often ineffective at clearing Mycoplasma bovis infection and may contribute to the pathogenesis of disease. M bovis possesses a surprisingly large repertoire of strategies to evade and modulate host responses. Unopsonized M bovis impairs phagocytosis and killing by neutrophils and macrophages. Apoptosis of neutrophils and lymphocytes is enhanced, whereas it is delayed in macrophages. Both proinflammatory and antiinflammatory cytokines are stimulated during M bovis infection depending on the cell type and location, and overall systemic responses tend to have a T-helper 2 bias. M bovis reduces proliferation of T cells and, in chronic infection, causes T-cell exhaustion.

Epidemiologic and economic analyses of pregnancy loss attributable to mastitis in primiparous Holstein cows.

The main objective of the study reported here was to examine the association between pregnancy loss (PL) and previous exposure to clinical or subclinical mastitis before breeding or during gestation in primiparous Holstein cows. A secondary objective was to estimate the cost of clinical mastitis during gestation, including that of PL attributable to mastitis in study cows. A total of 687 primiparous Holstein cows from 1 dairy farm were included in a matched case-control study. Study cows were declared pregnant via ultrasound on d 33 after timed artificial insemination (TAI). Case cows (n = 78) were those diagnosed as nonpregnant by rectal palpation on d 47 or 75 after TAI. Control cows were those confirmed as pregnant by rectal palpation on d 47 and 75 after TAI. Case cows were matched with eligible controls according to year of calving and calving-to-conception interval ±3 d. Cows were assigned to 1 of 3 groups: (1) cows not affected with clinical or subclinical mastitis; (2) cows affected with subclinical mastitis (Dairy Herd Improvement Association somatic cell score >4.5); and (3) cows affected with clinical mastitis during 2 exposure periods, 1 to 42 d before breeding or during gestation (1 to PL diagnosis day for case cows, and 1 to 75 d for control cows). Conditional logistic regression was used to model the odds of PL as a function of previous exposure to mastitis in study cows. Mastitis before breeding was not associated with PL. The odds of PL were 2.21 times greater in cows affected with clinical mastitis during gestation (95% confidence interval = 1.01, 4.83), compared with cows without mastitis, after controlling for breeding type and lameness. The cost of clinical mastitis during gestation was $149, which includes the cost ($27) of PL attributable to mastitis. In conclusion, this study provides evidence that clinical mastitis during gestation can cause PL in primiparous dairy cows leading to economic losses.

Evidence that mastitis can cause pregnancy loss in dairy cows: A systematic review of observational studies.

The objective of this study was to conduct a systematic review to identify and assess evidence and knowledge gaps in published observational studies that have investigated the relationship between mastitis and pregnancy loss (PL) in dairy cows. PubMed and ScienceDirect were used to search pertinent peer-reviewed research reports of interest. Screening of research reports was conducted at 3 levels: titles, abstracts, and full-text articles. The search identified 651 records for initial screening. The final screening process identified 8 qualified articles for review after removing 10 duplicate records, 582 titles, 31 abstracts, and 20 full-text articles. Two studies produced strong epidemiologic evidence indicating that (1) exposure to clinical mastitis during early gestation (first 45 d of gestation) is associated with subsequent PL during the following 90 d; and (2) subclinical mastitis 1 to 30 d before artificial insemination (AI) is associated with subsequent PL at 35 to 41 d of gestation. An additional study showed that exposure to clinical mastitis during early lactation in combination with low body condition can increase the risk of PL in dairy cows; however, the interaction effect between clinical mastitis and low body condition on PL was considered weak. Four other studies produced inconclusive evidence indicating that mastitis is a predisposing factor for PL in dairy cows, as the exposure risk period for mastitis overlapped with the follow-up period for diagnosis of PL in dairy cows. Finally, one study failed to identify a relationship between mastitis and PL in dairy cows. Further research is needed to (1) support the hypothesis that mastitis in combination with low body condition score (or other exposure factors) can increase the risk of PL, (2) compare the effect of clinical versus subclinical mastitis on PL, (3) compare the effect of mastitis before breeding and during gestation on PL, and (4) compare the effect of mastitis on PL in dairy cows during different lactations.

Evaluation of milk components as diagnostic indicators for rumen indigestion in dairy cows.

OBJECTIVE To identify milk component alterations that might be useful for detecting cows with rumen indigestion. DESIGN Prospective case-control study. ANIMALS 23 Holstein cows with rumen indigestion (cases) and 33 healthy cohorts (controls) from 1 herd. PROCEDURES Cases were defined as cows between 30 and 300 days postpartum with a > 10% decrease in milk yield for 2 consecutive milkings or > 20% decrease in milk yield from the 10-day rolling mean during any milking, abnormally decreased rumen motility, and no other abnormalities. Each case was matched with 2 healthy cows (controls) on the basis of pen, parity, days postpartum, and mean milk yield. Some cows were controls for multiple cases. All cows underwent a physical examination and collection of a rumen fluid sample for pH measurement at study enrollment. Individual-cow milk yield and milk component data were obtained for the 16 milkings before and after study enrollment. Rumen motility and pH and milk components were compared between cases and controls. RESULTS Rumen motility for cases was decreased from that of controls. Cases had an abrupt increase in milk fat percentage and the milk fat-to-lactose ratio during the 2 milkings immediately before diagnosis of rumen indigestion. Receiver operating characteristic analyses revealed that a 10% increase in the milk fat-to-lactose ratio had the highest combined sensitivity (57%) and specificity (85%) for identifying cows with rumen indigestion. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that a positive deviation in the milk fat-to-lactose ratio might be useful for identifying cows with rumen indigestion.

Oral inoculation of young dairy calves with Mycoplasma bovis results in colonization of tonsils, development of otitis media and local immunity.

Because M. bovis otitis media is an economically important problem, there is a need to understand the pathogenesis of disease, not only to improve our understanding of the factors contributing to the development of this disease but also to inform the development of improved diagnostic tests and therapy. Oral ingestion of M. bovis-contaminated milk is linked, but not definitively proven, to development of otitis media. In the current study, we demonstrate that oral ingestion of M. bovis infected colostrum can result in an ascending infection and development of otitis media. Importantly, M. bovis was found to have a previously unrecognized tendency for colonization of the tonsils of calves, which most likely contributed to the subsequent development of otitis media. In contrast, transtracheal inoculation failed to produce clinically significant upper respiratory tract disease, although did induce lower respiratory tract disease. The upper respiratory tract was the major site of M. bovis-specific B cell and mucosal IgA responses in calves inoculated by the oral route. The oral inoculation route of infection presented here is particularly suited to the study of host-pathogen interactions during initial colonization of the tonsils, expansion of infection and dissemination to the lower respiratory tract and middle ear. In addition, it could be used to investigate potential new preventative or control strategies, especially those aimed at limiting colonization of the tonsils and/or spread to the middle ear.