A systematic review of experimental evidence for antiviral effects of ivermectin and an in silico analysis of ivermectin's possible mode of action against SARS-CoV-2

Viral infections remain a major cause of economic loss with an unmet need for novel therapeutic agents. Ivermectin is a putative antiviral compound; the proposed mechanism is the inhibition of nuclear translocation of viral proteins, facilitated by mammalian host importins, a necessary process for propagation of infections. We systematically reviewed the evidence for the applicability of ivermectin against viral infections including SARS-CoV-2 regarding efficacy, mechanisms and selective toxicity. The SARS-CoV-2 genome was mined to determine potential nuclear location signals for ivermectin and meta-analyses for in vivo studies included all comparators over time, dose range and viral replication in multiple organs. Ivermectin inhibited the replication of many viruses including those in Flaviviridae, Circoviridae and Coronaviridae families in vitro. Real and mock nuclear location signals were identified in SARS-CoV-2, a potential target for ivermectin and predicting a sequestration bait for importin β, stopping infected cells from reaching a virus-resistant state. While pharmacokinetic evaluations indicate that ivermectin could be toxic if applied based on in vitro studies, inhibition of viral replication in vivo was shown for Porcine circovirus in piglets and Suid herpesvirus in mice. Overall standardized mean differences; 95% confidence intervals for ivermectin versus controls were: -4.43 (-5.81, -3.04), P < 0.00001. Based on current results, the potential for repurposing ivermectin as an antiviral agent is promising. However, further work is needed to reconcile in vitro studies with clinical efficacy. Developing ivermectin as an additional antiviral agent should be pursued with an emphasis on pre-clinical trials in validated models of infection

Utilisation and evaluation of cooperative case-based teaching for integration of microbiology and pharmacology in veterinary education

Purpose: Integrating basic sciences with clinical disciplines while fostering clinical reasoning capabilities is difficult. We investigated the utilisation of diagnostic specimens and, a cooperative, case-based learning and teaching model to integrate principles of antimicrobial drug pharmacology and microbiology in the fifth year of a veterinary course. Methods: In small groups, students were assigned diagnostic specimens from which they isolated and identified clinically relevant microorganisms and then performed antimicrobial susceptibility tests based on a review of pharmacology, microbiology and pathophysiology. Results were recorded and analysed followed by a student-led integrative tutorial. Learning outcomes were assessed via individually written reports discussing the disease process, interpretation of diagnostic results and, recommendations and rationales for therapeutic interventions. Results: This approach yielded high quality student reports that conformed to antimicrobial prescription guidelines with consistently high summative assessment scores. Mean scores for the final report in this learning activity were: 82 ± 12%, 80 ± 12% and 80 ± 11% for 2015, 2016 and 2017 cohorts respectively; over the same time period, 98 ± 1% of students indicated that these learning activities facilitated the development of confidence, professional knowledge and skills. Discussion: This was a consistent approach for integrating principles of veterinary pharmacology and microbiology in clinical disciplines. These data illustrate the benefit of a systematic application of a cooperative, case-based learning and teaching model in integrating pre-clinical and clinical disciplines in a bachelor of veterinary science course

Diet and genetics influence beef cattle performance and meat quality characteristics

A comprehensive review of the impact of tropical pasture grazing, nutritional supplementation during feedlot finishing and fat metabolism-related genes on beef cattle performance and meat-eating traits is presented. Grazing beef cattle on low quality tropical forages with less than 5.6% crude protein, 10% soluble starches and 55% digestibility experience liveweight loss. However, backgrounding beef cattle on high quality leguminous forages and feedlot finishing on high-energy diets increase meat flavour, tenderness and juiciness due to improved intramuscular fat deposition and enhanced mono- and polyunsaturated fatty acids. This paper also reviews the roles of stearoyl-CoA desaturase, fatty acid binding protein 4 and fatty acid synthase genes and correlations with meat traits. The review argues that backgrounding of beef cattle on Desmanthus, an environmentally well-adapted and vigorous tropical legume that can persistently survive under harsh tropical and subtropical conditions, has the potential to improve animal performance. It also identifies existing knowledge gaps and research opportunities in nutrition-genetics interactions aimed at a greater understanding of grazing nutrition, feedlot finishing performance, and carcass traits of northern Australian tropical beef cattle to enable red meat industry players to work on marbling, juiciness, tenderness and overall meat-eating characteristics

Chemical composition and in situ degradability of Desmanthus spp. forage harvested at different maturity stages

This study evaluated the change in nutritive value and in situ degradability of Desmanthus spp. (desmanthus) cultivars JCU2; D. virgatus, JCU4; D. bicornutus and JCU7; D. leptophyllus harvested at varying maturity stages to test the hypothesis that the nutritive value and in situ degradability of desmanthus differ between cultivars and with maturity stage at harvest. In Experiment 1, desmanthus was harvested at 11, 38, 72 and 103 days of regrowth (maturity), separated into the leaf and stem portion, dried and analysed for dry matter (DM) and chemical composition. In Experiment 2, desmanthus was harvested 78, 122 and 168 days after planting (maturity). Samples were dried, and DM, crude protein (CP) and neutral detergent fibre (NDF) and acid detergent fibre (ADF) degradation were determined using the in situ technique with three fistulated Droughtmaster steers. The results showed an interaction between cultivar and maturity on the leaf to stem mass ratio, leaf CP, stem NDF and the leaf ADF (p ≤ 0.04). The leaf-to-stem mass ratio declined more steeply with maturity in JCU7 compared to JCU2 and JCU4 (p = 0.04), while there was a higher decline in leaf CP of JCU4 than JCU2 and JCU7 (p < 0.01). The total potentially degradable fraction of DM and CP did not differ between cultivars (p ≥ 0.30) but declined with maturity (p ≤ 0.04). However, the effective DM degradability at a high particle outflow rate was higher in JCU4 than in JCU7. Taken together, these results indicate that differences exist between cultivars, and higher livestock production may be achieved by utilising the different cultivars in a blend and at earlier maturity stages. Therefore, the hypothesis that nutritive value and in situ degradability of desmanthus differ between cultivars and with maturity stage at harvest was accepted

Growth performance and plasma metabolites of grazing beef cattle backgrounded on Buffel or Buffel-Desmanthus mixed pastures

Dietary crude protein and dry matter digestibility are among the major factors limiting feed intake and weight gain of cattle grazing native and improved pastures in the subtropics of Northern Australia during the dry season. Incorporating a suitable legume into grasses improves pasture quality and cattle weight gain, but only a limited number of legume pastures can establish and persist in cracking clay soils. This study aimed to evaluate the effect of Desmanthusinclusion in buffel grass (Cenchrus ciliaris) pastures on the plasma metabolite profile and growth performance of grazing beef cattle during the dry season. We hypothesised that backgrounding steers on buffel grass-Desmanthusmixed pastures would elicit significant changes in plasma glucose, bilirubin, creatinine, non-esterified fatty acids and β-hydroxybutyrate, resulting in higher liveweight gains than in steers on buffel grass only pastures. Four hundred tropical composite steers were assigned to buffel grass only (n = 200) or buffel grass oversown with Desmanthus(11.5% initial sward dry matter) pastures (n = 200) and grazed for 147 days during the dry season. Desmanthusaccounted for 6.2% sward dry matter at the end of grazing period. Plasma metabolites results showed thatchanges in β-hydroxybutyrate, creatinine, bilirubin, glucose and non-esterified fatty acids were within the expected normal range for all the steers, indicating that with or withoutDesmanthusinclusion in the diet of grazing steers, animal health status was not compromised. It was also evident that Desmanthusinclusion in buffel grass pastures had no impact on the plasma metabolite profile, liveweight and daily weight gain of grazing steers. Therefore, our tested hypothesis of higher changes in plasma metabolite profile and higher liveweight gains due to backgrounding on low-level buffel grass-Desmanthus mixed pastures does not hold

Lipid metabolism, carcass characteristics and Longissimus dorsi muscle fatty acid composition of tropical crossbred beef cattle in response to Desmanthus spp. forage backgrounding

Lipid metabolism, carcass characteristics and fatty acid (FA) composition of the Longissimus dorsi (loin eye) muscle were evaluated in tropical crossbred steers backgrounded on Desmanthus spp. (desmanthus) with or without feedlot finishing. It was hypothesized that steers backgrounded on isonitrogenous diets augmented with incremental proportions of desmanthus will produce carcasses with similar characteristics and FA composition. Forty-eight Brahman, Charbray and Droughtmaster crossbred beef steers were backgrounded for 140 days on Rhodes grass (Chloris gayana) hay augmented with 0, 15, 30 or 45 percent desmanthus on dry matter basis. Lucerne (Medicago sativa) hay was added to the 0, 15 and 30 percent desmanthus diets to ensure that they were isonitrogenous with the 45 percent desmanthus diet. After backgrounding, the two heaviest steers in each pen were slaughtered and the rest were finished in the feedlot for 95 days before slaughter. Muscle biopsy samples were taken at the beginning and end of the backgrounding phase. Carcasses were sampled at slaughter for intramuscular fat (IMF) content, fat melting point (FMP) and FA composition analyses. Increasing the proportion of desmanthus in the diet led to a linear increase in docosanoic acid (p = 0.04) and omega-6/omega-3 polyunsaturated FA ratio (n-6/n-3 PUFA; p = 0.01), while docosahexaenoic acid decreased linearly (p = 0.01). Feedlot finishing increased hot carcass weight, subcutaneous fat depth at the P8 site and dressing percentage (p ≤ 0.04). The n-6/n-3 PUFA ratio was within the recommended < 5 for human diets. IMF was within the consumer-preferred ≥ 3% level for palatability. The hypothesis that steers backgrounded on isonitrogenous diets augmented with incremental proportions of desmanthus will produce similar carcass characteristics and FA composition was accepted. These findings indicate that a combination of tropical beef cattle backgrounding on desmanthus augmented forage and short-term feedlot finishing produces healthy and highly palatable meat

Towards sustainable sources of omega-3 long-chain polyunsaturated fatty acids in Northern Australian tropical crossbred beef steers through single nucleotide polymorphisms in lipogenic genes for meat eating quality

This study aimed to identify single nucleotide polymorphisms (SNP) in lipogenic genes of northern Australian tropically adapted crossbred beef cattle and to evaluate associations with healthy lipid traits of the Longissimus dorsi (loin eye) muscle. The hypothesis tested was that there are significant associations between SNP loci encoding for the fatty acid binding protein 4 (FABP4), stearoyl-CoA desaturase (SCD) and fatty acid synthase (FASN) genes and human health beneficial omega-3 long-chain polyunsaturated fatty acids (ω3 LC-PUFA) within the loin eye muscle of northern Australian crossbred beef cattle. Brahman, Charbray, and Droughtmaster crossbred steers were fed on Rhodes grass hay augmented with desmanthus, lucerne, or both, for 140 days and the loin eye muscle sampled for intramuscular fat (IMF), fat melting point (FMP), and fatty acid composition. Polymorphisms in FABP4, SCD, and FASN genes with significant effects on lipid traits were identified with next-generation sequencing. The GG genotype at the FABP4 g.44677239C>G locus was associated with higher proportion of linoleic acid than the CC and CG genotypes (p T locus indicated that the TT genotype had significantly higher eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids than GG genotype (p < 0.05). Significant correlations (p < 0.05) between FASN SNP and IMF, saturated and monounsaturated fatty acids were observed. These results provide insights into the contribution of lipogenic genes to intramuscular fat deposition and SNP marker-assisted selection for improvement of meat-eating quality, with emphasis on alternate and sustainable sources of ω3 LC-PUFA, in northern Australian tropical crossbred beef cattle, hence an acceptance of the tested hypothesis

Single nucleotide polymorphisms in the fatty acid binding protein 4, fatty acid synthase and stearoyl-CoA desaturase genes influence carcass characteristics of tropical crossbred beef steers

This study explored the identification of single nucleotide polymorphisms (SNP) in fatty acid binding protein 4 (FABP4), stearoyl-CoA desaturase (SCD), and fatty acid synthase (FASN) genes that may influence the carcass traits of tropical crossbred beef cattle. The hypothesis tested was that SNP in the FABP4, SCD, and FASN genes are associated with chiller-assessed carcass traits of tropically adapted northern Australian crossbred beef cattle. Fifty Bos indicus and Bos taurus crossbred steers were backgrounded on either buffel grass only, or buffel grass and desmanthus mixed pastures for 147 days and finished in a commercial feedlot for 110 days. Steers were slaughtered within 48 h of leaving the feedlot within a lairage period not exceeding 12 h and carcasses graded 12 h after slaughter. Next-generation sequencing of the FASN, FABP4, and SCD genes identified multiple SNP loci that were correlated and significantly associated with carcass traits. The FABP4 g.44677205A>G locus was significantly associated with hump height and correlated with loin eye muscle area (EMA; p A locus was associated with subcutaneous fat depth and marbling score (p < 0.05). The CC genotype had a higher subcutaneous fat depth and marbling score (p < 0.05) than the AA genotype. Significant correlations were observed between carcass marbling score and subcutaneous fat depth within the FASN SNP locus (p < 0.05). Therefore, the hypothesis that SNP in the FABP4, SCD, and FASN genes are associated with chiller-assessed carcass traits of tropically adapted northern Australian crossbred beef cattle was accepted. These findings suggest that SNP in the FABP4, SCD, and FASN genes may be used in carcass grading and meat quality improvement through marker-assisted selection of northern Australian crossbred beef cattle

Towards the elimination of excessive cobalt supplementation in racing horses: a pharmacological review

Cobalt is an essential trace element for many vital physiological functions. Cobalt is also known to stabilise hypoxia-inducible transcription factors leading to increased expression of erythropoietin which activates production of red blood cells. This implies that cobalt can be used to enhance aerobic performance in racing horses. If this becomes a pervasive practice, the welfare of racing animals would be at risk because cobalt is associated with cardiovascular, haematological, thyroid gland and reproductive toxicity as observed in laboratory animals\ud and humans. It is expected that similar effects may manifest in horses but direct evidence on equine specific effects of cobalt and the corresponding exposure conditions leading to such effects is lacking. Available pharmacokinetic data demonstrates that intravenously administered cobalt has a long elimination half-life (42–156 h) and a large volume of distribution (0.94 L/kg) in a horse implying that repeated administration of cobalt would accumulate in tissues over time attaining equilibrium after ~9–33 days. Based on these pharmacokinetic data and surveys of horses post racing, threshold cobalt concentrations of 2–10 μg/L in plasma and 75–200 μg/L in urine have been recommended. However, there is no clearly defined, presumably normal cobalt supplementation regimen for horses and characterisation of potential adverse effects of any established threshold cobalt concentrations has not been done. This review outlines the strengths and limitations of the existing literature on the pharmacological effects of cobalt in horses with some recommendations on what gaps to bridge to enable the determination of optimal threshold cobalt concentrations in racing horses