Multigeneric resistance to monepantel on a UK sheep farm

The amino acetonitrile derivative, monepantel, represented the first new broad spectrum anthelmintic to be brought to market for use in sheep for over 25 years when it was introduced in 2009. This study characterised monepantel efficacy, using faecal egg count reduction and controlled efficacy tests, against gastrointestinal nematodes following a report of treatment failure in a UK lowland sheep flock. Twelve lambs were each artificially administered 15,000 infective larvae that had been propagated from lamb faeces collected from the farm of interest. The controlled efficacy test showed that a recommended dose rate of monepantel (2.5 mg/kg body weight) administered at day 28 post infection was ineffective at removing the infection in the treated lambs. The result demonstrated simultaneous resistance to monepantel in Teladorsagia circumcincta, Trichostrongylus vitrinus and Oesophagostomum venulosum with efficacies based on adult worm burden reductions, compared to untreated controls, of 78%, 27% and 22% respectively. Monepantel efficacy based on undifferentiated egg count in treated animals, seven day post administration, compared to untreated controls was 85%. The results raise questions about the origins of, and predisposing factors for, resistance development in the three different species, and reinforces the value of differentiating post treatment faecal egg counts to genus or species level

Proliferation, apoptosis and their regulatory protein expression in colorectal adenomas and serrated lesions

Background Adenomas and serrated lesions represent heterogeneous sets of early precursors in the colorectum with varying malignant potential. They are often distinguished by their histopathologic differences, but little is known about potential differences in regulation of epithelial proliferation and apoptosis. Methods We conducted a protein expression analysis using tissue microarrays of 625 colorectal adenomas and 142 serrated lesions to determine potential differences in regulation of epithelial proliferation and apoptosis. We quantitated proliferation with Ki-67; apoptosis with activated caspase-3 (CASP3); up- and down-regulators of proliferation with cyclin D1, p16INK2, and p21Cip1; and apoptosis regulators with BAX, BCL2, and survivin. Linear mixed effects models and circos diagrams were used to determine relationships among expression and lesion characteristics. Results Adenomas had a significantly higher CASP-3 labeling index (LI) than serrated lesions, resulting in a lower net growth ratio (Ki-67 LI/activated CASP-3 LI, p-value<0.0001). Cyclin D1 LI, p16 LI and p21 LI were lower in adenomas compared to serrated lesions, while expression of both BCL2 and BAX were higher (p <0.001). Among adenomas, cyclin D1 LI and p16 LI levels increased with greater villous component, and the highest BAX expression was detected in adenomas larger than 2 cm (both p<0.0001). Right-sided adenomas had higher CASP3 LI than left colorectal adenomas (p = 0.008). Significant differences in cyclin D1 LI, p21 LI and survivin LI were also observed across histopathologic subtypes of serrated lesions. Conclusions Our findings demonstrate different patterns of regulatory protein expression in adenomas than serrated lesions, especially involving apoptosis

To what extent is climate change adaptation a novel challenge for agricultural modellers?

Modelling is key to adapting agriculture to climate change (CC), facilitating evaluation of the impacts and efficacy of adaptation measures, and the design of optimal strategies. Although there are many challenges to modelling agricultural CC adaptation, it is unclear whether these are novel or, whether adaptation merely adds new motivations to old challenges. Here, qualitative analysis of modellers’ views revealed three categories of challenge: Content, Use, and Capacity. Triangulation of findings with reviews of agricultural modelling and Climate Change Risk Assessment was then used to highlight challenges specific to modelling adaptation. These were refined through literature review, focussing attention on how the progressive nature of CC affects the role and impact of modelling. Specific challenges identified were: Scope of adaptations modelled, Information on future adaptation, Collaboration to tackle novel challenges, Optimisation under progressive change with thresholds, and Responsibility given the sensitivity of future outcomes to initial choices under progressive change

Increasing importance of anthelmintic resistance in European livestock: creation and meta-analysis of an open database

Trabajo presentado al: COMBAR meeting (Combatting Anthelmintic Resistance in Ruminants). Atenas (Grecia). Febrero. 2022

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease