Investigation of the association between the Enferplex bovine tuberculosis antibody test and the future risk of bovine tuberculosis in irish cattle in infected herds: a pilot field study

The Single Intradermal Comparative Tuberculin Test (SICTT) and the interferon-gamma (IFN-γ) assay are the approved diagnostic tests for bovine tuberculosis (bTB) in Ireland. The aim of this pilot study was to explore if there was any added diagnostic benefit from applying the Enferplex bTB test (an antibody test) in severe bTB herd breakdowns after the removal of cattle that had tested positive to the SICTT and the IFN-γ test. In addition to the normal bTB testing and management protocols, the animals in these herds that tested negative to SICTT and the IFN-γ test were followed forward for a period of two years. All animals were tested by Enferplex at enrolment. The time to subsequent bTB detection (diagnosed with SICTT/IFN-γ tests or detection of visible lesions at routine slaughter) for animals that tested positive or negative to the Enferplex bTB test at the start of the study was compared using Kaplan–Meier survival curves and Cox based survival models. Of the 484 enrolled animals (from 11 herds), 171 (35.3%) and 151 (31.1%) initially tested positive in the Enferplex assay under the high sensitivity and high specificity interpretation settings respectively. The results of the survival analysis showed that there was no difference in the survival time to a positive diagnosis with bTB during the follow-up period between animals initially classified as positive and negative by the Enferplex test. Further research is warranted to explore the potential benefit of using the Enferplex test in other scenarios.Department of Agriculture, Food and the MarineOpen Access funding provided by the IReL ConsortiumTo check citing and date details in 6

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK

Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions. </jats:sec

Seroprevalence of Leptospira Hardjo in the Irish suckler cattle population

Background: Prior to the present study, the seroprevalence of leptospirosis in Irish suckler herds was unknown. In this study, we describe the herd and animal-level prevalence of Leptospira Hardjo infection in the Irish suckler cattle population. For the purposes of the study, the 26 counties of the Republic of Ireland were divided into 6 regions from which a representative number of herds were selected. A herd was considered eligible for sampling if it was not vaccinating against leptospirosis and if it contained ≥ 9 breeding animals of beef breed ≥ 12 months of age. In total, 288 randomly selected herds were eligible for inclusion in the seroprevalence dataset analysis. Serological testing was carried out using a commercially available monoclonal antibody-capture ELISA, (sensitivity 100%; specificity 86.67%). Results: Herds were categorised as either “Free from Infection” or “Infected” using the epidemiological software tool, FreeCalc 2.0. Using this classification, 237 herds were “Infected” (82.29%). The South West and South East regions had the highest herd prevalence. The regional effect on herd prevalence was largely mirrored by breeding herd size. A true animal-level prevalence of 41.75% was calculated using the epidemiological software tool, TruePrev. There was a statistically significant regional trend, with true prevalence being highest in the South East (P < 0.05). The median Breeding Herd Size (BHS), when categorised into quartiles, had a statistically significant influence on individual animal true seroprevalence (P < 0.001); true seroprevalence increased with increasing BHS. Conclusions: Leptospirosis is a widespread endemic disease in the Republic of Ireland. It is possible that economic losses due to leptospirosis in unvaccinated Irish suckler herds may be underestimated.Deposited by bulk impor

Mastitis Control and Intramammary Antimicrobial Stewardship in Ireland: Challenges and Opportunities

The Veterinary Medicines Regulation (EU 2019/6) came into force in all EU member states on 28 January 2022. This regulation places particular emphasis on prudent and responsible antimicrobial use in food animal production. Key changes include restrictions on the prophylactic use of antimicrobials in animals, and the possibility to reserve certain antimicrobials for humans only. The Regulation presents challenges to the Irish dairy industry, particularly with respect to current approaches to dry cow therapy. In response, the CellCheck technical working group (TWG, a technical group working in support of CellCheck, the national mastitis control programme) have developed pragmatic national and farm-level recommendations in support of improved mastitis control and intramammary antimicrobial stewardship in the Irish dairy industry. This paper outlines these recommendations, and provides an overview of the evidence considered to inform the TWG during its work (including the Regulation, policy perspectives, international best-practice, international scientific reviews and specific Irish challenges). In many key areas of concern, the TWG recognises the challenges in seeking to shape recommendations in the absence of robust and practical scientific evidence. For this reason, some of the recommended actions are pragmatic in nature, informed by national and international experiences. Periodic programme review will be needed, informed by ongoing monitoring of key performance indicators, to identify those actions that are most effective in an Irish context

The effect of growth rate on reproductive outcomes in replacement dairy heifers in seasonally calving, pasture-based systems

The effect of average daily gain (ADG) on reproductive outcomes in replacement dairy heifers was investigated. All heifers were managed in the typical Irish spring calving, pasture-based system, where the herd calves in 1 block between January and April and the majority of the diet comprises grazed grass. Heifer calves (n = 399) from 7 herds were weighed at birth and at the beginning of the breeding season, and ADG was calculated. Service dates and pregnancy diagnosis results were recorded, and conception dates were calculated. Days open (DO) was defined as the number of days between the beginning of the breeding season and conception. Genetic data were retrieved from the Irish Cattle Breeding Federation database. A Cox proportional hazard model was constructed to identify variables with a significant effect on DO. An accelerated failure time model was used to predict survival curves and median survival times for different combinations of the significant variables. The ADG ranged from 0.41 to 0.91 kg/d, with a median of 0.70 kg/d. Frailty effect of farm within year, maintenance subindex of the economic breeding index, and ADG had a significant effect on DO. Derived from the final accelerated failure time model, the predicted median DO for a heifer with an ADG of 0.40, 0.70, or 0.90 kg/d aged 443 d at the beginning of the breeding season and with a maintenance subindex in the second tercile were 27, 16, and 11 d, respectively

Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses.

Funder: Trinity College DublinMacrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the 'classically activated' M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis. By contrast, 'alternatively activated' M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here, we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection

Characterization of the inflammatory response to severe COVID-19 illness.

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood. Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness. Methods: Levels of IL-1β, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated. Measurements and Main Results: IL-1β, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population. Measurements and Main Results: IL-1β, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.</p