Relative importance of herd-level risk factors for probability of infection with paratuberculosis in Irish dairy herds

Control of paratuberculosis is challenging due to the relatively poor performance of diagnostic tests, a prolonged incubation period, and protracted environmental survival. Prioritization of herd-level interventions is not possible because putative risk factors are often not supported by risk factor studies. The objective for this study was to investigate the relative importance of risk factors for an increased probability of herd paratuberculosis infection. Risk assessment data, comprehensive animal purchase history, and diagnostic test data were available for 936 Irish dairy herds. Both logistic regression and a Bayesian β regression on the outcome of a latent class analysis were conducted. Population attributable fractions and proportional reduction in variance explained were calculated for each variable in the logistic and Bayesian models, respectively. Routine use of the calving area for sick or lame cows was found to be a significant explanatory covariate in both models. Purchasing behavior for the previous 10 yr was not found to be significant. For the logistic model, length of time calves spend in the calving pen (25%) and routine use of the calving pen for sick or lame animals (14%) had the highest attributable fractions. For the Bayesian model, the overall R2 was 16%. Dry cow cleanliness (7%) and routine use of the calving area for sick or lame cows (6%) and had the highest proportional reduction in variance explained. These findings provide support for several management practices commonly recommended as part of paratuberculosis control programs; however, a large proportion of the observed variation in probability of infection remained unexplained, suggesting other important risks factors may exist

Seroprevalence of Mycoplasma bovis in bulk milk samples in Irish dairy herds and risk factors associated with herd seropositive status

Mycoplasma bovis is a serious disease of cattle worldwide; mastitis, pneumonia, and arthritis are particularly important clinical presentations in dairy herds. Mycoplasma bovis was first identified in Ireland in 1994, and the reporting of Mycoplasma-associated disease has substantially increased over the last 5 years. Despite the presumed endemic nature of M. bovis in Ireland, there is a paucity of data on the prevalence of infection, and the effect of this disease on the dairy industry. The aim of this observational study was to estimate apparent herd prevalence for M. bovis in Irish dairy herds using routinely collected bulk milk surveillance samples and to assess risk factors for herd seropositivity. In autumn 2018, 1,500 herds out of the 16,858 herds that submitted bulk tank milk (BTM) samples to the Department of Agriculture testing laboratory for routine surveillance were randomly selected for further testing. A final data set of 1,313 sampled herds with a BTM ELISA result were used for the analysis. Testing was conducted using an indirect ELISA kit (ID Screen Mycoplasma bovis). Herd-level risk factors were used as explanatory variables to determine potential risk factors associated with positive herd status (reflecting past or current exposure to M. bovis). A total of 588 of the 1,313 BTM samples were positive to M. bovis, providing an apparent herd prevalence of 0.45 (95% CI: 0.42, 0.47) in Irish dairy herds in autumn 2018. Multivariable analysis was conducted using logistic regression. The final model identified herd size, the number of neighboring farms, in-degree and county as statistically significant risk factors for herd BTM seropositivity to M. bovis. The results suggest a high apparent herd prevalence of seropositivity to M. bovis, and evidence that M. bovis infection is now endemic in the Irish dairy sector. In addition, risk factors identified are closely aligned to what we would expect of an infectious disease. Awareness raising and education about this important disease is warranted given the widespread nature of exposure and likely infection in Irish herds. Further work on the validation of diagnostic tests for herd-level diagnosis should be undertaken as a matter of priority.University College DublinScience Foundation IrelandWellcome Trust -- Submitted for publication after 1 Jan 2021: 0m embargo and CC-BY licenseHealth Research BoardUCD Wellcome Institutional Strategic Support FundSFI-HRB-Wellcome Biomedical Research Partnershi

A review of paratuberculosis in dairy herds — Part 1: Epidemiology

Bovine paratuberculosis is a chronic infectious disease of cattle caused by Mycobacterium avium subspecies paratuberculosis (MAP). This is the first in a two-part review of the epidemiology and control of paratuberculosis in dairy herds. Paratuberculosis was originally described in 1895 and is now considered endemic among farmed cattle worldwide. MAP has been isolated from a wide range of non-ruminant wildlife as well as humans and non-human primates. In dairy herds, MAP is assumed to be introduced predominantly through the purchase of infected stock with additional factors modulating the risk of persistence or fade-out once an infected animal is introduced. Faecal shedding may vary widely between individuals and recent modelling work has shed some light on the role of super-shedding animals in the transmission of MAP within herds. Recent experimental work has revisited many of the assumptions around age susceptibility, faecal shedding in calves and calf-to-calf transmission. Further efforts to elucidate the relative contributions of different transmission routes to the dissemination of infection in endemic herds will aid in the prioritisation of efforts for control on farm

A review of paratuberculosis in dairy herds — Part 2: On-farm control

Bovine paratuberculosis is a chronic infectious disease of cattle, caused by Mycobacterium avium subspecies paratuberculosis (MAP). This is the second in a two-part review of the epidemiology and control of paratuberculosis in dairy herds. Several negative production effects associated with MAP infection have been described, but perhaps the most significant concern in relation to the importance of paratuberculosis as a disease of dairy cattle is the potential link with Crohn’s disease in humans. Milk is considered a potential transmission route to humans and it is recognised that pasteurisation does not necessarily eliminate the bacterium. Therefore, control must also include reduction of the levels of MAP in bulk milk supplied from dairy farms. There is little field evidence in support of specific control measures, although several studies seem to show a decreased prevalence associated with the implementation of a combined management and test-and-cull programme. Improvements in vaccination efficacy and reduced tuberculosis (TB) test interference may increase uptake of vaccination as a control option. Farmer adoption of best practice recommendations at farm level for the control of endemic diseases can be challenging. Improved understanding of farmer behaviour and decision making will help in developing improved communication strategies which may be more efficacious in affecting behavioural change on farm

An observational study of ear-tagged calf mortality (1 to 100 days) on Irish dairy farms and associations between biosecurity practices and calf mortality on farms participating in a Johne's disease control program

Postnatal mortality among replacement stock has a detrimental effect on the social, economic, and environmental sustainability of dairy production. Calf mortality rates vary between countries and show differences in temporal trends; most, however, are characterized by high levels of between-farm variability. Explaining this variation can be difficult because herd-level information on management practices relevant to calf health is often not available. The Irish Johne's Control Programme (IJCP) contains a substantial on-farm monitoring program called the Veterinary Risk Assessment and Management Plan (VRAMP). Although this risk assessment is largely focused on factors relevant to the transmission of paratuberculosis, many of its principles are good practice biocontainment policies that are also advocated for the protection of calf health. The objectives of this study were (1) to quantify mortality in ear-tagged Irish dairy calves between 2016 and 2020 using both survival and risk approaches, (2) to determine risk factors for 100-d cumulative mortality hazard in ear-tagged Irish dairy calves between 2016 and 2020, (3) to determine whether 100-d cumulative mortality hazard was higher in ear-tagged calves within herds registered in the IJCP versus those that were not registered in the IJCP and whether there were differences between these cohorts over time, and (4) within IJCP herds, to determine whether VRAMP score or changes in VRAMP score were associated with 100-d cumulative mortality hazard. Excluding perinatal mortality, the overall 100-d cumulative mortality hazard was 4.1%. Calf mortality was consistently underestimated using risk approaches that did not account for calf censoring. Cox proportional hazards models showed that cumulative mortality hazard was greater in male calves; particularly, calves born to Jersey breed dams and those with a beef breed sire. Mortality hazard increased with increasing herd size, was highest in calves born in herds that contract-reared heifers, and lowest in those born in mixed dairy-beef enterprises. Mortality hazard decreased over time with the mortality hazard in 2020 being 0.83 times that of 2016. Mortality hazard was higher in IJCP-registered herds than nonregistered herds (hazard ratio 1.06, 95% CI 1.01–1.12), likely reflecting differences in herds that enrolled in the national program. However, we detected a significant interaction between IJCP status (enrolled vs. not enrolled) and year (hazard ratio 0.96, 95% CI 0.92–1.00), indicating that the decrease in mortality hazard between 2016 and 2020 was greater in IJCP herds versus non-IJCP herds. Finally, increasing VRAMP scores (indicating higher risk for paratuberculosis transmission) were positively associated with increased calf mortality hazard. Postnatal calf mortality rates in Irish dairy herds declined between 2016 and 2020. Our study suggests that implementation of recommended biocontainment practices to control paratuberculosis in IJCP herds was associated with a reduction in calf mortality hazard

CaMKK2 as an emerging treatment target for bipolar disorder

Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder

Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis

AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis and a therapeutic target for metabolic diseases. Co/post-translational N-myristoylation of glycine-2 (Gly2) of the AMPK β subunit has been suggested to regulate the distribution of the kinase between the cytosol and membranes through a “myristoyl switch” mechanism. However, the relevance of AMPK myristoylation for metabolic signaling in cells and in vivo is unclear. Here, we generated knockin mice with a Gly2-to-alanine point mutation of AMPKβ1 (β1-G2A). We demonstrate that non-myristoylated AMPKβ1 has reduced stability but is associated with increased kinase activity and phosphorylation of the Thr172 activation site in the AMPK α subunit. Using proximity ligation assays, we show that loss of β1 myristoylation impedes colocalization of the phosphatase PPM1A/B with AMPK in cells. Mice carrying the β1-G2A mutation have improved metabolic health with reduced adiposity, hepatic lipid accumulation, and insulin resistance under conditions of high-fat diet-induced obesity

Bayesian estimation of prevalence of paratuberculosis in dairy herds enrolled in a voluntary Johne’s Disease Control Programme in Ireland

Bovine paratuberculosis is a disease characterised by chronic granulomatous enteritis which manifests clinically as a protein-losing enteropathy causing diarrhoea, hypoproteinaemia, emaciation and, eventually death. Some evidence exists to suggest a possible zoonotic link and a national voluntary Johne’s Disease Control Programme was initiated by Animal Health Ireland in 2013. The objective of this study was to estimate herd-level true prevalence (HTP) and animal-level true prevalence (ATP) of paratuberculosis in Irish herds enrolled in the national voluntary JD control programme during 2013–14. Two datasets were used in this study. The first dataset had been collected in Ireland during 2005 (5822 animals from 119 herds), and was used to construct model priors. Model priors were updated with a primary (2013–14) dataset which included test records from 99,101 animals in 1039 dairy herds and was generated as part of the national voluntary JD control programme. The posterior estimate of HTP from the final Bayesian model was 0.23–0.34 with a 95% probability. Across all herds, the median ATP was found to be 0.032 (0.009, 0.145). This study represents the first use of Bayesian methodology to estimate the prevalence of paratuberculosis in Irish dairy herds. The HTP estimate was higher than previous Irish estimates but still lower than estimates from other major dairy producing countries

The effect of paratuberculosis on milk yield—A systematic review and meta-analysis

peer-reviewedBovine paratuberculosis is a disease characterized by chronic granulomatous enteritis causing protein-losing enteropathy. Adverse effects on animal productivity are key drivers in the attempt to control paratuberculosis at the farm level. Economic models require an accurate estimation of the production effects associated with paratuberculosis. The aim of this study was to conduct a systematic review and meta-analysis to investigate the effect of paratuberculosis on milk production. A total of 20 effect estimates from 15 studies were included in the final meta-analysis. Substantial between-study heterogeneity was observed. Subgroup analysis by case definition and study design was carried out to investigate heterogeneity. The majority of between-study variation was attributed to studies that defined cases on serology. Calculation of a pooled effect estimate was only appropriate for studies that defined cases by organism detection. A reduction in milk yield, corrected for lactation number and herd of origin of 1.87 kg/d, equivalent to 5.9% of yield, was associated with fecal culture or PCR positivity in individual cows