Knowledge of Objective 'Oughts': Monotonicity and the New Miners Puzzle

In the classic Miners case, an agent subjectively ought to do what they know is objectively wrong. This case shows that the subjective and objective ‘oughts’ are somewhat independent. But there remains a powerful intuition that the guidance of objective ‘oughts’ is more authoritative—so long as we know what they tell us. We argue that this intuition must be given up in light of a monotonicity principle, which undercuts the rationale for saying that objective ‘oughts’ are an authoritative guide for agents and advisors

Comparative efficacy of two Ivermectin Pour-on anthelmintics in beef steers in a commercial feedyard

Generic products generally have a cost advantage for beef producers over brand-name products. Recently, many beef producers have debated whether to utilize generic anthelmintics in cow/calf herds and feeder cattle. If generics are to be justified, the products must be proven to have efficacy similar to the brand-name product. Previous studies have indicated that generic macrocyclic lactones are less effective in controlling gastrointestinal parasites of cattle than the original brand-name products. The objective of this study was to compare the efficacy of Vetrimec (Norbrook Laboratories Limited, Newry, Co. Down, Northern Ireland) pour-on and Ivomec (Merial Animal Health, Duluth, GA) pour-on by utilizing the fecal egg reduction test in newly arrived feedlot steers

Potential associations between fecal shedding of Salmonella in feedlot cattle treated for apparent respiratory disease and subsequent adverse health outcomes

A prospective cohort study was used to assess whether Salmonella fecal shedding in commercial feedlot cattle treated with antimicrobials for respiratory disease was associated with subsequent adverse health outcomes. Feces were collected per rectum from cattle that were examined for apparent respiratory disease, had a rectal temperature ≥40 °C, and subsequently received antimicrobial treatment. Salmonella were recovered from 918 (73.7%) of 1 245 fecal samples and weekly prevalence estimates ranged from 49 to 100% over the 3-month study. Genotypic and phenotypic characteristics of Salmonella strains in the population were determined. Serogroup E Salmonella were most common (73.3%), followed by C1 (11.0%), C3 (8.6%), and B (1.1%). Predominant serotypes were Orion (46.5%), Anatum (19.8%), Kentucky (8.7%), Montevideo (7.5%), and Senftenberg (4.9%). Few isolates (36/918) were positive for antimicrobial resistance-associated integron gene intI1. Phenotypic susceptibility was associated with isolate intI1 status. Crude re-pull, re-treatment and case fatality risks were higher for cattle that were Salmonella-positive versus -negative at initial treatment, but not statistically different on multivariable analysis. However, case fatality risk was higher for cattle shedding Group B Salmonella than for cattle shedding other serogroups. Lots (groups) with a higher Salmonella prevalence at first treatment had a higher proportion of mortalities occur in a hospital pen, higher overall re-treatment risks, and were more likely to be sampled later in the study. Results indicate a high prevalence of Salmonella in this population of cattle treated for apparent respiratory disease, but that effects associated with clinical outcomes may depend on the Salmonella strain

A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve.

AimsThe mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling.Materials and resultsRandomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD [invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI)]. Short-term oral ranolazine 500-1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (-3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041).ConclusionsIn this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects.Trial registrationclinicaltrials.gov Identifier: NCT01342029

Global analysis of the mammalian RNA degradome reveals widespread miRNA-dependent and miRNA-independent endonucleolytic cleavage

The Ago2 component of the RNA-induced silencing complex (RISC) is an endonuclease that cleaves mRNAs that base pair with high complementarity to RISC-bound microRNAs. Many examples of such direct cleavage have been identified in plants, but not in vertebrates, despite the conservation of catalytic capacity in vertebrate Ago2. We performed parallel analysis of RNA ends (PAREs), a deep sequencing approach that identifies 5′-phosphorylated, polyadenylated RNAs, to detect potential microRNA-directed mRNA cleavages in mouse embryo and adult tissues. We found that numerous mRNAs are potentially targeted for cleavage by endogenous microRNAs, but at very low levels relative to the mRNA abundance, apart from miR-151-5p-guided cleavage of the N4BP1 mRNA. We also find numerous examples of non-miRNA-directed cleavage, including cleavage of a group of mRNAs within a CA-repeat consensus sequence. The PARE analysis also identified many examples of adenylated small non-coding RNAs, including microRNAs, tRNA processing intermediates and various other small RNAs, consistent with adenylation being part of a widespread proof-reading and/or degradation pathway for small RNAs

Cattle handling technique can induce fatigued cattle syndrome in cattle not fed a beta adrenergic agonist

Citation: Frese, D. A., Reinhardt, C. D., Bartle, S. J., Rethorst, D. N., Hutcheson, J. P., Nichols, W. T., . . . Thomson, D. U. (2016). Cattle handling technique can induce fatigued cattle syndrome in cattle not fed a beta adrenergic agonist. Journal of Animal Science, 94(2), 581-591. doi:10.2527/jas2015-9824Angus crossbred steers (n = 40; 563 +/- 44 kg) were used to examine the effects of handling method and fat thickness on the blood chemistry and physiology of market steers. Steers were blocked by backfat (BF) thickness and were randomly assigned to treatment groups: low-stress handling (LSH) and aggressive handling (AH). Cattle were then ran-domly assigned to one of 5 blocks containing 4 steers from the LSH and AH treatments. Steers in the LSH treatment were walked and AH cattle were run through a course of 1,540 m. Blood samples were obtained via jugular venipuncture before handling (BASE), at 770 m (LAP1), at 1,540 m (LAP2), and at1 h (1H) and 2 h (2H) after finishing the course. Blood samples were analyzed for plasma lactate (LAC), creatinine kinase (CK), base excess (BE), blood pH (pH), serum cortisol (CORT) concentrations, and venous carbon dioxide (PvCO2) and oxygen (PvO2) pressures. Heart rate (HR), respiratory rate (RR), and rectal temperature (TEMP) were measured at the same intervals. Cattle in the AH treatment had greater (P 0.14). Blood pH in AH cattle was decreased compared with that in LSH cattle (P 0.13) at BASE, 1H, or 2H. Heart rate and TEMP were increased in AH cattle compared to LSH (P > 0.01). Serum cortisol was increased (P < 0.05) in AH compared to that in LSH cattle at LAP1 (87.5 vs. 58.9 nmol/ L), LAP2 (144.4 vs. 93.1 nmol/ L), and 1H (113.5 vs. 53.1 nmol/ L). Although RR was not differ-ent between LSH and AH, PvCO2 was decreased in AH compared to that in LSH (P < 0.05) at LAP2 (30.6 vs. 39.3 mmHg) and PvO2 was increased at LAP1 (42.7 vs. 33.5 mmHg) and at LAP2 (51.5 vs. 36.6 mmHg). Lactate was increased in AH cattle in the thicker BF group at 1H (P < 0.05), and blood pH was decreased at LAP1, LAP2, and 1H (P < 0.05) compared to the thinner BF cohorts. Four AH steers became exhausted (EXH) and did not complete the course. Increased CK, decreased PvCO2, and muscle tremors occurred in EXH steers compared to non-exhausted AH cohorts. Results of this study show that AH causes physiologic and blood chemistry changes in steers, which can be potentially detrimental to cattle, emphasizing the need for lowstress handling practices

Anomalies in T cell function are associated with individuals at risk of mycobacterium abscessus complex infection

The increasing global incidence and prevalence of non-tuberculous mycobacteria (NTM) infection is of growing concern. New evidence of person-to-person transmission of multidrug-resistant NTM adds to the global concern. The reason why certain individuals are at risk of NTM infections is unknown. Using high definition flow cytometry, we studied the immune profiles of two groups that are at risk of Mycobacterium abscessus complex infection and matched controls. The first group was cystic fibrosis (CF) patients and the second group was elderly individuals. CF individuals with active M. abscessus complex infection or a history of M. abscessus complex infection exhibited a unique surface T cell phenotype with a marked global deficiency in TNFa production during mitogen stimulation. Importantly, immune-based signatures were identified that appeared to predict at baseline the subset of CF individuals who were at risk of M. abscessus complex infection. In contrast, elderly individuals with M. abscessus complex infection exhibited a separate T cell phenotype underlined by the presence of exhaustion markers and dysregulation in type 1 cytokine release during mitogen stimulation. Collectively, these data suggest an association between T cell signatures and individuals at risk of M. abscessus complex infection, however, validation of these immune anomalies as robust biomarkers will require analysis on larger patient cohorts

Length of the weaning period affects postweaning growth, health, and carcass merit of ranch-direct beef calves weaned during the fall

Bovine respiratory disease (BRD) is the most economically devastating feedlot disease. Risk factors associated with incidence of BRD include (1) stress associated with maternal separation, (2) stress associated with introduction to an unfamiliar environment, (3) poor intake associated with introduction of novel feedstuffs into the animal\u27s diet, (4) exposure to novel pathogens upon transport to a feeding facility and commingling with unfamiliar cattle, (5) inappropriately administered respiratory disease vaccination programs, and (6) poor response to respiratory disease vaccination programs. Management practices that are collectively referred to as preconditioning are thought to minimize damage to the beef carcass from the BRD complex. Preconditioning management reduces the aforementioned risk factors for respiratory disease by (1) using a relatively long ranch-of-origin weaning period following maternal separation, (2) exposing calves to concentrate-type feedstuffs, and (3) producing heightened resistance to respiratory disease-causing organisms through a preweaning vaccination program. The effectiveness of such programs for preserving animal performance is highly touted by certain segments of the beef industry. Ranch-of-origin weaning periods of up to 60 days are suggested for preconditioning beef calves prior to sale; however, optimal length of the ranch-of-origin weaning period has not been determined experimentally. The objective of this study was to test the validity of beef industry assumptions about appropriate length of ranch-of-origin weaning periods for calves aged 160 to 220 days and weaned during the fall

Lifespan extension and the doctrine of double effect

Recent developments in biogerontology—the study of the biology of ageing—suggest that it may eventually be possible to intervene in the human ageing process. This, in turn, offers the prospect of significantly postponing the onset of age-related diseases. The biogerontological project, however, has met with strong resistance, especially by deontologists. They consider the act of intervening in the ageing process impermissible on the grounds that it would (most probably) bring about an extended maximum lifespan—a state of affairs that they deem intrinsically bad. In a bid to convince their deontological opponents of the permissibility of this act, proponents of biogerontology invoke an argument which is grounded in the doctrine of double effect. Surprisingly, their argument, which we refer to as the ‘double effect argument’, has gone unnoticed. This article exposes and critically evaluates this ‘double effect argument’. To this end, we first review a series of excerpts from the ethical debate on biogerontology in order to substantiate the presence of double effect reasoning. Next, we attempt to determine the role that the ‘double effect argument’ is meant to fulfil within this debate. Finally, we assess whether the act of intervening in ageing actually can be justified using double effect reasoning