186 research outputs found
Reconciling Horse Welfare, Worker Safety, and Public Expectations: Horse Event Incident Management Systems in Australia
Human-horse interactions have a rich tradition and can be highly rewarding, particularly within sport and recreation pursuits, but they can also be dangerous or even life-threatening. In parallel, sport and recreation pursuits involving animals, including horses, are facing an increased level of public scrutiny in relation to the use of animals for these purposes. However, the challenge lies with event organisers to reconcile the expectations of the public, the need to meet legal requirements to reduce or eliminate risks to paid and volunteer workers, and address horse welfare. In this article we explore incident management at horse events as an example of a situation where volunteers and horses can be placed at risk during a rescue. We introduce large animal rescue skills as a solution to improving worker safety and improving horse welfare outcomes. Whilst there are government and horse industry initiatives to improve safety and address animal welfare, there remains a pressing need to invest in a strong communication plan which will improve the safety of workplaces in which humans and horses interact
Reconciling Horse Welfare, Worker Safety, and Public Expectations: Horse Event Incident Management Systems in Australia
Human-horse interactions have a rich tradition and can be highly rewarding, particularly within sport and recreation pursuits, but they can also be dangerous or even life-threatening. In parallel, sport and recreation pursuits involving animals, including horses, are facing an increased level of public scrutiny in relation to the use of animals for these purposes. However, the challenge lies with event organisers to reconcile the expectations of the public, the need to meet legal requirements to reduce or eliminate risks to paid and volunteer workers, and address horse welfare. In this article we explore incident management at horse events as an example of a situation where volunteers and horses can be placed at risk during a rescue. We introduce large animal rescue skills as a solution to improving worker safety and improving horse welfare outcomes. Whilst there are government and horse industry initiatives to improve safety and address animal welfare, there remains a pressing need to invest in a strong communication plan which will improve the safety of workplaces in which humans and horses interact
Thoroughbred Racehorse Welfare through the Lens of âSocial License to OperateâWith an Emphasis on a U.S. Perspective
This review addresses the question of whether Thoroughbred horse racing is sustainable in the context of current social values. A recently acknowledged framework, known as âSocial License to Operateâ (SLO), provides us with a lens through which to view and assess racehorse welfare. In multiple surveys of the general public, the horse owning public, and university students, the primary topics of concern regarding Thoroughbred racing show considerable concordance: concern about catastrophic injuriesâparticularly as related to track surfaces, concern over the racing of two-year-olds, whip use by jockeys, drug/medication policies, and aftercare opportunities for retired Thoroughbred racehorses. Legitimacy of an industry, consent from industry stakeholders, and trust between the community players, are all essential to have and maintain SLO. In the current era of 24/7 global media access, and the proliferation of social media providing an interactive platform for all interested parties, a dramatic change has occurred in commentary related to racehorse welfare concerns. The situation at Santa Anita (California, USA) from late December 2018 through mid-November 2019 demonstrated just how tenuous the SLO for horse racing is. This article will provide a brief review of what âSocial License to Operateâ is, along with a brief literature review of five of the areas of primary concern voiced by stakeholders
Enhancement of Otolith Specific Ocular Responses Using Vestibular Stochastic Resonance
Introduction: Astronauts experience disturbances in sensorimotor function after spaceflight during the initial introduction to a gravitational environment, especially after long-duration missions. Our goal is to develop a countermeasure based on vestibular stochastic resonance (SR) that could improve central interpretation of vestibular input and mitigate these risks. SR is a mechanism by which noise can assist and enhance the response of neural systems to relevant, imperceptible sensory signals. We have previously shown that imperceptible electrical stimulation of the vestibular system enhances balance performance while standing on an unstable surface. Methods: Eye movement data were collected from 10 subjects during variable radius centrifugation (VRC). Subjects performed 11 trials of VRC that provided equivalent tilt stimuli from otolith and other graviceptor input without the normal concordant canal cues. Bipolar stochastic electrical stimulation, in the range of 0-1500 microamperes, was applied to the vestibular system using a constant current stimulator through electrodes placed over the mastoid process behind the ears. In the VRC paradigm, subjects were accelerated to 216 deg./s. After the subjects no longer sensed rotation, the chair oscillated along a track at 0.1 Hz to provide tilt stimuli of 10 deg. Eye movements were recorded for 6 cycles while subjects fixated on a target in darkness. Ocular counter roll (OCR) movement was calculated from the eye movement data during periods of chair oscillations. Results: Preliminary analysis of the data revealed that 9 of 10 subjects showed an average increase of 28% in the magnitude of OCR responses to the equivalent tilt stimuli while experiencing vestibular SR. The signal amplitude at which performance was maximized was in the range of 100-900 microamperes. Discussion: These results indicate that stochastic electrical stimulation of the vestibular system can improve otolith specific responses. This will have a significant impact on development of vestibular SR delivery systems to aid recovery of function in astronauts after long-duration spaceflight or in people with balance disorders
Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections
AbstractAcute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N=182) vs linezolid (N=171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48â72h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p=0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment
Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function
Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [± standard error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 ± 0.02 ΌM versus 6.4 ± 1.2 ΌM). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC50 in 84% of tedizolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies
Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohnâs Disease
Inflammatory bowel disease (IBD), clinically defined as Crohnâs disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents â„ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0â18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohnâs Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7â10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohnâs Disease
Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis
Herein, we report the first identification of biallelic-inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function. ALPI mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patientsâ biopsies, and ALPI activity was undetectable in ALPI-deficient patient\u27s stool. Our findings highlight the crucial role of ALPI in regulating hostâmicrobiota interactions and restraining host inflammatory responses. These results indicate that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders
Nitroxyl (HNO) Stimulates Soluble Guanylyl Cyclase to Suppress Cardiomyocyte Hypertrophy and Superoxide Generation
Background: New therapeutic targets for cardiac hypertrophy, an independent risk factor for heart failure and death, are essential. HNO is a novel redox sibling of NON attracting considerable attention for the treatment of cardiovascular disorders, eliciting cGMP-dependent vasodilatation yet cGMP-independent positive inotropy. The impact of HNO on cardiac hypertrophy (which is negatively regulated by cGMP) however has not been investigated. Methods: Neonatal rat cardiomyocytes were incubated with angiotensin II (Ang II) in the presence and absence of the HNO donor Angeliâs salt (sodium trioxodinitrate) or B-type natriuretic peptide, BNP (all 1 mmol/L). Hypertrophic responses and its triggers, as well as cGMP signaling, were determined. Results: We now demonstrate that Angeliâs salt inhibits Ang II-induced hypertrophic responses in cardiomyocytes, including increases in cardiomyocyte size, de novo protein synthesis and b-myosin heavy chain expression. Angeliâs salt also suppresses Ang II induction of key triggers of the cardiomyocyte hypertrophic response, including NADPH oxidase (on both Nox2 expression and superoxide generation), as well as p38 mitogen-activated protein kinase (p38MAPK). The antihypertrophic, superoxide-suppressing and cGMP-elevating effects of Angeliâs salt were mimicked by BNP. We also demonstrate that the effects of Angeliâs salt are specifically mediated by HNO (with no role for NON or nitrite), with subsequent activation of cardiomyocyte soluble guanylyl cyclase (sGC) and cGMP signaling (on both cGMP-dependen
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