Proposing the VetCompass clinical grading tool for heat-related illness in dogs

Heat-related illness is a potentially fatal condition in dogs. Rapid and accurate recognition of the severity can improve clinical management in affected dogs and lead to better outcomes. This study explored retrospective VetCompass veterinary clinical records to investigate the clinical signs recorded for dogs presenting with heat-related illness to primary-care veterinary practice from 2016 to 2018. The relative risk of death associated with these clinical signs was reported and used to develop a novel clinical grading tool. From the clinical records of 856 heat-related illness events, the most frequently recorded clinical signs were respiratory changes (68.73%) and lethargy (47.79%). The clinical signs with the highest relative risk of death were neurological dysfunction, gastrointestinal haemorrhage and bleeding disorders. The novel VetCompass Clinical Grading Tool for Heat-Related Illness in dogs defines three grades: mild (altered respiration, lethargy), moderate (gastrointestinal signs, a single seizure, episodic collapse) and severe (neurological dysfunction, gastrointestinal haemorrhage, bleeding disorders). This novel grading tool offers a simple, evidence-based device to improve recognition of heat-related illness in dogs and promote improved decision-making for earlier interventions such as cooling and hospitalisation. This could improve outcomes and protect the welfare of dogs in the face of rising global temperatures

Randomised controlled feasibility trial of a web-based weight management intervention with nurse support for obese patients in primary care

<b>Background</b><p></p> There is a need for cost-effective weight management interventions that primary care can deliver to reduce the morbidity caused by obesity. Automated web-based interventions might provide a solution, but evidence suggests that they may be ineffective without additional human support. The main aim of this study was to carry out a feasibility trial of a web-based weight management intervention in primary care, comparing different levels of nurse support, to determine the optimal combination of web-based and personal support to be tested in a full trial.<p></p> <b>Methods</b><p></p> This was an individually randomised four arm parallel non-blinded trial, recruiting obese patients in primary care. Following online registration, patients were randomly allocated by the automated intervention to either usual care, the web-based intervention only, or the web-based intervention with either basic nurse support (3 sessions in 3 months) or regular nurse support (7 sessions in 6 months). The main outcome measure (intended as the primary outcome for the main trial) was weight loss in kg at 12 months. As this was a feasibility trial no statistical analyses were carried out, but we present means, confidence intervals and effect sizes for weight loss in each group, uptake and retention, and completion of intervention components and outcome measures.<p></p> <b>Results</b><p></p> All randomised patients were included in the weight loss analyses (using Last Observation Carried Forward). At 12 months mean weight loss was: usual care group (n = 43) 2.44 kg; web-based only group (n = 45) 2.30 kg; basic nurse support group (n = 44) 4.31 kg; regular nurse support group (n = 47) 2.50 kg. Intervention effect sizes compared with usual care were: d = 0.01 web-based; d = 0.34 basic nurse support; d = 0.02 regular nurse support. Two practices deviated from protocol by providing considerable weight management support to their usual care patients.<p></p> <b>Conclusions</b><p></p> This study demonstrated the feasibility of delivering a web-based weight management intervention supported by practice nurses in primary care, and suggests that the combination of the web-based intervention with basic nurse support could provide an effective solution to weight management support in a primary care context

The Expression of Inflammatory Mediators in Bladder Pain Syndrome.

Background: Bladder pain syndrome (BPS) pathology is poorly understood. Treatment strategies are empirical, with limited efficacy, and affected patients have diminished quality of life. Objective: We examined the hypothesis that inflammatory mediators within the bladder contribute to BPS pathology. Design, setting, and participants: Fifteen women with BPS and 15 women with stress urinary incontinence without bladder pain were recruited from Cork University Maternity Hospital from October 2011 to October 2012. During cystoscopy, 5-mm bladder biopsies were taken and processed for gene expression analysis. The effect of the identified genes was tested in laboratory animals. Outcome measures and statistical analysis: We studied the expression of 96 inflammation-related genes in diseased and healthy bladders. We measured the correlation between genes and patient clinical profiles using the Pearson correlation coefficient. Results and limitations: Analysis revealed 15 differentially expressed genes, confirmed in a replication study. FGF7 and CCL21 correlated significantly with clinical outcomes. Intravesical CCL21 instillation in rats caused increased bladder excitability and increased c-fos activity in spinal cord neurons. CCL21 atypical receptor knockout mice showed significantly more c-fos upon bladder stimulation with CCL21 than wild-type littermates. There was no change in FGF7-treated animals. The variability in patient samples presented as the main limitation. We used principal component analysis to identify similarities within the patient group. Conclusions: Our study identified two biologically relevant inflammatory mediators in BPS and demonstrated an increase in nociceptive signalling with CCL21. Manipulation of this ligand is a potential new therapeutic strategy for BPS. Patient summary: We compared gene expression in bladder biopsies of patients with bladder pain syndrome (BPS) and controls without pain and identified two genes that were increased in BPS patients and correlated with clinical profiles. We tested the effect of these genes in laboratory animals, confirming their role in bladder pain. Manipulating these genes in BPS is a potential treatment strategy

Transplantation of canine olfactory ensheathing cells producing chondroitinase ABC promotes chondroitin sulphate proteoglycan digestion and axonal sprouting following spinal cord injury

Olfactory ensheathing cell (OEC) transplantation is a promising strategy for treating spinal cord injury (SCI), as has been demonstrated in experimental SCI models and naturally occurring SCI in dogs. However, the presence of chondroitin sulphate proteoglycans within the extracellular matrix of the glial scar can inhibit efficient axonal repair and limit the therapeutic potential of OECs. Here we have used lentiviral vectors to genetically modify canine OECs to continuously deliver mammalian chondroitinase ABC at the lesion site in order to degrade the inhibitory chondroitin sulphate proteoglycans in a rodent model of spinal cord injury. We demonstrate that these chondroitinase producing canine OECs survived at 4 weeks following transplantation into the spinal cord lesion and effectively digested chondroitin sulphate proteoglycans at the site of injury. There was evidence of sprouting within the corticospinal tract rostral to the lesion and an increase in the number of corticospinal axons caudal to the lesion, suggestive of axonal regeneration. Our results indicate that delivery of the chondroitinase enzyme can be achieved with the genetically modified OECs to increase axon growth following SCI. The combination of these two promising approaches is a potential strategy for promoting neural regeneration following SCI in veterinary practice and human patients

Risk factors for severe and fatal heat-related illness in UK dogs—a VetCompass study

Heat-related illness (HRI) is predicted to increase in dogs due to rising global temperatures. This study evaluated retrospective VetCompass veterinary clinical records to explore geographical variability and ambient conditions associated with HRI events in UK dogs, and report the intrinsic (canine) and extrinsic (location, trigger, ambient weather) risk factors for severe disease and fatal outcome in dogs affected by HRI. Dogs living in London had the greatest odds for developing HRI compared with dogs living in the North West (OR 1.9, 95% CI 1.31–2.74). The median ambient temperature on days of HRI events was 16.9 °C. For dogs with HRI, age, bodyweight and trigger were risk factors associated with severe disease. Age, skull shape and clinical grade of HRI presentation were associated with a fatal outcome. Whilst the majority of HRI events overall were triggered by exertion, the risk of severe disease was greater in situations where dogs could not escape the heat source (vehicular confinement), and the risk of death in HRI cases was greater for those dogs with reduced capacity to thermoregulate (older and brachycephalic dogs). These results highlight the need for better owner awareness of the factors that increase the risk of severe and fatal HRI, as a first stage in protecting canine welfare in the face of rising global temperatures

Refining rodent models of spinal cord injury.

This report was produced by an Expert Working Group (EWG) consisting of UK-based researchers, veterinarians and regulators of animal experiments with specialist knowledge of the use of animal models of spinal cord injury (SCI). It aims to facilitate the implementation of the Three Rs (Replacement, Reduction and Refinement), with an emphasis on refinement. Specific animal welfare issues were identified and discussed, and practical measures proposed, with the aim of reducing animal use and suffering, reducing experimental variability, and increasing translatability within this critically important research field

The soft mechanical signature of glial scars in the central nervous system

Injury to the central nervous system (CNS) alters the molecular and cellular composition of neural tissue and leads to glial scarring, which inhibits the regrowth of damaged axons. Mammalian glial scars supposedly form a chemical and mechanical barrier to neuronal regeneration. While tremendous effort has been devoted to identifying molecular characteristics of the scar, very little is known about its mechanical properties. Here we characterize spatiotemporal changes of the elastic stiffness of the injured rat neocortex and spinal cord at 1.5 and three weeks post-injury using atomic force microscopy. In contrast to scars in other mammalian tissues, CNS tissue significantly softens after injury. Expression levels of glial intermediate filaments (GFAP, vimentin) and extracellular matrix components (laminin, collagen IV) correlate with tissue softening. As tissue stiffness is a regulator of neuronal growth, our results may help to understand why mammalian neurons do not regenerate after injury.We are grateful for financial support by the Herchel Smith Foundation and Wellcome Trust-MIT Fellowships to E.M., an EMBO Long-Term Fellowship (ALTF 1263-2015; European Commission FP7 (Marie Curie Actions, LTFCOFUND2013, GA-2013- 609409)) to I.P.W., the German National Academic Foundation (Scholarship to D.E.K.) and the UK Medical Research Council (Career Development Award G1100312/1 to K.F.)

Clinician-facilitated physical activity intervention versus pulmonary rehabilitation for improving physical activity in COPD: a feasibility study

Pulmonary rehabilitation (PR) may not suit all individuals with chronic obstructive pulmonary disease (COPD) and may not result in increased physical activity. Higher levels of physical activity are associated with reduced mortality and morbidity. The aim of this study was to assess the feasibility of conducting a trial to investigate the effectiveness of a clinician-facilitated physical activity intervention (PAI) versus PR in improving physical activity in patients with COPD referred to PR. In this randomised controlled mixed methods feasibility study, all patients referred to PR who were eligible and willing were assessed at baseline and then randomised to the PAI or to PR. The assessments were repeated post-intervention and at 3-month follow-up. The main outcome was step count measured by Actigraph. Semi-structured interviews were conducted post-intervention. The N = 50 patients; mean (SD) age, 64.1(8.6) years, 24M were recruited and randomised; N = 23 (PAI) and n = 26 (PR): one patient was excluded from the analysis as that person did not meet the GOLD diagnostic criteria. Key feasibility criteria were met; recruitment was 11%, dropouts in PAI were 26% (n = 6) and 50% (n = 13/26) PR. Participants in both groups experienced a range of health benefits from their respective programmes. The PAI appears to be effective in increasing step counts in people with COPD: mean change (standard deviation) [confidence interval] for the PAI group was 972.0(3230.3)[–1080.3 to 3024.4], n = 12 and 4.3(662.7)[-440.9 to 449.5], n = 11 for the PR group. The PAI met all domains of fidelity. This study provides key information to inform a future-randomised controlled trial in physical activity

Comparative genomics of isolates of a pseudomonas aeruginosa epidemic strain associated with chronic lung infections of cystic fibrosis patients

Pseudomonas aeruginosa is the main cause of fatal chronic lung infections among individuals suffering from cystic fibrosis (CF). During the past 15 years, particularly aggressive strains transmitted among CF patients have been identified, initially in Europe and more recently in Canada. The aim of this study was to generate high-quality genome sequences for 7 isolates of the Liverpool epidemic strain (LES) from the United Kingdom and Canada representing different virulence characteristics in order to: (1) associate comparative genomics results with virulence factor variability and (2) identify genomic and/or phenotypic divergence between the two geographical locations. We performed phenotypic characterization of pyoverdine, pyocyanin, motility, biofilm formation, and proteolytic activity. We also assessed the degree of virulence using the Dictyostelium discoideum amoeba model. Comparative genomics analysis revealed at least one large deletion (40-50 kb) in 6 out of the 7 isolates compared to the reference genome of LESB58. These deletions correspond to prophages, which are known to increase the competitiveness of LESB58 in chronic lung infection. We also identified 308 non-synonymous polymorphisms, of which 28 were associated with virulence determinants and 52 with regulatory proteins. At the phenotypic level, isolates showed extensive variability in production of pyocyanin, pyoverdine, proteases and biofilm as well as in swimming motility, while being predominantly avirulent in the amoeba model. Isolates from the two continents were phylogenetically and phenotypically undistinguishable. Most regulatory mutations were isolate-specific and 29% of them were predicted to have high functional impact. Therefore, polymorphism in regulatory genes is likely to be an important basis for phenotypic diversity among LES isolates, which in turn might contribute to this strain's adaptability to varying conditions in the CF lung

Chondroitinase and Growth Factors Enhance Activation and Oligodendrocyte Differentiation of Endogenous Neural Precursor Cells after Spinal Cord Injury

The adult spinal cord harbours a population of multipotent neural precursor cells (NPCs) with the ability to replace oligodendrocytes. However, despite this capacity, proliferation and endogenous remyelination is severely limited after spinal cord injury (SCI). In the post-traumatic microenvironment following SCI, endogenous spinal NPCs mainly differentiate into astrocytes which could contribute to astrogliosis that exacerbate the outcomes of SCI. These findings emphasize a key role for the post-SCI niche in modulating the behaviour of spinal NPCs after SCI. We recently reported that chondroitin sulphate proteoglycans (CSPGs) in the glial scar restrict the outcomes of NPC transplantation in SCI by reducing the survival, migration and integration of engrafted NPCs within the injured spinal cord. These inhibitory effects were attenuated by administration of chondroitinase (ChABC) prior to NPC transplantation. Here, in a rat model of compressive SCI, we show that perturbing CSPGs by ChABC in combination with sustained infusion of growth factors (EGF, bFGF and PDGF-AA) optimize the activation and oligodendroglial differentiation of spinal NPCs after injury. Four days following SCI, we intrathecally delivered ChABC and/or GFs for seven days. We performed BrdU incorporation to label proliferating cells during the treatment period after SCI. This strategy increased the proliferation of spinal NPCs, reduced the generation of new astrocytes and promoted their differentiation along an oligodendroglial lineage, a prerequisite for remyelination. Furthermore, ChABC and GF treatments enhanced the response of non-neural cells by increasing the generation of new vascular endothelial cells and decreasing the number of proliferating macrophages/microglia after SCI. In conclusions, our data strongly suggest that optimization of the behaviour of endogenous spinal NPCs after SCI is critical not only to promote endogenous oligodendrocyte replacement, but also to reverse the otherwise detrimental effects of their activation into astrocytes which could negatively influence the repair process after SCI