Construction and analysis of causally dynamic hybrid bond graphs

Engineering systems are frequently abstracted to models with discontinuous behaviour (such as a switch or contact), and a hybrid model is one which contains continuous and discontinuous behaviours. Bond graphs are an established physical modelling method, but there are several methods for constructing switched or ‘hybrid’ bond graphs, developed for either qualitative ‘structural’ analysis or efficient numerical simulation of engineering systems. This article proposes a general hybrid bond graph suitable for both. The controlled junction is adopted as an intuitive way of modelling a discontinuity in the model structure. This element gives rise to ‘dynamic causality’ that is facilitated by a new bond graph notation. From this model, the junction structure and state equations are derived and compared to those obtained by existing methods. The proposed model includes all possible modes of operation and can be represented by a single set of equations. The controlled junctions manifest as Boolean variables in the matrices of coefficients. The method is more compact and intuitive than existing methods and dispenses with the need to derive various modes of operation from a given reference representation. Hence, a method has been developed, which can reach common usage and form a platform for further study

Prevalence of Disorders Recorded in Dogs Attending Primary-Care Veterinary Practices in England

Purebred dog health is thought to be compromised by an increasing occurence of inherited diseases but inadequate prevalence data on common disorders have hampered efforts to prioritise health reforms. Analysis of primary veterinary practice clinical data has been proposed for reliable estimation of disorder prevalence in dogs. Electronic patient record (EPR) data were collected on 148,741 dogs attending 93 clinics across central and south-eastern England. Analysis in detail of a random sample of EPRs relating to 3,884 dogs from 89 clinics identified the most frequently recorded disorders as otitis externa (prevalence 10.2%, 95% CI: 9.1-11.3), periodontal disease (9.3%, 95% CI: 8.3-10.3) and anal sac impaction (7.1%, 95% CI: 6.1-8.1). Using syndromic classification, the most prevalent body location affected was the head-and-neck (32.8%, 95% CI: 30.7-34.9), the most prevalent organ system affected was the integument (36.3%, 95% CI: 33.9-38.6) and the most prevalent pathophysiologic process diagnosed was inflammation (32.1%, 95% CI: 29.8-34.3). Among the twenty most-frequently recorded disorders, purebred dogs had a significantly higher prevalence compared with crossbreds for three: otitis externa (P = 0.001), obesity (P = 0.006) and skin mass lesion (P = 0.033), and popular breeds differed significantly from each other in their prevalence for five: periodontal disease (P = 0.002), overgrown nails (P = 0.004), degenerative joint disease (P = 0.005), obesity (P = 0.001) and lipoma (P = 0.003). These results fill a crucial data gap in disorder prevalence information and assist with disorder prioritisation. The results suggest that, for maximal impact, breeding reforms should target commonly-diagnosed complex disorders that are amenable to genetic improvement and should place special focus on at-risk breeds. Future studies evaluating disorder severity and duration will augment the usefulness of the disorder prevalence information reported herein

An evidence-based decision assistance model for predicting training outcome in juvenile guide dogs

Working dog organisations, such as Guide Dogs, need to regularly assess the behaviour of the dogs they train. In this study we developed a questionnaire-style behaviour assessment completed by training supervisors of juvenile guide dogs aged 5, 8 and 12 months old (n = 1,401), and evaluated aspects of its reliability and validity. Specifically, internal reliability, temporal consistency, construct validity, predictive criterion validity (comparing against later training outcome) and concurrent criterion validity (comparing against a standardised behaviour test) were evaluated. Thirty-nine questions were sourced either from previously published literature or created to meet requirements identified via Guide Dogs staff surveys and staff feedback. Internal reliability analyses revealed seven reliable and interpretable trait scales named according to the questions within them as: Adaptability; Body Sensitivity; Distractibility; Excitability; General Anxiety; Trainability and Stair Anxiety. Intra-individual temporal consistency of the scale scores between 5±8, 8±12 and 5±12 months was high. All scales excepting Body Sensitivity showed some degree of concurrent criterion validity. Predictive criterion validity was supported for all seven scales, since associations were found with training outcome, at at-least one age. Thresholds of z-scores on the scales were identified that were able to distinguish later training outcome by identifying 8.4% of all dogs withdrawn for behaviour and 8.5% of all qualified dogs, with 84% and 85% specificity. The questionnaire assessment was reliable and could detect traits that are consistent within individuals over time, despite juvenile dogs undergoing development during the study period. By applying thresholds to scores produced from the questionnaire this assessment could prove to be a highly valuable decision-making tool for Guide Dogs. This is the first questionnaire-style assessment of juvenile dogs that has shown value in predicting the training outcome of individual working dogs

From Africa to Europe and back: refugia and range shifts cause high genetic differentiation in the Marbled White butterfly Melanargia galathea

<p>Abstract</p> <p>Background</p> <p>The glacial-interglacial oscillations caused severe range modifications of biota. Thermophilic species became extinct in the North and survived in southern retreats, e.g. the Mediterranean Basin. These repeated extinction and (re)colonisation events led to long-term isolation and intermixing of populations and thus resulted in strong genetic imprints in many European species therefore being composed of several genetic lineages. To better understand these cycles of repeated expansion and retraction, we selected the Marbled White butterfly <it>Melanargia galathea</it>. Fourty-one populations scattered over Europe and the Maghreb and one population of the sibling taxon <it>M. lachesis </it>were analysed using allozyme electrophoresis.</p> <p>Results</p> <p>We obtained seven distinct lineages applying neighbour joining and STRUCTURE analyses: (i) Morocco, (ii) Tunisia, (iii) Sicily, (iv) Italy and southern France, (v) eastern Balkans extending to Central Europe, (vi) western Balkans with western Carpathian Basin as well as (vii) south-western Alps. The hierarchy of these splits is well matching the chronology of glacial and interglacial cycles since the Günz ice age starting with an initial split between the <it>galathea </it>group in North Africa and the <it>lachesis </it>group in Iberia. These genetic structures were compared with past distribution patterns during the last glacial stage calculated with distribution models.</p> <p>Conclusions</p> <p>Both methods suggest climatically suitable areas in the Maghreb and the southern European peninsulas with distinct refugia during the last glacial period and underpin strong range expansions to the North during the Postglacial. However, the allozyme patterns reveal biogeographical structures not detected by distribution modelling as two distinct refugia in the Maghreb, two or more distinct refugia at the Balkans and a close link between the eastern Maghreb and Sicily. Furthermore, the genetically highly diverse western Maghreb might have acted as source or speciation centre of this taxon, while the eastern, genetically impoverished Maghreb population might result from a relatively recent recolonisation from Europe via Sicily.</p

A Tale of Switched Functions: From Cyclooxygenase Inhibition to M-Channel Modulation in New Diphenylamine Derivatives

Cyclooxygenase (COX) enzymes are molecular targets of nonsteroidal anti-inflammatory drugs (NSAIDs), the most used medication worldwide. However, the COX enzymes are not the sole molecular targets of NSAIDs. Recently, we showed that two NSAIDs, diclofenac and meclofenamate, also act as openers of Kv7.2/3 K+ channels underlying the neuronal M-current. Here we designed new derivatives of diphenylamine carboxylate to dissociate the M-channel opener property from COX inhibition. The carboxylate moiety was derivatized into amides or esters and linked to various alkyl and ether chains. Powerful M-channel openers were generated, provided that the diphenylamine moiety and a terminal hydroxyl group are preserved. In transfected CHO cells, they activated recombinant Kv7.2/3 K+ channels, causing a hyperpolarizing shift of current activation as measured by whole-cell patch-clamp recording. In sensory dorsal root ganglion and hippocampal neurons, the openers hyperpolarized the membrane potential and robustly depressed evoked spike discharges. They also decreased hippocampal glutamate and GABA release by reducing the frequency of spontaneous excitatory and inhibitory post-synaptic currents. In vivo, the openers exhibited anti-convulsant activity, as measured in mice by the maximal electroshock seizure model. Conversion of the carboxylate function into amide abolished COX inhibition but preserved M-channel modulation. Remarkably, the very same template let us generating potent M-channel blockers. Our results reveal a new and crucial determinant of NSAID-mediated COX inhibition. They also provide a structural framework for designing novel M-channel modulators, including openers and blockers

Conditionally reprogrammed primary airway epithelial cells maintain morphology, lineage and disease specific functional characteristics

© 2017 The Author(s). Current limitations to primary cell expansion led us to test whether airway epithelial cells derived from healthy children and those with asthma and cystic fibrosis (CF), co-cultured with an irradiated fibroblast feeder cell in F-medium containing 10 µM ROCK inhibitor could maintain their lineage during expansion and whether this is influenced by underlying disease status. Here, we show that conditionally reprogrammed airway epithelial cells (CRAECs) can be established from both healthy and diseased phenotypes. CRAECs can be expanded, cryopreserved and maintain phenotypes over at least 5 passages. Population doublings of CRAEC cultures were significantly greater than standard cultures, but maintained their lineage characteristics. CRAECs from all phenotypes were also capable of fully differentiating at air-liquid interface (ALI) and maintained disease specific characteristics including; defective CFTR channel function cultures and the inability to repair wounds. Our findings indicate that CRAECs derived from children maintain lineage, phenotypic and importantly disease-specific functional characteristics over a specified passage range

Social psychiatry and psychiatric epidemiology functional impairment among people with severe and enduring mental disorder in rural Ethiopia: a cross-sectional study

Purpose: Evidence regarding functional impairment in people with severe mental disorders (SMD) is sparse in low and middle-income countries. The aim of this study was to identify factors associated with functional impairment in people with enduring SMD in a rural African setting. Methods: A cross-sectional study was conducted at the baseline of a health service intervention trial. A total of 324 participants were recruited from an existing communityascertained cohort of people with SMD (n= 218), and attendees at the Butajira General Hospital psychiatric clinic (n= 106). Inclusion criteria defined people with SMD who had ongoing need for care: those who were on psychotropic medication, currently symptomatic or had a relapse in the preceding two years. The World Health Organization Disability Assessment schedule (WHODAS-2.0) and the Butajira Functioning Scale (BFS), were used to assess functional impairment. Multivariable negative binomial regression models were fitted to investigate the association between demographic, socio-economic and clinical characteristics, and functional impairment. Results: Increasing age, being unmarried, rural residence, poorer socio-economic status, symptom severity, continuous course of illness, medication side effects and internalized stigma were associated with functional impairment across self reported and caregiver responses for both the WHODAS and the BFS. Diagnosis per se was not associated consistently with functional impairment. Conclusion: To optimize functioning in people with chronic SMD in this setting, services need to target residual symptoms, poverty, medication side effects and internalized stigma. Testing the impact of community interventions to promote recovery will be useful. Advocacy for more tolerable treatment options is warranted

“They accept me, because I was one of them”: formative qualitative research supporting the feasibility of peer-led outreach for people who use drugs in Dakar, Senegal

Background: Peer outreach harm reduction initiatives are being developed with and for people who use drugs in Dakar, Senegal. This is in response to growing injecting drug use across the West Africa region and linked emerging epidemics of HIV and hepatitis C. We undertook formative qualitative research to explore the feasibility and potential of peer outreach in this context and in particular how outreach could be linked to fostering community-level processes of change. Methods: We undertook a total of 44 semi-structured qualitative interviews. Thirty-four interviews were with people who used drugs (comprised of 25 participants who had injected at least once in their life) and included 11 peer educators who delivered “awareness-raising” harm reduction activities. We also interviewed 10 service providers involved in the planning and monitoring of peer outreach initiatives. We used thematic analysis to identify key characteristics of how peer-led outreach is being delivered, beneficiary need, and the nature of the social networks in which the awareness-raising activities operate. Results: Through interviews with peer educators, people who use drugs, and service providers, four main overlapping themes are identified as follows: peer educators as a bridge to responsibilization through awareness-raising activities, awareness-raising activities as an enactment of recovery, awareness raising through social network diffusion, and the contexts and constraints of peer outreach engagement through awareness-raising activities. Conclusions: The study results suggest that peer education is on a trajectory to develop into a central role for harm reduction interventions in Dakar, Senegal. This research shows how peer education is bound in processes of responsibilization and self-change, which link to varying possibilities for risk reduction or recovery. For peer education to achieve a range of significant goals, broader structural and system changes should be implemented in the region. We caution that without such changes, awareness-raising activities and the role of peer educators may instead become part of state- and agency-sponsored processes of seeking to responsibilize individuals for health and harm reduction

An exceptionally well-preserved skeleton of Palaeothentes from the Early Miocene of Patagonia, Argentina: new insights into the anatomy of extinct paucituberculatan marsupials

International audienc