Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Pigmentation plasticity enhances crypsis in larval newts: Associated metabolic cost and background choice behaviour

In heterogeneous environments, the capacity for colour change can be a valuable adaptation enhancing crypsis against predators. Alternatively, organisms might achieve concealment by evolving preferences for backgrounds that match their visual traits, thus avoiding the costs of plasticity. Here we examined the degree of plasticity in pigmentation of newt larvae (Lissotriton boscai) in relation to predation risk. Furthermore, we tested for associated metabolic costs and pigmentation-dependent background choice behaviour. Newt larvae expressed substantial changes in pigmentation so that light, high-reflecting environment induced depigmentation whereas dark, low-reflecting environment induced pigmentation in just three days of exposure. Induced pigmentation was completely reversible upon switching microhabitats. Predator cues, however, did not enhance cryptic phenotypes, suggesting that environmental albedo induces changes in pigmentation improving concealment regardless of the perceived predation risk. Metabolic rate was higher in heavily pigmented individuals from dark environments, indicating a high energetic requirement of pigmentation that could impose a constraint to larval camouflage in dim habitats. Finally, we found partial evidence for larvae selecting backgrounds matching their induced phenotypes. However, in the presence of predator cues, larvae increased the time spent in light environments, which may reflect a escape response towards shallow waters rather than an attempt at increasing crypsisFinancial support was provided by the Spanish Ministry of Science and Innovation (MICINN), Grant CGL2012-40044 to IGM, and by the Universidad Autónoma de Madrid, Short Stay Grant to NPC. Additional financial support was provided by the MICINN, Grant CGL2015-68670-R to NP

Little evidence for a selective advantage of armour-reduced threespined stickleback individuals in an invertebrate predation experiment

The repeated colonization of freshwater habitats by the ancestrally marine threespined stickleback Gasterosteus aculeatus has been associated with many instances of parallel reduction in armour traits, most notably number of lateral plates. The change in predation regime from marine systems, dominated by gape-limited predators such as piscivorous fishes, to freshwater habitats where grappling invertebrate predators such as insect larvae can dominate the predation regime, has been hypothesized as a driving force. Here we experimentally test the hypothesis that stickleback with reduced armour possess a selective advantage in the face of predation by invertebrates, using a natural population of stickleback that is highly polymorphic for armour traits and a common invertebrate predator from the same location. Our results provide no compelling evidence for selection in this particular predator–prey interaction. We suggest that the postulated selective advantage of low armour in the face of invertebrate predation may not be universal

Guiding principles for the development and application of solid-phase phosphorus adsorbents for freshwater ecosystems

While a diverse array of phosphorus (P)-adsorbent materials is currently available for application to freshwater aquatic systems, selection of the most appropriate P-adsorbents remains problematic. In particular, there has to be a close correspondence between attributes of the P-adsorbent, its field performance, and the management goals for treatment. These management goals may vary from a rapid reduction in dissolved P to address seasonal enrichments from internal loading, targeting external fluxes due to anthropogenic sources, or long term inactivation of internal P inventories contained within bottom sediments. It also remains a challenge to develop new methods and materials that are ecologically benign and cost-effective. We draw on evidence in the literature and the authors’ personal experiences in the field, to summarise the attributes of a range of P-adsorbent materials. We offer 'guiding principles' to support practical use of existing materials and outline key development needs for new materials

Clostridium difficile infection.

Infection of the colon with the Gram-positive bacterium Clostridium difficile is potentially life threatening, especially in elderly people and in patients who have dysbiosis of the gut microbiota following antimicrobial drug exposure. C. difficile is the leading cause of health-care-associated infective diarrhoea. The life cycle of C. difficile is influenced by antimicrobial agents, the host immune system, and the host microbiota and its associated metabolites. The primary mediators of inflammation in C. difficile infection (CDI) are large clostridial toxins, toxin A (TcdA) and toxin B (TcdB), and, in some bacterial strains, the binary toxin CDT. The toxins trigger a complex cascade of host cellular responses to cause diarrhoea, inflammation and tissue necrosis - the major symptoms of CDI. The factors responsible for the epidemic of some C. difficile strains are poorly understood. Recurrent infections are common and can be debilitating. Toxin detection for diagnosis is important for accurate epidemiological study, and for optimal management and prevention strategies. Infections are commonly treated with specific antimicrobial agents, but faecal microbiota transplants have shown promise for recurrent infections. Future biotherapies for C. difficile infections are likely to involve defined combinations of key gut microbiota

Using a psychosocial subgroup assignment to predict sickness absence in a working population with neck and back pain

<p>Abstract</p> <p>Background</p> <p>The overall objective was to evaluate the predictive validity of a subgroup classification based on the Swedish version of the MPI, the MPI-S, among gainfully employed workers with neck pain (NP) and/or low back pain (LBP) during a follow-up period of 18 and 36 months.</p> <p>Methods</p> <p>This is a prospective cohort study that is part of a larger longitudinal multi-centre study entitled Work and Health in the Process and Engineering Industries (AHA). The attempt was to classify individuals at risk for developing chronic disabling NP and LBP. This is the first study using the MPI-questionnaire in a working population with NP and LBP.</p> <p>Results</p> <p>Dysfunctional individuals (DYS) demonstrated more statistically significant sickness absence compared to adaptive copers (AC) after 36 months. DYS also had a threefold increase in the risk ratio of long-term sickness absence at 18 months. Interpersonally distressed (ID) subgroup showed overall more sickness absence compared to the AC subgroup at the 36-month follow-up and had a twofold increase in the risk ratio of long-term sickness absence at 18 months. There was a significant difference in bodily pain, mental and physical health for ID and DYS subgroups compared to the AC group at both follow-ups.</p> <p>Conclusions</p> <p>The present study shows that this multidimensional approach to the classification of individuals based on psychological and psychosocial characteristics can distinguish different groups in gainfully employed working population with NP/LBP. The results in this study confirm the predictive validity of the MPI-S subgroup classification system.</p

Development of the interRAI Pressure Ulcer Risk Scale (PURS) for use in long-term care and home care settings

<p>Abstract</p> <p>Background</p> <p>In long-term care (LTC) homes in the province of Ontario, implementation of the Minimum Data Set (MDS) assessment and The Braden Scale for predicting pressure ulcer risk were occurring simultaneously. The purpose of this study was, using available data sources, to develop a bedside MDS-based scale to identify individuals under care at various levels of risk for developing pressure ulcers in order to facilitate targeting risk factors for prevention.</p> <p>Methods</p> <p>Data for developing the interRAI Pressure Ulcer Risk Scale (interRAI PURS) were available from 2 Ontario sources: three LTC homes with 257 residents assessed during the same time frame with the MDS and Braden Scale for Predicting Pressure Sore Risk, and eighty-nine Ontario LTC homes with 12,896 residents with baseline/reassessment MDS data (median time 91 days), between 2005-2007. All assessments were done by trained clinical staff, and baseline assessments were restricted to those with no recorded pressure ulcer. MDS baseline/reassessment samples used in further testing included 13,062 patients of Ontario Complex Continuing Care Hospitals (CCC) and 73,183 Ontario long-stay home care (HC) clients.</p> <p>Results</p> <p>A data-informed Braden Scale cross-walk scale using MDS items was devised from the 3-facility dataset, and tested in the larger longitudinal LTC homes data for its association with a future new pressure ulcer, giving a c-statistic of 0.676. Informed by this, LTC homes data along with evidence from the clinical literature was used to create an alternate-form 7-item additive scale, the interRAI PURS, with good distributional characteristics and c-statistic of 0.708. Testing of the scale in CCC and HC longitudinal data showed strong association with development of a new pressure ulcer.</p> <p>Conclusions</p> <p>interRAI PURS differentiates risk of developing pressure ulcers among facility-based residents and home care recipients. As an output from an MDS assessment, it eliminates duplicated effort required for separate pressure ulcer risk scoring. Moreover, it can be done manually at the bedside during critical early days in an admission when the full MDS has yet to be completed. It can be calculated with established MDS instruments as well as with the newer interRAI suite instruments designed to follow persons across various care settings (interRAI Long-Term Care Facilities, interRAI Home Care, interRAI Palliative Care).</p

Validation of a maritime usability study with eye tracking data

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Evaluating Research and Impact: A Bibliometric Analysis of Research by the NIH/NIAID HIV/AIDS Clinical Trials Networks

Evaluative bibliometrics uses advanced techniques to assess the impact of scholarly work in the context of other scientific work and usually compares the relative scientific contributions of research groups or institutions. Using publications from the National Institute of Allergy and Infectious Diseases (NIAID) HIV/AIDS extramural clinical trials networks, we assessed the presence, performance, and impact of papers published in 2006–2008. Through this approach, we sought to expand traditional bibliometric analyses beyond citation counts to include normative comparisons across journals and fields, visualization of co-authorship across the networks, and assess the inclusion of publications in reviews and syntheses. Specifically, we examined the research output of the networks in terms of the a) presence of papers in the scientific journal hierarchy ranked on the basis of journal influence measures, b) performance of publications on traditional bibliometric measures, and c) impact of publications in comparisons with similar publications worldwide, adjusted for journals and fields. We also examined collaboration and interdisciplinarity across the initiative, through network analysis and modeling of co-authorship patterns. Finally, we explored the uptake of network produced publications in research reviews and syntheses. Overall, the results suggest the networks are producing highly recognized work, engaging in extensive interdisciplinary collaborations, and having an impact across several areas of HIV-related science. The strengths and limitations of the approach for evaluation and monitoring research initiatives are discussed