Patient preferences for stratified medicine in psoriasis: a discrete choice experiment.

BACKGROUND: New technologies have enabled the potential for stratified medicine in psoriasis. It is important to understand patients' preferences to enable the informed introduction of stratified medicine, which is likely to involve a number of individual tests that could be collated into a prescribing algorithm for biological drug selection to be used in clinical practice. OBJECTIVES: To quantify patient preferences for an algorithm-based approach to prescribing biologics ('biologic calculator') in psoriasis. METHODS: An online survey comprising a discrete choice experiment (DCE) was conducted to elicit the preferences of two purposive samples of adults living with psoriasis in the UK, identified from a psoriasis patient organization (Psoriasis Association) and an online panel provider (Dynata). Respondents chose between two biologic calculators and conventional prescribing described using five attributes: treatment delay; positive predictive value; negative predictive value; risk of infection; and cost saving to the National Health Service. Each participant selected their preferred alternative from six hypothetical choice sets. Additional data, including sociodemographic characteristics, were collected. Choice data were analysed using conditional logit and fully correlated random parameters logit models. RESULTS: Data from 212 respondents (67 from the Psoriasis Association and 145 from Dynata) were analysed. The signs of all estimated coefficients were consistent with a priori expectations. Respondents had a strong preference for a high predictive accuracy and avoiding serious infection, but there was evidence of systematic differences in preferences between the samples. CONCLUSIONS: This study indicates that individuals with psoriasis would value a biologic calculator and suggested that such a biologic calculator should have sufficient accuracy to predict future response and risk of serious infection from the biologic.

Counting niches: Abundance-by-trait patterns reveal niche partitioning in a Neotropical forest.

Tropical forests challenge us to understand biodiversity, as numerous seemingly similar species persist on only a handful of shared resources. Recent ecological theory posits that biodiversity is sustained by a combination of species differences reducing interspecific competition and species similarities increasing time to competitive exclusion. Together, these mechanisms counterintuitively predict that competing species should cluster by traits, in contrast with traditional expectations of trait overdispersion. Here, we show for the first time that trees in a tropical forest exhibit a clustering pattern. In a 50-ha plot on Barro Colorado Island in Panama, species abundances exhibit clusters in two traits connected to light capture strategy, suggesting that competition for light structures community composition. Notably, we find four clusters by maximum height, quantitatively supporting the classical grouping of Neotropical woody plants into shrubs, understory, midstory, and canopy layers.

Signs of stabilisation and stable coexistence.

Many empirical studies motivated by an interest in stable coexistence have quantified negative density dependence, negative frequency dependence, or negative plant-soil feedback, but the links between these empirical results and ecological theory are not straightforward. Here, we relate these analyses to theoretical conditions for stabilisation and stable coexistence in classical competition models. By stabilisation, we mean an excess of intraspecific competition relative to interspecific competition that inherently slows or even prevents competitive exclusion. We show that most, though not all, tests demonstrating negative density dependence, negative frequency dependence, and negative plant-soil feedback constitute sufficient conditions for stabilisation of two-species interactions if applied to data for per capita population growth rates of pairs of species, but none are necessary or sufficient conditions for stable coexistence of two species. Potential inferences are even more limited when communities involve more than two species, and when performance is measured at a single life stage or vital rate. We then discuss two approaches that enable stronger tests for stable coexistence-invasibility experiments and model parameterisation. The model parameterisation approach can be applied to typical density-dependence, frequency-dependence, and plant-soil feedback data sets, and generally enables better links with mechanisms and greater insights, as demonstrated by recent studies.

Beyond the fast-slow continuum: demographic dimensions structuring a tropical tree community.

Life-history theory posits that trade-offs between demographic rates constrain the range of viable life-history strategies. For coexisting tropical tree species, the best established demographic trade-off is the growth-survival trade-off. However, we know surprisingly little about co-variation of growth and survival with measures of reproduction. We analysed demographic rates from seed to adult of 282 co-occurring tropical tree and shrub species, including measures of reproduction and accounting for ontogeny. Besides the well-established fast-slow continuum, we identified a second major dimension of demographic variation: a trade-off between recruitment and seedling performance vs. growth and survival of larger individuals (≥ 1 cm dbh) corresponding to a 'stature-recruitment' axis. The two demographic dimensions were almost perfectly aligned with two independent trait dimensions (shade tolerance and size). Our results complement recent analyses of plant life-history variation at the global scale and reveal that demographic trade-offs along multiple axes act to structure local communities.

Decoupled dimensions of leaf economic and anti-herbivore defense strategies in a tropical canopy tree community.

Trade-offs among plant functional traits indicate diversity in plant strategies of growth and survival. The leaf economics spectrum (LES) reflects a trade-off between short-term carbon gain and long-term leaf persistence. A related trade-off, between foliar growth and anti-herbivore defense, occurs among plants growing in contrasting resource regimes, but it is unclear whether this trade-off is maintained within plant communities, where resource gradients are minimized. The LES and the growth-defense trade-off involve related traits, but the extent to which these trade-off dimensions are correlated is poorly understood. We assessed the relationship between leaf economic and anti-herbivore defense traits among sunlit foliage of 345 canopy trees in 83 species on Barro Colorado Island, Panama. We quantified ten traits related to resource allocation and defense, and identified patterns of trait co-variation using multivariate ordination. We tested whether traits and ordination axes were correlated with patterns of phylogenetic relatedness, juvenile demographic trade-offs, or topo-edaphic variation. Two independent axes described ~ 60% of the variation among canopy trees. Axis 1 revealed a trade-off between leaf nutritional and structural investment, consistent with the LES. Physical defense traits were largely oriented along this axis. Axis 2 revealed a trade-off between investments in phenolic defenses versus other foliar defenses, which we term the leaf defense spectrum. Phylogenetic relationships and topo-edaphic variation largely did not explain trait co-variation. Our results suggest that some trade-offs among the growth and defense traits of outer-canopy trees may be captured by the LES, while others may occur along additional resource allocation dimensions.

Identifying variation in models of care for the genomic-based diagnosis of inherited retinal dystrophies in the United Kingdom.

PurposeAdvances in genomic technologies are prompting a realignment of diagnostic and management pathways for rare inherited disease. New models of care are being developed as genomic-based diagnostic testing becomes increasingly relevant within more and more aspects of medicine. This study describes current care models for the provision of a genomic-based diagnosis for patients with inherited retinal dystrophy (IRD) in UK clinical practice.MethodsA structured telephone survey, conducted (in 2014) with all 23 UK Regional Genetics Centres and a sample of specialist ophthalmology centres (n=4), was used to describe models of service delivery and current levels of genomic-based diagnostic testing. Quantitative data were summarised using descriptive statistics. Responses to open-ended questions were summarised using thematic analysis.ResultsOf the 27 centres 10 of them saw IRD patients in 'generic' clinics and 17 centres offered ophthalmic-specific clinics. Extensive regional variation was observed in numbers of patients seen and in how care for the diagnosis and management of IRD was provided.ConclusionsUnderstanding current practice is a necessary first step in the development and evaluation of complex interventions, such as care models for the genomic-based diagnosis of inherited eye conditions. Presented findings here relating to disparities in care provision are potentially linked to previously reported evidence of perceived unmet needs and expectations of IRD service users. This work provides a foundation for the integration of new care models in mainstream medicine.

Stem, root, and older leaf N:P ratios are more responsive indicators of soil nutrient availability than new foliage.

Foliar nitrogen to phosphorus (N:P) ratios are widely used to indicate soil nutrient availability and limitation, but the foliar ratios of woody plants have proven more complicated to interpret than ratios from whole biomass of herbaceous species. This may be related to tissues in woody species acting as nutrient reservoirs during active growth, allowing maintenance of optimal N:P ratios in recently produced, fully expanded leaves (i.e., "new" leaves, the most commonly sampled tissue). Here we address the hypothesis that N:P ratios of newly expanded leaves are less sensitive indicators of soil nutrient availability than are other tissue types in woody plants. Seedlings of five naturally established tree species were harvested from plots receiving two years of fertilizer treatments in a lowland tropical forest in the Republic of Panama. Nutrient concentrations were determined in new leaves, old leaves, stems, and roots. For stems and roots, N:P ratios increased after N addition and decreased after P addition, and trends were consistent across all five species. Older leaves also showed strong responses to N and P addition, and trends were consistent for four of five species. In comparison, overall N:P ratio responses in new leaves were more variable across species. These results indicate that the N:P ratios of stems, roots, and older leaves are more responsive indicators of soil nutrient availability than are those of new leaves. Testing the generality of this result could improve the use of tissue nutrient ratios as indices of soil nutrient availability in woody plants.

Are functional traits good predictors of demographic rates? Evidence from five neotropical forests.

A central goal of comparative plant ecology is to understand how functional traits vary among species and to what extent this variation has adaptive value. Here we evaluate relationships between four functional traits (seed volume, specific leaf area, wood density, and adult stature) and two demographic attributes (diameter growth and tree mortality) for large trees of 240 tree species from five Neotropical forests. We evaluate how these key functional traits are related to survival and growth and whether similar relationships between traits and demography hold across different tropical forests. There was a tendency for a trade-off between growth and survival across rain forest tree species. Wood density, seed volume, and adult stature were significant predictors of growth and/or mortality. Both growth and mortality rates declined with an increase in wood density. This is consistent with greater construction costs and greater resistance to stem damage for denser wood. Growth and mortality rates also declined as seed volume increased. This is consistent with an adaptive syndrome in which species tolerant of low resource availability (in this case shade-tolerant species) have large seeds to establish successfully and low inherent growth and mortality rates. Growth increased and mortality decreased with an increase in adult stature, because taller species have a greater access to light and longer life spans. Specific leaf area was, surprisingly, only modestly informative for the performance of large trees and had ambiguous relationships with growth and survival. Single traits accounted for 9-55% of the interspecific variation in growth and mortality rates at individual sites. Significant correlations with demographic rates tended to be similar across forests and for phylogenetically independent contrasts as well as for cross-species analyses that treated each species as an independent observation. In combination, the morphological traits explained 41% of the variation in growth rate and 54% of the variation in mortality rate, with wood density being the best predictor of growth and mortality. Relationships between functional traits and demographic rates were statistically similar across a wide range of Neotropical forests. The consistency of these results strongly suggests that tropical rain forest species face similar trade-offs in different sites and converge on similar sets of solutions.

Seedling interactions in a tropical forest in Panama.

Competition is believed to be a central force limiting local diversity and controlling the structure of plant communities. However, it has been proposed that the stressed understory environment limits total understory plant density to such low levels that competitive exclusion cannot be an important factor limiting the local diversity of understory plants. To evaluate the importance of inter-seedling competition, we performed a seedling competition experiment with five shade-tolerant species in a tropical moist forest in Panama. Three-month-old seedlings were transplanted into the forest singly or with their roots intertwined with a single conspecific or heterospecific seedling in all pairwise species combinations. If competition is important, performance (survival, stem height, and number of leaves after one and six years) would be expected to be lowest with a conspecific neighbor and greatest without a neighbor. The experiment was replicated in five 0.24-m(2) plots at each of 20 sites in tall secondary forest. To test whether seedling performance differed among treatments we fitted linear mixed models (LMM) and generalized linear mixed models (GLMM), treating species identity and microsite (site and plot) as random effects. The five shade-tolerant study species all experienced good establishment with relatively high survival and growth rates. The neighbor treatment consistently affected seedling performance, but the effect was always very small, both in absolute terms and relative to the much stronger species and microsite effects. Seedlings with a conspecific neighbor consistently performed worse than seedlings with a heterospecific neighbor, but having no neighbor generally did not cause superior performance relative to the other treatments. We conclude that direct competitive interactions are relatively unimportant among understory plants in humid tropical forests.

A review of policy change regarding how patients access their HIV test results at two genitourinary medicine services in Central London.

A retrospective note audit was carried out across two genitourinary (GU) medicine services in Central London to review a radical change in policy one year after its implementation that allows patients assessed as low risk for HIV infection to receive their HIV result by post. Sixteen patients tested positive across the two clinics but had arranged to receive their results by post. Their recall management and outcomes are discussed.

Seasonal, El Niño and longer term changes in flower and seed production in a moist tropical forest.

It has recently been reported that humid tropical forests are changing rapidly in response to global anthropogenic change and that these forests experience greater tree mortality and even fire during droughts associated with El Niño events. The former reports are controversial largely because a single method has been used - repeated censuses of tree plots. The latter reports focus on recent extreme El Niño events. Here, we show that flower and seed production both increase during El Niño events in an old-growth tropical forest in Panama. Flower production, but not seed production, has also increased over the past 18 years. The sustained increase in flower production was greater for 33 liana species than for 48 tree species. These results indicate that moderate El Niño events favour seed production, document long-term increases in flower production for the first time, and corroborate long-term increases in the importance of lianas using independent methods. Changes in levels of solar irradiance might contribute to all three patterns.

Species differences in the pharmacokinetics and metabolism of reparixin in rat and dog.

The pharmacokinetics and metabolism of reparixin (formerly repertaxin), a potent and specific inhibitor of the chemokine CXCL8, were investigated in rats and dogs after intravenous administration of [14C]-reparixin L-lysine salt. Protein binding of reparixin was investigated in vitro in rat, dog, rabbit, cynomolgus monkey and human plasma. Plasma protein binding of reparixin was >99% in the laboratory animals and humans up to 50 microg ml-1, but lower at higher concentrations. Although radioactivity was rapidly distributed into rat tissues, Vss was low (about 0.15 l kg-1) in both rat and dog. Nevertheless, reparixin was more rapidly eliminated in rats (t1/2 approximately 0.5 h) than in dogs (t1/2 approximately 10 h). Systemic exposure in dog was due primarily to parent drug, but metabolites played a more prominent role in rat. Oxidation of the isobutyl side-chain was the major metabolic pathway in rat, whereas hydrolysis of the amide bond predominated in dog. Urinary excretion, which accounted for 80-82% of the radioactive dose, was the major route of elimination in both species, and biotransformation of reparixin was complete before excretion.

Optimization of intensity-modulated radiation therapy with biological objectives.

IMRT treatment planning via biological objectives gives rise to constrained nonlinear optimization problems. We consider formulations with nonlinear objectives based on the equivalent uniform dose (EUD), with bound constraints on the beamlet weights, and describe fast, flexible variants of the two-metric gradient-projection approach for solving them efficiently and in a mathematically sound manner. We conclude that an approach that calculates the Newton component of the step iteratively, by means of the conjugate-gradient algorithm and an implicit representation of the Hessian matrix, is most effective. We also present an efficient heuristic for obtaining an approximate solution with a smoother distribution of beamlet weights. The effectiveness of the methods is verified by testing on a medium-scale clinical case.

In vitro/in vivo correlation for 14C-methylated lysozyme release from poly(ether-ester) microspheres.

PURPOSE: The purpose of this study was to obtain an in vitro/in vivo correlation for the sustained release of a protein from poly(ethylene glycol) terephthalate (PEGT)/poly(butylene terephthalate) (PBT) microspheres. METHODS: Radiolabeled lysozyme was encapsulated in PEGT/PBT microspheres via a water-in-oil-in-water emulsion. Three microsphere formulations varying in copolymer composition were administered subcutaneously to rats. The blood plasma was analyzed for radioactivity content representing released lysozyme at various time points post-dose. The in vitro release was studied in phosphate-buffered saline. RESULTS: The encapsulation efficiency, calculated from the radioactivity in the outer water phase of the emulsion, varied from 60-87%. Depending on the PEG segment length and wt% PEGT, the lysozyme was released completely in vitro within 14 to 28 days without initial burst. 14C-methylated lysozyme could be detected in the plasma over the same time courses. The in vitro/in vivo correlation coefficients obtained from point-to-point analysis were greater than 0.96 for all microsphere formulations. In addition, less then 10% of administered radioactivity remained at dose site at 28 days for the microsphere formulations, indicating no notable retention of the protein at the injection site. CONCLUSION: The in vitro release in phosphate-buffered saline and the in vivo release in rats showed an excellent congruence independent of the release rate of 14C-methylated lysozyme from PEGT/PBT microspheres.

Biodiversity meets the atmosphere: a global view of forest canopies.

The forest canopy is the functional interface between 90% of Earth's terrestrial biomass and the atmosphere. Multidisciplinary research in the canopy has expanded concepts of global species richness, physiological processes, and the provision of ecosystem services. Trees respond in a species-specific manner to elevated carbon dioxide levels, while climate change threatens plant-animal interactions in the canopy and will likely alter the production of biogenic aerosols that affect cloud formation and atmospheric chemistry.

Is transcutaneous electrical nerve stimulation an effective analgesia during colonoscopy?

OBJECTIVES: To evaluate the efficacy of transcutaneous electrical nerve stimulation (TENS) as analgesia during colonoscopy. DESIGN: In a randomised controlled trial, patients undergoing diagnostic colonoscopy were assigned to one of three groups: standard medication only (midazolam); active TENS plus standard medication; or non-functioning TENS and standard medication. Efficacy of TENS was determined using numerical rating scores for pain and the post-procedural evaluation questionnaire. SETTING: Patients undergoing diagnostic colonoscopy in a teaching hospital. MAIN OUTCOME: There was no statistically significant differences between the three groups. However in the active TENS group there was a greater variation in "physical discomfort" and "psychological distress", suggesting TENS may be effective in subgroup of patients.

Effects of spaceflight on human calf hemodynamics.

Chronic microgravity may modify adaptations of the leg circulation to gravitational pressures. We measured resting calf compliance and blood flow with venous occlusion plethysmography, and arterial blood pressure with sphygmomanometry, in seven subjects before, during, and after spaceflight. Calf vascular resistance equaled mean arterial pressure divided by calf flow. Compliance equaled the slope of the calf volume change and venous occlusion pressure relationship for thigh cuff pressures of 20, 40, 60, and 80 mmHg held for 1, 2, 3, and 4 min, respectively, with 1-min breaks between occlusions. Calf blood flow decreased 41% in microgravity (to 1.15 +/- 0.16 ml x 100 ml(-1) x min(-1)) relative to 1-G supine conditions (1.94 +/- 0.19 ml x 100 ml(-1) x min(-1), P = 0.01), and arterial pressure tended to increase (P = 0.05), such that calf vascular resistance doubled in microgravity (preflight: 43 +/- 4 units; in-flight: 83 +/- 13 units; P < 0.001) yet returned to preflight levels after flight. Calf compliance remained unchanged in microgravity but tended to increase during the first week postflight (P > 0.2). Calf vasoconstriction in microgravity qualitatively agrees with the "upright set-point" hypothesis: the circulation seeks conditions approximating upright posture on Earth. No calf hemodynamic result exhibited obvious mechanistic implications for postflight orthostatic intolerance.