The physiological cost of diazotrophy for Trichodesmium erythraeum IMS101

Trichodesmium plays a significant role in the oligotrophic oceans, fixing nitrogen in an area corresponding to half of the Earth’s surface, representing up to 50% of new production in some oligotrophic tropical and subtropical oceans. Whilst Trichodesmium blooms at the surface exhibit a strong dependence on diazotrophy, colonies at depth or at the surface after a mixing event could be utilising additional N-sources. We conducted experiments to establish how acclimation to varying N-sources affects the growth, elemental composition, light absorption coefficient, N2 fixation, PSII electron transport rate and the relationship between net and gross photosynthetic O2 exchange in T. erythraeum IMS101. To do this, cultures were acclimated to growth medium containing NH4+ and NO3- (replete concentrations) or N2 only (diazotrophic control). The light dependencies of O2 evolution and O2 uptake were measured using membrane inlet mass spectrometry (MIMS), while PSII electron transport rates were measured from fluorescence light curves (FLCs). We found that at a saturating light intensity, Trichodesmium growth was ~ 10% and 13% lower when grown on N2 than with NH4+ and NO3-, respectively. Oxygen uptake increased linearly with net photosynthesis across all light intensities ranging from darkness to 1100 μmol photons m-2 s-1. The maximum rates and initial slopes of light response curves for C-specific gross and net photosynthesis and the slope of the relationship between gross and net photosynthesis increased significantly under non-diazotrophic conditions. We attribute these observations to a reduced expenditure of reductant and ATP for nitrogenase activity under non-diazotrophic conditions which allows NADPH and ATP to be re-directed to CO2 fixation and/or biosynthesis. The energy and reductant conserved through utilising additional N-sources could enhance Trichodesmium’s productivity and growth and have major implications for its role in ocean C and N cycles

Robust analysis of stepped wedge trials using cluster-level summaries within periods.

In stepped-wedge trials (SWTs), the intervention is rolled out in a random order over more than 1 time-period. SWTs are often analysed using mixed-effects models that require strong assumptions and may be inappropriate when the number of clusters is small. We propose a non-parametric within-period method to analyse SWTs. This method estimates the intervention effect by comparing intervention and control conditions in a given period using cluster-level data corresponding to exposure. The within-period intervention effects are combined with an inverse-variance-weighted average, and permutation tests are used. We present an example and, using simulated data, compared the method to (1) a parametric cluster-level within-period method, (2) the most commonly used mixed-effects model, and (3) a more flexible mixed-effects model. We simulated scenarios where period effects were common to all clusters, and when they varied according to a distribution informed by routinely collected health data. The non-parametric within-period method provided unbiased intervention effect estimates with correct confidence-interval coverage for all scenarios. The parametric within-period method produced confidence intervals with low coverage for most scenarios. The mixed-effects models' confidence intervals had low coverage when period effects varied between clusters but had greater power than the non-parametric within-period method when period effects were common to all clusters. The non-parametric within-period method is a robust method for analysing SWT. The method could be used by trial statisticians who want to emphasise that the SWT is a randomised trial, in the common position of being uncertain about whether data will meet the assumptions necessary for mixed-effect models

Diabetes status and post-load plasma glucose concentration in relation to site-specific cancer mortality: findings from the original Whitehall study

ObjectiveWhile several studies have reported on the relation of diabetes status with pancreatic cancer risk, the predictive value of this disorder for other malignancies is unclear. Methods: The Whitehall study, a 25year follow-up for mortality experience of 18,006 men with data on post-challenge blood glucose and self-reported diabetes, allowed us to address these issues. Results: There were 2158 cancer deaths at follow-up. Of the 15 cancer outcomes, diabetes status was positively associated with mortality from carcinoma of the pancreas and liver, while the relationship with lung cancer was inverse, after controlling for a range of potential covariates and mediators which included obesity and socioeconomic position. After excluding deaths occurring in the first 10years of follow-up to examine the effect of reverse causality, the magnitude of the relationships for carcinoma of the pancreas and lung was little altered, while for liver cancer it was markedly attenuated. Conclusions: In the present study, diabetes status was related to pancreatic, liver, and lung cancer risk. Cohorts with serially collected data on blood glucose and covariates are required to further examine this area

Spatial distribution of podoconiosis in relation to environmental factors in Ethiopia: a historical review

BACKGROUND An up-to-date and reliable map of podoconiosis is needed to design geographically targeted and cost-effective intervention in Ethiopia. Identifying the ecological correlates of the distribution of podoconiosis is the first step for distribution and risk maps. The objective of this study was to investigate the spatial distribution and ecological correlates of podoconiosis using historical and contemporary survey data. METHODS Data on the observed prevalence of podoconiosis were abstracted from published and unpublished literature into a standardized database, according to strict inclusion and exclusion criteria. In total, 10 studies conducted between 1969 and 2012 were included, and data were available for 401,674 individuals older than 15 years of age from 229 locations. A range of high resolution environmental factors were investigated to determine their association with podoconiosis prevalence, using logistic regression. RESULTS The prevalence of podoconiosis in Ethiopia was estimated at 3.4% (95% CI 3.3%-3.4%) with marked regional variation. We identified significant associations between mean annual Land Surface Temperature (LST), mean annual precipitation, topography of the land and fine soil texture and high prevalence of podoconiosis. The derived maps indicate both widespread occurrence of podoconiosis and a marked variability in prevalence of podoconiosis, with prevalence typically highest at altitudes >1500 m above sea level (masl), with >1500 mm annual rainfall and mean annual LST of 19-21°C. No (or very little) podoconiosis occurred at altitudes 24°C. CONCLUSION Podoconiosis remains a public health problem in Ethiopia over considerable areas of the country, but exhibits marked geographical variation associated in part with key environmental factors. This is work in progress and the results presented here will be refined in future work

Mapping and modelling the geographical distribution and environmental limits of podoconiosis in Ethiopia

BACKGROUND Ethiopia is assumed to have the highest burden of podoconiosis globally, but the geographical distribution and environmental limits and correlates are yet to be fully investigated. In this paper we use data from a nationwide survey to address these issues. METHODOLOGY Our analyses are based on data arising from the integrated mapping of podoconiosis and lymphatic filariasis (LF) conducted in 2013, supplemented by data from an earlier mapping of LF in western Ethiopia in 2008-2010. The integrated mapping used woreda (district) health offices' reports of podoconiosis and LF to guide selection of survey sites. A suite of environmental and climatic data and boosted regression tree (BRT) modelling was used to investigate environmental limits and predict the probability of podoconiosis occurrence. PRINCIPAL FINDINGS Data were available for 141,238 individuals from 1,442 communities in 775 districts from all nine regional states and two city administrations of Ethiopia. In 41.9% of surveyed districts no cases of podoconiosis were identified, with all districts in Affar, Dire Dawa, Somali and Gambella regional states lacking the disease. The disease was most common, with lymphoedema positivity rate exceeding 5%, in the central highlands of Ethiopia, in Amhara, Oromia and Southern Nations, Nationalities and Peoples regional states. BRT modelling indicated that the probability of podoconiosis occurrence increased with increasing altitude, precipitation and silt fraction of soil and decreased with population density and clay content. Based on the BRT model, we estimate that in 2010, 34.9 (95% confidence interval [CI]: 20.2-51.7) million people (i.e. 43.8%; 95% CI: 25.3-64.8% of Ethiopia's national population) lived in areas environmentally suitable for the occurrence of podoconiosis. CONCLUSIONS Podoconiosis is more widespread in Ethiopia than previously estimated, but occurs in distinct geographical regions that are tied to identifiable environmental factors. The resultant maps can be used to guide programme planning and implementation and estimate disease burden in Ethiopia. This work provides a framework with which the geographical limits of podoconiosis could be delineated at a continental scale

Podoconiosis and soil-transmitted helminths (STHs): double burden of neglected tropical diseases in Wolaita zone, rural southern Ethiopia

Background Both podoconiosis and soil-transmitted helminth (STH) infections occur among barefoot people in areas of extreme poverty; however, their co-morbidity has not previously been investigated. We explored the overlap of STH infection and podoconiosis in Southern Ethiopia and quantified their separate and combined effects on prevalent anemia and hemoglobin levels in podoconiosis patients and health controls from the same area. Methods and Principal Findings A two-part comparative cross-sectional study was conducted in Wolaita zone, southern Ethiopia. Data were collected from adult patients presenting with clinically confirmed podoconiosis, and unmatched adult neighborhood controls living in the same administrative area. Information on demographic and selected lifestyle factors was collected using interviewer-administered questionnaires. Stool samples were collected and examined qualitatively using the modified formalin-ether sedimentation method. Hemoglobin level was determined using two different methods: hemoglobinometer and automated hematology analyzer. A total of 913 study subjects (677 podoconiosis patients and 236 controls) participated. The prevalence of any STH infection was 47.6% among patients and 33.1% among controls (p<0.001). The prevalence of both hookworm and Trichuris trichiura infections was significantly higher in podoconiosis patients than in controls (AOR 1.74, 95% CI 1.25 to2.42, AOR 6.53, 95% CI 2.34 to 18.22, respectively). Not wearing shoes and being a farmer remained significant independent predictors of infection with any STH. There was a significant interaction between STH infection and podoconiosis on reduction of hemoglobin level (interaction p value = 0.002). Conclusions Prevalence of any STH and hookworm infection was higher among podoconiosis patients than among controls. A significant reduction in hemoglobin level was observed among podoconiosis patients co-infected with hookworm and ‘non-hookworm STH’. Promotion of consistent shoe-wearing practices may have double advantages in controlling both podoconiosis and hookworm infection in the study area

Association between footwear use and neglected tropical diseases: a systematic review and meta-analysis

BACKGROUND The control of neglected tropical diseases (NTDs) has primarily focused on preventive chemotherapy and case management. Less attention has been placed on the role of ensuring access to adequate water, sanitation, and hygiene and personal preventive measures in reducing exposure to infection. Our aim was to assess whether footwear use was associated with a lower risk of selected NTDs. METHODOLOGY We conducted a systematic review and meta-analysis to assess the association between footwear use and infection or disease for those NTDs for which the route of transmission or occurrence may be through the feet. We included Buruli ulcer, cutaneous larva migrans (CLM), leptospirosis, mycetoma, myiasis, podoconiosis, snakebite, tungiasis, and soil-transmitted helminth (STH) infections, particularly hookworm infection and strongyloidiasis. We searched Medline, Embase, Cochrane, Web of Science, CINAHL Plus, and Popline databases, contacted experts, and hand-searched reference lists for eligible studies. The search was conducted in English without language, publication status, or date restrictions up to January 2014. Studies were eligible for inclusion if they reported a measure of the association between footwear use and the risk of each NTD. Publication bias was assessed using funnel plots. Descriptive study characteristics and methodological quality of the included studies were summarized. For each study outcome, both outcome and exposure data were abstracted and crude and adjusted effect estimates presented. Individual and summary odds ratio (OR) estimates and corresponding 95% confidence intervals (CIs) were calculated as a measure of intervention effect, using random effects meta-analyses. PRINCIPAL FINDINGS Among the 427 studies screened, 53 met our inclusion criteria. Footwear use was significantly associated with a lower odds of infection of Buruli ulcer (OR=0.15; 95% CI: 0.08-0.29), CLM (OR=0.24; 95% CI: 0.06-0.96), tungiasis (OR=0.42; 95% CI: 0.26-0.70), hookworm infection (OR=0.48; 95% CI: 0.37-0.61), any STH infection (OR=0.57; 95% CI: 0.39-0.84), strongyloidiasis (OR=0.56; 95% CI: 0.38-0.83), and leptospirosis (OR=0.59; 95% CI: 0.37-0.94). No significant association between footwear use and podoconiosis (OR=0.63; 95% CI: 0.38-1.05) was found and no data were available for mycetoma, myiasis, and snakebite. The main limitations were evidence of heterogeneity and poor study quality inherent to the observational studies included. CONCLUSIONS/SIGNIFICANCE Our results show that footwear use was associated with a lower odds of several different NTDs. Access to footwear should be prioritized alongside existing NTD interventions to ensure a lasting reduction of multiple NTDs and to accelerate their control and elimination. PROTOCOL REGISTRATION PROSPERO International prospective register of systematic reviews CRD42012003338

Intraspecfic variation in cold-temperature metabolic phenotypes of Arabidopsis lyrata ssp petraea

Atmospheric temperature is a key factor in determining the distribution of a plant species. Alongside this, plant populations growing at the margin of their range may exhibit traits that indicate genetic differentiation and adaptation to their local abiotic environment. We investigated whether geographically separated marginal populations of Arabidopsis lyrata ssp. petraea have distinct metabolic phenotypes associated with exposure to cold temperatures. Seeds of A. petraea were obtained from populations along a latitudinal gradient, namely Wales, Sweden and Iceland and grown in a controlled cabinet environment. Mannose, glucose, fructose, sucrose and raffinose concentrations were different between cold treatments and populations, especially in the Welsh population, but polyhydric alcohol concentrations were not. The free amino acid compositions were population specific, with fold differences in most amino acids, especially in the Icelandic populations, with gross changes in amino acids, particularly those associated with glutamine metabolism. Metabolic fingerprints and profiles were obtained. Principal component analysis (PCA) of metabolite fingerprints revealed metabolic characteristic phenotypes for each population and temperature. It is suggested that amino acids and carbohydrates were responsible for discriminating populations within the PCA. Metabolite fingerprinting and profiling has proved to be sufficiently sensitive to identify metabolic differences between plant populations at different atmospheric temperatures. These findings show that there is significant natural variation in cold metabolism among populations of A. l. petraea which may signify plant adaptation to local climates

Active Inference in OpenAI Gym: A Paradigm for Computational Investigations Into Psychiatric Illness

Background: Artificial intelligence has recently attained humanlike performance in a number of gamelike domains. These advances have been spurred by brain-inspired architectures and algorithms such as hierarchical filtering and reinforcement learning. OpenAI Gym is an open-source platform in which to train, test, and benchmark algorithms—it provides a range of tasks, including those of classic arcade games such as Doom. Here we describe how the platform might be used as a simulation, test, and diagnostic paradigm for psychiatric conditions. Methods: To illustrate how active inference models of game play could be used to test mechanistic and algorithmic properties of psychiatric disorders, we provide two exemplar analyses. The first speaks to the impact of aging on cognition, examining game-play behaviors in a model of aging in which we compared age-dependent changes of younger (n = 9, 22 ± 1 years of age) and older (n = 7, 56 ± 5 years of age) adult players. The second is an illustration of a putative feature of anhedonia in which we simulated diminished sensitivity to reward. Results: These simulations demonstrate how active inference can be used to test predicted changes in both neurobiology and beliefs in psychiatric cohorts. We show that, as well as behavioral measures, putative neural correlates of active inference can be simulated, and hypothesized (model-based) differences in local field potentials and blood oxygen level–dependent responses can be produced. Conclusions: We show that active inference, through epistemic and value-based goals, enables simulated subjects to actively develop detailed representations of gaming environments, and we demonstrate the use of a principled algorithmic and neurobiological framework for testing hypotheses in psychiatric illness

A Status Report on Conflict Analysis in Mixed Integer Nonlinear Programming

Mixed integer nonlinear programs (MINLPs) are arguably among the hardest optimization problems, with a wide range of applications. MINLP solvers that are based on linear relaxations and spatial branching work similar as mixed integer programming (MIP) solvers in the sense that they are based on a branch-and-cut algorithm, enhanced by various heuristics, domain propagation, and presolving techniques. However, the analysis of infeasible subproblems, which is an important component of most major MIP solvers, has been hardly studied in the context of MINLPs. There are two main approaches for infeasibility analysis in MIP solvers: conflict graph analysis, which originates from artificial intelligence and constraint programming, and dual ray analysis. The main contribution of this short paper is twofold. Firstly, we present the first computational study regarding the impact of dual ray analysis on convex and nonconvex MINLPs. In that context, we introduce a modified generation of infeasibility proofs that incorporates linearization cuts that are only locally valid. Secondly, we describe an extension of conflict analysis that works directly with the nonlinear relaxation of convex MINLPs instead of considering a linear relaxation. This is work-in-progress, and this short paper is meant to present first theoretical considerations without a computational study for that part