Biased efficacy estimates in phase-III dengue vaccine trials due to heterogeneous exposure and differential detectability of primary infections across trial arms.

Vaccine efficacy (VE) estimates are crucial for assessing the suitability of dengue vaccine candidates for public health implementation, but efficacy trials are subject to a known bias to estimate VE toward the null if heterogeneous exposure is not accounted for in the analysis of trial data. In light of many well-characterized sources of heterogeneity in dengue virus (DENV) transmission, our goal was to estimate the potential magnitude of this bias in VE estimates for a hypothetical dengue vaccine. To ensure that we realistically modeled heterogeneous exposure, we simulated city-wide DENV transmission and vaccine trial protocols using an agent-based model calibrated with entomological and epidemiological data from long-term field studies in Iquitos, Peru. By simulating a vaccine with a true VE of 0.8 in 1,000 replicate trials each designed to attain 90% power, we found that conventional methods underestimated VE by as much as 21% due to heterogeneous exposure. Accounting for the number of exposures in the vaccine and placebo arms eliminated this bias completely, and the more realistic option of including a frailty term to model exposure as a random effect reduced this bias partially. We also discovered a distinct bias in VE estimates away from the null due to lower detectability of primary DENV infections among seronegative individuals in the vaccinated group. This difference in detectability resulted from our assumption that primary infections in vaccinees who are seronegative at baseline resemble secondary infections, which experience a shorter window of detectable viremia due to a quicker immune response. This resulted in an artefactual finding that VE estimates for the seronegative group were approximately 1% greater than for the seropositive group. Simulation models of vaccine trials that account for these factors can be used to anticipate the extent of bias in field trials and to aid in their interpretation

Differential validity and slant on the predictability of the admisson tests to the chilean universities (PSU)

La preocupación por la equidad en la medición educacional ha llevado a desarrollar diversos procedimientos para evaluar el potencial sesgo asociado a características sociodemográficas de los examinados. Estos procedimientos incluyen la validez y la predicción diferencial de los tests. En el primer caso, se analiza el grado de asociación entre los tests y alguna variable criterio (como el rendimiento académico), comparando dicha asociación entre grupos. En el segundo caso, se trata de establecer si la capacidad predictiva de los instrumentos de medición es equivalente para diversos grupos de examinados, comparando los errores de predicción. Empleando esta metodología con datos de las Pruebas de Selección Universitaria chilenas de Matemática y de Lenguaje y Comunicación, además de las Notas de Educación Media (como predictores) y el rendimiento académico de los estudiantes en el primer año de sus estudios universitarios (como criterio), se calcularon y compararon indicadores de validez y predicción diferencial según género y dependencia de los establecimientos educacionales. Los resultados, que presentan un patrón semejante al observado con pruebas de admisión norteamericanas, revelan una leve presencia de validez diferencial, especialmente cuando se considera el género de los estudiantes, revelando una consistente pero leve subpredicción del rendimiento de las mujere

Gaining insights in the nutritional metabolism of amphibians : analyzing body nutrient profiles of the African clawed frog, Xenopus laevis

Whole bodies of Xenopus laevis (n = 19) were analysed for chemical composition and morphometrics. The nutrient profile (macronutrients, amino acids, fatty acids and minerals) was evaluated by sex; interactions among variables with body weights and lengths, and comparisons made with different species of marine and fresh water fish. Significant differences were found in morphometric measurements, water content, several minerals and fatty acids between sexes of X. laevis. Amino acid profiles differed in methionine, proline and cysteine, which could underlie different metabolic pathways in frogs when compared to fish. In addition, fatty acid profiles revealed more monounsaturated and n - 6 polyunsaturated fatty acids in frogs than in fish, more similar to values reported for terrestrial than aquatic vertebrates. Important interactions were also found between body measurements and fat, calcium, and phosphorus, as well as between essential and non-essential amino acids. The results indicate that frogs might have particular biochemical pathways for several nutrients, dependent on sex and linked to body weight, which ultimately could reflect specific nutrient needs

PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression

<p>Abstract</p> <p>Background</p> <p>The selective absorption of nutrients and other food constituents in the small intestine is mediated by a group of transport proteins and metabolic enzymes, often collectively called 'intestinal barrier proteins'. An important receptor that mediates the effects of dietary lipids on gene expression is the peroxisome proliferator-activated receptor alpha (PPARα), which is abundantly expressed in enterocytes. In this study we examined the effects of acute nutritional activation of PPARα on expression of genes encoding intestinal barrier proteins. To this end we used triacylglycerols composed of identical fatty acids in combination with gene expression profiling in wild-type and PPARα-null mice. Treatment with the synthetic PPARα agonist WY14643 served as reference.</p> <p>Results</p> <p>We identified 74 barrier genes that were PPARα-dependently regulated 6 hours after activation with WY14643. For eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and oleic acid (OA) these numbers were 46, 41, and 19, respectively. The overlap between EPA-, DHA-, and WY14643-regulated genes was considerable, whereas OA treatment showed limited overlap. Functional implications inferred form our data suggested that nutrient-activated PPARα regulated transporters and phase I/II metabolic enzymes were involved in a) fatty acid oxidation, b) cholesterol, glucose, and amino acid transport and metabolism, c) intestinal motility, and d) oxidative stress defense.</p> <p>Conclusion</p> <p>We identified intestinal barrier genes that were PPARα-dependently regulated after acute activation by fatty acids. This knowledge provides a better understanding of the impact dietary fat has on the barrier function of the gut, identifies PPARα as an important factor controlling this key function, and underscores the importance of PPARα for nutrient-mediated gene regulation in intestine.</p

Adding tightly-integrated task scheduling acceleration to a RISC-V multi-core processor

Task Parallelism is a parallel programming model that provides code annotation constructs to outline tasks and describe how their pointer parameters are accessed so that they might be executed in parallel, and asynchronously, by a runtime capable of inferring and honoring their data dependence relationships. It is supported by several parallelization frameworks, as OpenMP and StarSs. Overhead related to automatic dependence inference and to the scheduling of ready-to-run tasks is a major performance limiting factor of Task Parallel systems. To amortize this overhead, programmers usually trade the higher parallelism that could be leveraged from finer-grained work partitions for the higher runtime-efficiency of coarser-grained work partitions. Such problems are even more severe for systems with many cores, as the task spawning frequency required for preserving cores from starvation grows linearly with their number. To mitigate these problems, researchers have designed hardware accelerators to improve runtime performance. Nevertheless, the high CPU-accelerator communication overheads of these solutions hampered their gains. We thus propose a RISC-V based architecture that minimizes communication overhead between the HW Task Scheduler and the CPU by allowing Task Scheduling software to directly interact with the former through custom instructions. Empirical evaluation of the architecture is made possible by an FPGA prototype featuring an eight-core Linux-capable Rocket Chip implementing such instructions. To evaluate the prototype performance, we both (1) adapted Nanos, a mature Task Scheduling runtime, to benefit from the new task-scheduling-accelerating instructions; and (2) developed Phentos, a new HW-accelerated light weight Task Scheduling runtime. Our experiments show that task parallel programs using Nanos-RV --- the Nanos version ported to our system --- are on average 2.13 times faster than those being serviced by baseline Nanos, while programs running on Phentos are 13.19 times faster, considering geometric means. Using eight cores, Nanos-RV is able to deliver speedups with respect to serial execution of up to 5.62 times, while Phentos produces speedups of up to 5.72 times.This work was supported by the Spanish Government (projects SEV-2015-0493 and TIN2015-65316-P), the Generalitat de Catalunya (2017-SGR-1414 and 2017-SGR1328), FAPESP (grants 2017/02682-2, 2018/00687-0, and 2014/25694-8), CNPq (grant 408782/2016-1), and CAPES.Peer ReviewedPostprint (author's final draft

Does canine inflammatory bowel disease influence gut microbial profile and host metabolism?

Background: Inflammatory bowel disease (IBD) refers to a diverse group of chronic gastrointestinal diseases, and gut microbial dysbiosis has been proposed as a modulating factor in its pathogenesis. Several studies have investigated the gut microbial ecology of dogs with IBD but it is yet unclear if this microbial profile can alter the nutrient metabolism of the host. The aim of the present study was to characterize the faecal bacterial profile and functionality as well as to determine host metabolic changes in IBD dogs. Twenty-three dogs diagnosed with IBD and ten healthy control dogs were included. Dogs with IBD were given a clinical score using the canine chronic enteropathy clinical activity index (CCECAI). Faecal short-chain fatty acids (SCFA) and ammonia concentrations were measured and quantitative PCR was performed. The concentration of plasma amino acids, acylcarnitines, serum folate, cobalamin, and indoxyl sulfate was determined. Results: No significant differences in the abundance of a selection of bacterial groups and fermentation metabolites were observed between the IBD and control groups. However, significant negative correlations were found between CCECAI and the faecal proportion of Lactobacillus as well as between CCECAI and total SCFA concentration. Serum folate and plasma citrulline were decreased and plasma valine was increased in IBD compared to control dogs. Increased plasma free carnitine and total acylcarnitines were observed in IBD compared with control dogs, whereas short-chain acylcarnitines (butyrylcarnitine + isobutyrylcarnitine and, methylmalonylcarnitine) to free carnitine ratios decreased. Dogs with IBD had a higher 3-hydroxyisovalerylcarnitine + isovalerylcarnitine to leucine ratio compared to control dogs. Conclusions: Canine IBD induced a wide range of changes in metabolic profile, especially for the plasma concentrations of short-chain acylcarnitines and amino acids, which could have evolved from tissue damage and alteration in host metabolism. In addition, dogs with more severe IBD were characterised by a decrease in faecal proportion of Lactobacillus

The effects of dietary fibre type on satiety-related hormones and voluntary food intake in dogs

Depending on type and inclusion level, dietary fibre may increase and maintain satiety and postpone the onset of hunger. This 7-week study evaluated the effect of fibre fermentability on physiological satiety-related metabolites and voluntary food intake (VFI) in dogs. Sixteen healthy adult dogs were fed a low-fermentable fibre (LFF) diet containing 8·5% cellulose or a high-fermentable fibre (HFF) diet containing 8·5% sugarbeet pulp and 2% inulin. Large intestinal fibre degradation was evaluated by apparent faecal digestibility of nutrients and faecal SCFA and NH3 concentrations. Postprandial blood samples were obtained to determine postprandial plasma glucose, insulin, total peptide tyrosine–tyrosine (PYY), total glucagon-like peptide-1 (GLP-1) and total ghrelin concentrations. At the end of the study, the dogs were given a single meal of a dry dog food to determine VFI. Dogs fed the HFF diet had a significantly higher large intestinal fibre degradation and production of SCFA compared with the dogs fed the LFF diet. The HFF-fed dogs tended (P=0·058) to show a lower VFI at the end of the study. No treatment effects were found for postprandial plasma glucose, PYY, GLP-1 and ghrelin responses. The concentrations of these metabolites could not be related to the observed difference in VFI. The inclusion of fermentable fibre in canine diets may contribute to the prevention or mitigation of obesity through its effects on satiety. The underlying mechanisms require further investigation

NNLO corrections to inclusive semileptonic B decays in the shape-function region

We compute 2-loop QCD corrections to the hard coefficient functions which arise in the factorization formula for B -> X_u l nu decays in the shape-function region. Our calculation provides the last missing piece required for a NNLO analysis of inclusive semileptonic B decays, which may significantly reduce the theoretical uncertainty in the extraction of the CKM matrix element |V_ub|. Among the technical aspects, we find that the 2-loop hard coefficient functions are free of infrared singularities as predicted by the factorization framework. We perform a brief numerical analysis of the NNLO corrections and include a discussion on charm mass effects.Comment: 29 pages, 6 figures. v2: minor changes, matches published versio