1,209 research outputs found

    HIV and Hepatitis C-Coinfected Patients Have Lower Low-Density Lipoprotein Cholesterol Despite Higher Proprotein Convertase Subtilisin Kexin 9 (PCSK9): An Apparent "PCSK9-Lipid Paradox".

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    BackgroundProprotein convertase subtilisin kexin 9 (PCSK9) inhibitors reduce low-density lipoprotein cholesterol (LDL-C) and improve outcomes in the general population. HIV-infected individuals are at increased risk for cardiovascular events and have high rates of dyslipidemia and hepatitis C virus (HCV) coinfection, making PCSK9 inhibition a potentially attractive therapy.Methods and resultsWe studied 567 participants from a clinic-based cohort to compare PCSK9 levels in patients with HIV/HCV coinfection (n=110) with those with HIV infection alone (n=385) and with uninfected controls (n=72). The mean age was 49 years, and the median LDL-C level was 100 mg/dL (IQR 77-124 mg/dL); 21% were taking statins. The 3 groups had similar rates of traditional risk factors. Total cholesterol, LDL-C, and high-density lipoprotein cholesterol levels were lower in coinfected patients compared with controls (P<0.001). PCSK9 was 21% higher in HIV/HCV-coinfected patients versus controls (95% CI 9-34%, P<0.001) and 11% higher in coinfected individuals versus those with HIV infection alone (95% CI 3-20%, P=0.008). After adjustment for cardiovascular risk factors, HIV/HCV coinfection remained significantly associated with 20% higher PCSK9 levels versus controls (95% CI 8-33%, P=0.001). Interleukin-6 levels increased in a stepwise fashion from controls (lowest) to HIV-infected to HIV/HCV-coinfected individuals (highest) and correlated with PCSK9 (r=0.11, P=0.018).ConclusionsDespite having lower LDL-C, circulating PCSK9 levels were increased in patients coinfected with HIV and HCV in parallel with elevations in the inflammatory, proatherogenic cytokine interleukin-6. Clinical trials should be conducted to determine the efficacy of targeted PCSK9 inhibition in the setting of HIV/HCV coinfection

    Enhanced Characterization of Drug Metabolism and the Influence of the Intestinal Microbiome: A Pharmacokinetic, Microbiome, and Untargeted Metabolomics Study.

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    Determining factors that contribute to interindividual and intra-individual variability in pharmacokinetics (PKs) and drug metabolism is essential for the optimal use of drugs in humans. Intestinal microbes are important contributors to variability; however, such gut microbe-drug interactions and the clinical significance of these interactions are still being elucidated. Traditional PKs can be complemented by untargeted mass spectrometry coupled with molecular networking to study the intricacies of drug metabolism. To show the utility of molecular networking on metabolism we investigated the impact of a 7-day course of cefprozil on cytochrome P450 (CYP) activity using a modified Cooperstown cocktail and assessed plasma, urine, and fecal data by targeted and untargeted metabolomics and molecular networking in healthy volunteers. This prospective study revealed that cefprozil decreased the activities of CYP1A2, CYP2C19, and CYP3A, decreased alpha diversity and increased interindividual microbiome variability. We further demonstrate a relationship between the loss of microbiome alpha diversity caused by cefprozil and increased drug and metabolite formation in fecal samples. Untargeted metabolomics/molecular networking revealed several omeprazole metabolites that we hypothesize may be metabolized by both CYP2C19 and bacteria from the gut microbiome. Our observations are consistent with the hypothesis that factors that perturb the gut microbiome, such as antibiotics, alter drug metabolism and ultimately drug efficacy and toxicity but that these effects are most strongly revealed on a per individual basis

    Human-Centric Process-Aware Information Systems (HC-PAIS)

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    Process-Aware Information Systems (PAIS) support organizations in managing and automating their processes. A full automation of processes is in particular industries, such as service-oriented markets, not practicable. The integration of humans in PAIS is necessary to manage and perform processes that require human capabilities, judgments and decisions. A challenge of interdisciplinary PAIS research is to provide concepts and solutions that support human integration in PAIS and human orientation of PAIS in a way that provably increase the PAIS users' satisfaction and motivation with working with the Human-Centric Process Aware Information System (HC-PAIS) and consequently influence users' performance of tasks. This work is an initial step of research that aims at providing a definition of Human-Centric Process Aware Information Systems (HC-PAIS) and future research challenges of HC-PAIS. Results of focus group research are presented.Comment: 8 page

    A Novel Method for Calculating the Radiated Disturbance from Pantograph Arcing in High-speed Railway

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    Pantograph arcing is a key electromagnetic disturbance source to affect train control system in high-speed railway. Since the characteristics of pantograph arcing is related to train speed, it is necessary to investigate effective numerical modeling and measurement method. However, due to the uncontrollable train speed during on-site measurement, it is difficult to study the radiated disturbance from arcing in the corresponding speed and repeat the same measurement. Therefore, a method combined numerical modeling and reverberation chamber measurements for calculating the radiated disturbance from pantograph arcing in a high-speed railway is proposed. Numerical models of train and sensitive equipment are built to calculate the coupling coefficient in CONCEPT II. And a new measurement procedure in reverberation chamber using pulse signal as the reference source is proposed based on a speed-controllable laboratory replica to measure the total radiated power of pantograph arcing. Then the radiated disturbance from pantograph arcing to the sensitive equipment is achieved with the coupling coefficient and the total radiated power of arcing. The method is verified laboratory experiments. This method can solve the uncontrollable train speed problem during on-site measurement and improve the repeatability of measurement

    Lignin-Modified Phenolic Syntan: A Contributor to Our Bio-Based Solutions

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    Content: In order to contribute to a more sustainable leather manufacturing process and leather value chain, in 2016 Smit & zoon started its own designing process of new products through the Bio-Based innovation platform. As a logical first step, answers to several key questions have been looked for: What is Bio-Based? What is renewable? Which term and method do we use to define the Bio-Based content in the Bio-Based platform? What is biodegradable? How do our current products perform? What is our vision for future products? In the process of answering these questions and guided by the Cradle-to-Cradle (C2C) CertifiedTM program, Material Reutilization Score (MRS) was used to obtain deeper insights into the formulation and environmental performance of our leather chemicals and treated as the basis for the design of new generation bio-based chemicals. Three main focus areas are setting the tone of current activities in the Bio-based platform: 1. increasing the renewable contents of the existing product groups; 2. smart valorization of industrial side streams from biological origin and 3. improving the biodegradability of leather chemicals. While focusing on these topics, it is well-understood that a proper balance needs to be found between cost, sustainability and performance. In the meantime, leather’s end of life scenario plays a role and needs to be looked at again. One of the first results of this focused approach is our patentpending polyphenolic syntan product, in which industrial lignins are used during the chemical conversion process to replace part of the phenol (40-50 w/w%) used in the production of otherwise 100% petro-based polyphenolic retanning chemicals. We have shown that our innovative technology is compatible with most of the industrial lignins (kraft, soda, organosolv, hydrolysis) from different origins (soft/hard wood, grass, straw). The obtained polyphenolic products have real tanning power and are suitable to be used as retanning agents for various types of leather rendering good organoleptic properties with additional added value of increased bio-based content, improved biodegradability thus a higher MRS. The improved biodegradability of these products can contribute to decrease the effluent treatment load. Moreover, these products can be tailor-made to meet low emission (low free phenol, low free formaldehyde) requirements as well. In addition to the lignin-based polymers, the quickly developing project portfolio within the biobased platform manifests that Smit & zoon is making steady steps towards a largely sustainable leather value chain by 2025. Take-Away: Bio-Based products contritbute to a sustainable leather manufacturing process and leather value chain. Both the raw material renewability and product biodegradability are important parameters to evaluate the environmental impact of leather chemicals. Smit & zoon has developed a patent-pending bio-based synthan product using industrial lignins to replace part of the petro-based phenols in the production process

    Annotation Sensitivity: Training Data Collection Methods Affect Model Performance

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    When training data are collected from human annotators, the design of the annotation instrument, the instructions given to annotators, the characteristics of the annotators, and their interactions can impact training data. This study demonstrates that design choices made when creating an annotation instrument also impact the models trained on the resulting annotations. We introduce the term annotation sensitivity to refer to the impact of annotation data collection methods on the annotations themselves and on downstream model performance and predictions. We collect annotations of hate speech and offensive language in five experimental conditions of an annotation instrument, randomly assigning annotators to conditions. We then fine-tune BERT models on each of the five resulting datasets and evaluate model performance on a holdout portion of each condition. We find considerable differences between the conditions for 1) the share of hate speech/offensive language annotations, 2) model performance, 3) model predictions, and 4) model learning curves. Our results emphasize the crucial role played by the annotation instrument which has received little attention in the machine learning literature. We call for additional research into how and why the instrument impacts the annotations to inform the development of best practices in instrument design.Comment: EMNLP 2023 Findings: https://aclanthology.org/2023.findings-emnlp.992

    Phenology and interspecific association of Forficula auricularia and Forficula pubescens in apple orchards

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    The European earwig Forficula auricularia L. (Dermaptera: Forficulidae) has been widely studied as a key predator of pests in temperate regions, but its phenology and behavior may differ in warmer areas such as the Mediterranean. Here we assessed the phenology, aggregation, and interspecific association of F. auricularia and Forficula pubescens Gené, the only two species found consistently in both ground and canopy shelters in Mediterranean apple orchards. In addition to F. auricularia and F. pubescens, three other earwig species, namely Labidura riparia Pallas, Nala lividipes Dufour and Euborellia moesta Gené, were found occasionally. The mature stages of F. auricularia were observed mainly from May to November in tree shelters and immature ones from October to June in ground shelters. Adult individuals of F. pubescens were observed year-round and nymph instars were detected from April to June in ground as well as in tree shelters. The suitability of the current degree-days models for temperate regions was evaluated for the prediction of European earwig phenology in a Mediterranean climate. Regarding interspecific association, F. auricularia and F. pubescens co-occurred in canopies without apparent competition. This study provides useful weekly data about the phenology of the two earwig species throughout the year that can be used to detect the key periods during which to enhance their populations in pip fruit orchards or to control them in stone fruit crops. Furthermore, our results are of relevance for the development of new phenological models of earwigs in Mediterranean areas where nymphs hibernate, a feature that makes current models inaccurate.Funding: This study was funded by the Spanish project Programa Nacional de Investigación y Desarrollo Agrario nº AGL2010- 17486 (AGR) Control integrado de plagas en frutales de pepita y hueso
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