von Willebrand disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding. Early diagnosis and treatment are important to prevent and treat these... Show morevon Willebrand disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of diagnostic tests using different cutoff values of von Willebrand factor antigen (VWF:Ag) and platelet-dependent von Willebrand factor (VWF) activity assays in the diagnosis of VWD. We searched Cochrane Central Register for Controlled Trials, MEDLINE, and Embase databases for eligible studies. We pooled estimates of sensitivity and specificity and reported patient-important outcomes when relevant. This review included 21 studies that evaluated VWD diagnosis. The results showed low certainty in the evidence for a net health benefit from reconsidering the diagnosis of VWD vs removing the disease diagnosis in patients with VWF levels that have normalized with age. For the diagnosis of type 1 VWD, VWF sequence variants were detected in 75% to 82% of patients with VWF:Ag < 0.30 IU/mL and in 44% to 60% of patients with VWF:Ag between 0.30 and 0.50 IU/mL. A sensitivity of 0.90 (95% confidence interval [CI], 0.83-0.94) and a specificity of 0.91 (95% CI, 0.76-0.97) were observed for a platelet-dependent VWF activity/VWF:Ag ratio < 0.7 in detecting type 2 VWD (moderate certainty in the test accuracy results). VWF:Ag and platelet-dependent activity are continuous variables that are associated with an increase in bleeding risk with decreasing levels. This systematic review shows that using a VWF activity/VWF:Ag ratio < 0.7 vs lower cutoff levels in patients with an abnormal initial VWD screen is more accurate for the diagnosis of type 2 VWD. Show less
Background\Objectives\Methods\Results\Conclusions\Collateral effects of antibiotic resistance occur when resistance to one antibiotic agent leads to increased resistance or increased sensitivity to... Show moreBackground\Objectives\Methods\Results\Conclusions\Collateral effects of antibiotic resistance occur when resistance to one antibiotic agent leads to increased resistance or increased sensitivity to a second agent, known respectively as collateral resistance (CR) and collateral sensitivity (CS). Collateral effects are relevant to limit impact of antibiotic resistance in design of antibiotic treatments. However, methods to detect antibiotic collateral effects in clinical population surveillance data of antibiotic resistance are lacking.\nTo develop a methodology to quantify collateral effect directionality and effect size from large-scale antimicrobial resistance population surveillance data. We propose a methodology to quantify and test collateral effects in clinical surveillance data based on a conditional t-test. Our methodology was evaluated using MIC data for 419 Escherichia coli strains, containing MIC data for 20 antibiotics, which were obtained from the Pathosystems Resource Integration Center (PATRIC) database. We demonstrate that the proposed approach identifies several antibiotic combinations that show symmetrical or non-symmetrical CR and CS. For several of these combinations, collateral effects were previously confirmed in experimental studies. We furthermore provide insight into the power of our method for multiple collateral effect sizes and MIC distributions. Our proposed approach is of relevance as a tool for analysis of large-scale population surveillance studies to provide broad systematic identification of collateral effects related to antibiotic resistance, and is made available to the community as an R package. This method can help mapping CS and CR, which could guide combination therapy and prescribing in the future. Show less
Fraga-González, G.; Smit, D.J.A.; Molen, M.J.W. van der; Tijms, J.; Stam, C.J.; Geus, E.J.C. de; Molen, M.W. van der 2021
We performed an EEG graph analysis on data from 31 typical readers (22.27 ± 2.53 y/o) and 24 dyslexics (22.99 ± 2.29 y/o), recorded while they were engaged in an audiovisual task and during resting... Show moreWe performed an EEG graph analysis on data from 31 typical readers (22.27 ± 2.53 y/o) and 24 dyslexics (22.99 ± 2.29 y/o), recorded while they were engaged in an audiovisual task and during resting-state. The task simulates reading acquisition as participants learned new letter-sound mappings via feedback. EEG data was filtered for the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), and beta (13-30 Hz) bands. We computed the Phase Lag Index (PLI) to provide an estimate of the functional connectivity between all pairs of electrodes per band. Then, networks were constructed using a Minimum Spanning Tree (MST), a unique sub-graph connecting all nodes (electrodes) without loops, aimed at minimizing bias in between groups and conditions comparisons. Both groups showed a comparable accuracy increase during task blocks, indicating that they correctly learned the new associations. The EEG results revealed lower task-specific theta connectivity, and lower theta degree correlation over both rest and task recordings, indicating less network integration in dyslexics compared to typical readers. This pattern suggests a role of theta oscillations in dyslexia and may reflect differences in task engagement between the groups, although robust correlations between MST metrics and performance indices were lacking. Show less
Lamprecht, A.L.; Palmblad, M.; Ison, J.; Schwämmle, V.; Al Manir, M.S.; Altinas, I.; ... ; Wolstencroft, K.J. 2021
Scientific data analyses often combine several computational tools in automated pipelines, or workflows. Thousands of such workflows have been used in the life sciences, though their composition... Show moreScientific data analyses often combine several computational tools in automated pipelines, or workflows. Thousands of such workflows have been used in the life sciences, though their composition has remained a cumbersome manual process due to a lack of standards for annotation, assembly, and implementation. Recent technological advances have returned the long-standing vision of automated workflow composition into focus. This article summarizes a recent Lorentz Center workshop dedicated to automated composition of workflows in the life sciences. We survey previous initiatives to automate the composition process, and discuss the current state of the art and future perspectives. We start by drawing the "big picture" of the scientific workflow development life cycle, before surveying and discussing current methods, technologies and practices for semantic domain modelling, automation in workflow development, and workflow assessment. Finally, we derive a roadmap of individual and community-based actions to work toward the vision of automated workflow development in the forthcoming years. A central outcome of the workshop is a general description of the workflow life cycle in six stages: 1) scientific question or hypothesis, 2) conceptual workflow, 3) abstract workflow, 4) concrete workflow, 5) production workflow, and 6) scientific results. The transitions between stages are facilitated by diverse tools and methods, usually incorporating domain knowledge in some form. Formal semantic domain modelling is hard and often a bottleneck for the application of semantic technologies. However, life science communities have made considerable progress here in recent years and are continuously improving, renewing interest in the application of semantic technologies for workflow exploration, composition and instantiation. Combined with systematic benchmarking with reference data and large-scale deployment of production-stage workflows, such technologies enable a more systematic process of workflow development than we know today. We believe that this can lead to more robust, reusable, and sustainable workflows in the future. Show less
We provide a sound and relatively complete Hoare logic for reasoning about partial correctness of recursive procedures in presence of local variables and the call-by-value parameter mechanism and... Show moreWe provide a sound and relatively complete Hoare logic for reasoning about partial correctness of recursive procedures in presence of local variables and the call-by-value parameter mechanism and in which the correctness proofs support contracts and are linear in the length of the program. We argue that in spite of the fact that Hoare logics for recursive procedures were intensively studied, no such logic has been proposed in the literature. Show less
Mushrooms such as the dermocyboid Cortinarius rubrophyllus are characterized by strikingly colorful fruiting bodies. The molecular dyes responsible for such colors recently experienced a comeback... Show moreMushrooms such as the dermocyboid Cortinarius rubrophyllus are characterized by strikingly colorful fruiting bodies. The molecular dyes responsible for such colors recently experienced a comeback as photoactive compounds with remarkable photophysical and photobiological properties. One of them-7,7'-biphyscion-is a dimeric anthraquinone that showed promising anticancer effects in the low nanomolar range under blue-light irradiation. Compared to acidic anthraquinones, 7,7'-biphyscion was more efficiently taken up by cells and induced apoptosis after photoactivation. However, seasonal collection of mushrooms producing this compound, low extraction yields, and tricky fungal identification hamper further developments to the clinics. To bypass these limitations, we demonstrate here an alternative approach utilizing a precursor of 7,7'-biphyscion, i.e., the pre-anthraquinone flavomannin-6,6'-dimethyl ether, which is abundant in many species of the subgenus Dermocybe. Controlled oxidation of the crude extract significantly increased the yield of 7,7'-biphyscion by 100%, which eased the isolation process. We also present the mycochemical and photobiological characterization of the yet chemically undescribed species, i.e. C. rubrophyllus. In total, eight pigments (1-8) were isolated, including two new glycosylated anthraquinones (1 and 2). Light-dependent generation of singlet oxygen was detected for the first time for emodin-1-O-beta-D-glucopyranoside (3) [photophysical measurement: Phi(Delta) =0.11 (CD3OD)]. Furthermore, emodin (7) was characterized as promising compound in the photocytotoxicity assay with EC50-values in the low micromolar range under irradiation against cells of the cancer cell lines AGS, A549, and T24. Show less
The institutional development of European Union (EU) agencies is striking. Over the past decades, forty-six EU agencies have been established to support the European Commission and member states in... Show moreThe institutional development of European Union (EU) agencies is striking. Over the past decades, forty-six EU agencies have been established to support the European Commission and member states in their regulatory and executive tasks. Today, EU agencies are a vital part of the EU’s administrative capacity. EU agencies have received considerable scholarly attention that used a myriad of theoretical approaches—ranging from institutional, organizational, and bureaucratic reputation to interest group theories—to explain why EU agencies have been created; how they develop over time; whether they are wielders of supranational or intergovernmental power; how they legitimize themselves and cultivate a positive bureaucratic reputation; and how they form alliances or insulate themselves from specific stakeholders. This chapter reviews the rise of EU agencies and introduces a selection of theoretical perspectives that have been used by EU agency scholars to study EU-level agencification and EU agency behaviour, regulatory processes, and outputs. Show less
The vitamin A derivative, retinoid acid (RA) is key player in guiding adaptive mucosal immune responses. However, data on the uptake and metabolism of vitamin A within human immune cells has... Show moreThe vitamin A derivative, retinoid acid (RA) is key player in guiding adaptive mucosal immune responses. However, data on the uptake and metabolism of vitamin A within human immune cells has remained largely elusive because retinoids are small, lipophilic molecules which are difficult to detect. To overcome this problem and to be able to study the effect of vitamin A metabolism in human immune cell subsets, we have synthesized novel bio-orthogonal retinoid-based probes (clickable probes), which are structurally and functionally indistinguishable from vitamin A. The probes contain a functional group (an alkyne) to conjugate to a fluorogenic dye to monitor retinoid molecules in real-time in immune cells. We demonstrate, by using flow cytometry and microscopy, that multiple immune cells have the capacity to internalize retinoids to varying degrees, including human monocyte-derived dendritic cells (DCs) and naïve B lymphocytes. We observed that naïve B cells lack the enzymatic machinery to produce RA, but use exogenous retinoic acid to enhance CD38 expression. Furthermore, we showed that human DCs metabolize retinal into retinoic acid, which in co-culture with naïve B cells led to of the induction of CD38 expression. These data demonstrate that in humans, DCs can serve as an exogenous source of RA for naïve B cells. Taken together, through the use of clickable vitamins our data provide valuable insight in the mechanism of vitamin A metabolism and its importance for human adaptive immunity. Show less
Recognizing the imperative to evaluate species recovery and conservation impact, in 2012 the International Union for Conservation of Nature (IUCN) called for development of a "Green List of Species... Show moreRecognizing the imperative to evaluate species recovery and conservation impact, in 2012 the International Union for Conservation of Nature (IUCN) called for development of a "Green List of Species" (now the IUCN Green Status of Species). A draft Green Status framework for assessing species' progress toward recovery, published in 2018, proposed 2 separate but interlinked components: a standardized method (i.e., measurement against benchmarks of species' viability, functionality, and preimpact distribution) to determine current species recovery status (herein species recovery score) and application of that method to estimate past and potential future impacts of conservation based on 4 metrics (conservation legacy, conservation dependence, conservation gain, and recovery potential). We tested the framework with 181 species representing diverse taxa, life histories, biomes, and IUCN Red List categories (extinction risk). Based on the observed distribution of species' recovery scores, we propose the following species recovery categories: fully recovered, slightly depleted, moderately depleted, largely depleted, critically depleted, extinct in the wild, and indeterminate. Fifty-nine percent of tested species were considered largely or critically depleted. Although there was a negative relationship between extinction risk and species recovery score, variation was considerable. Some species in lower risk categories were assessed as farther from recovery than those at higher risk. This emphasizes that species recovery is conceptually different from extinction risk and reinforces the utility of the IUCN Green Status of Species to more fully understand species conservation status. Although extinction risk did not predict conservation legacy, conservation dependence, or conservation gain, it was positively correlated with recovery potential. Only 1.7% of tested species were categorized as zero across all 4 of these conservation impact metrics, indicating that conservation has, or will, play a role in improving or maintaining species status for the vast majority of these species. Based on our results, we devised an updated assessment framework that introduces the option of using a dynamic baseline to assess future impacts of conservation over the short term to avoid misleading results which were generated in a small number of cases, and redefines short term as 10 years to better align with conservation planning. These changes are reflected in the IUCN Green Status of Species Standard. Show less
