In this study, 20% of patients with Covid-19 had a prolonged activated partial-thromboplastin time. In 90% of these cases, the cause was lupus anticoagulant, with no associated bleeding. Patients ...with Covid-19 are susceptible to thromboses. The presence of a prolonged aPTT should, in general, not be considered a contraindication to anticoagulation.
Abstract
The emergence of large gene expression datasets has revealed the need for improved tools to identify enriched gene categories and visualize enrichment patterns. While gene ontogeny (GO) ...provides a valuable tool for gene set enrichment analysis, it has several limitations. First, it is difficult to graph multiple GO analyses for comparison. Second, genes from some model systems are not well represented. For example, ∼30% of Caenorhabditis elegans genes are missing from the analysis in commonly used databases. To allow categorization and visualization of enriched C. elegans gene sets in different types of genome-scale data, we developed WormCat, a web-based tool that uses a near-complete annotation of the C. elegans genome to identify coexpressed gene sets and scaled heat map for enrichment visualization. We tested the performance of WormCat using a variety of published transcriptomic datasets, and show that it reproduces major categories identified by GO. Importantly, we also found previously unidentified categories that are informative for interpreting phenotypes or predicting biological function. For example, we analyzed published RNA-seq data from C. elegans treated with combinations of lifespan-extending drugs, where one combination paradoxically shortened lifespan. Using WormCat, we identified sterol metabolism as a category that was not enriched in the single or double combinations, but emerged in a triple combination along with the lifespan shortening. Thus, WormCat identified a gene set with potential. phenotypic relevance not found with previous GO analysis. In conclusion, WormCat provides a powerful tool for the analysis and visualization of gene set enrichment in different types of C. elegans datasets.
The life-long inhibitor risk in non-severe hemophilia A has been an important clinical and research focus in recent years. Non-severe hemophilia A is most commonly caused by point mutation, missense
...genotypes, of which over 500 variants are described. The immunogenic potential of just a single amino acid change within a complex 2,332 amino acid protein is an important reminder of the challenges of protein replacement therapies in diverse, global populations. Although some
genotypes have been identified as "high risk" mutations in non-severe hemophilia A (e.g., R593C), this is likely, in part at least, a reporting bias and oversimplification of the underlying immunological mechanism. Bioinformatic approaches offer a strategy to dissect the contribution of
genotype in the context of the wider HLA diversity through which antigenic peptides will necessarily be presented. Extensive modeling of all permutations of FVIII-derived fifteen-mer peptides straddling all reported
genotype positions demonstrate the likely heterogeneity of peptide binding affinity to different HLA II grooves. For the majority of
genotypes it is evident that inhibitor risk prediction is dependent on the combination of
genotype and available HLA II. Only a minority of FVIII-derived peptides are predicted to bind to all candidate HLA molecules.
predictions still over call the risk of inhibitor occurrence, suggestive of mechanisms of "protection" against clinically meaningful inhibitor events. The structural homology between FVIII and FV provides an attractive mechanism by which some
genotypes may be afforded co-incidental tolerance through homology of FV and FVIII primary amino sequence.
strategies enable the extension of this hypothesis to analyse the extent to which co-incidental cross-matching exists between FVIII-derived primary peptide sequences and any other protein in the entire human proteome and thus potential central tolerance. This review of complimentary
, and clinical epidemiology data documents incremental insights into immunological mechanism of inhibitor occurrence in non-severe hemophilia A over the last decade. However, complex questions remain about antigenic processing and presentation to truly understand and predict an individual person with hemophilia risk of inhibitor occurrence.
The direct synthesis of monolayer and multilayer ReS2 by chemical vapor deposition at a low temperature of 450 °C is reported. Detailed characterization of this material is performed using various ...spectroscopy and microscopy methods. Furthermore initial field‐effect transistor characteristics are evaluated, which highlight the potential in being used as an n‐type semiconductor.
An AAV5 vector containing the factor IX Padua allele was administered to 54 men with hemophilia B. Factor IX expression increased to approximately 39% of normal, and the annualized bleeding rate was ...decreased to 1.5.
haemophilia is an inherited bleeding disorder caused by a deficiency in one of the blood coagulation factors. For people affected by severe haemophilia, the deficiency can cause spontaneous internal ...bleeding. Most young people with severe haemophilia in the UK follow a preventative treatment regimen (prophylaxis) consisting of several intravenous injections of factor concentrate each week. There is good evidence that prophylaxis reduces bleeds whilst also improving quality of life. However, levels of adherence among young people with haemophilia reported in the existing literature vary widely and are predominately based on estimations made by healthcare professionals and parents. Additionally, drivers of (non)adherence among young people specifically have not been evidenced.
to assess self-reported adherence among young people with haemophilia, provide evidence of psychosocial predictors of adherence, and to establish the associations between non-adherence and number of bleeds and hospital visits.
91 participants were recruited during outpatient appointments in 13 haemophilia centres across England and Wales, and invited to complete a questionnaire assessing self-reported adherence (VERITAS-Pro), Haemophilia-related pain and impact of pain, Illness Perceptions, Beliefs about Medications, Self-efficacy, Outcome expectations, Positive and Negative Affect, and Social support. Number of hospital visits and bleeds during the previous six months were collected from medical files.
Of 78 participants with complete data, just 18% had scores indicating non-adherence. Psychosocial predictors differed between intentional (skipping) and un-intentional (forgetting) non-adherence. Overall, however, better adherence was reported where participants perceived the need for prophylaxis was greater than their concern over taking it as well as having a positive expectancy of its effectiveness, good social support and a stronger emotional reaction to having haemophilia.
The findings indicate that adherence is generally good, and that assessing illness and treatment beliefs, social support and outcome expectations may play a valuable role in identifying which individuals are at risk of non-adherence. Interventions aimed at improving adherence should particularly consider improving social support, reducing patients' concerns about prophylaxis, increasing their belief in the necessity of prophylaxis, and increasing positive outcome expectations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction
Adeno‐associated virus (AAV)‐based gene therapy for haemophilia presents a challenge to the existing structure of haemophilia centres and requires a rethink of current collaboration and ...information exchange with the aim of ensuring a system that is fit‐for‐purpose for advanced therapies to maximise benefits and minimise risks. In Europe, a certification process based on the number of patients and facilities is offered to the haemophilia centres by European Haemophilia Network (EUHANET).
Aim and methods
This joint European Association for Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) publication describes criteria for centres participating in gene therapy care that require a reassessment of the infrastructure of comprehensive care and provides an outlook on how these criteria can be implemented in the future work of haemophilia centres.
Results
The core definition of a haemophilia treatment centre remains, but additional roles could be implemented. A modifiable ‘hub‐and‐spoke’ model addresses all aspects associated with gene therapy, including preparation and administration of the gene therapy product, determination of coagulation and immunological parameters, joint score and function, and liver health. This will also include the strategy on how to follow‐up patients for a long‐term safety and efficacy surveillance.
Conclusion
We propose a modifiable, networked ‘hub and spoke’ model with a long term safety and efficacy surveillance system. This approach will be progressively developed with the goal of making haemophilia centres better qualified to deliver gene therapy and to make gene therapy accessible to all persons with haemophilia, irrespective of their country or centre of origin.
PDF
