Utrecht University

About: Utrecht University is a education organization based out in Utrecht, Utrecht, Netherlands. It is known for research contribution in the topics: Population & Context (language use). The organization has 58176 authors who have published 139351 publications receiving 6214282 citations. The organization is also known as: UU & Universiteit Utrecht.

Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU

Abstract: Objective:To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU.Design:Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups g

Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP

Abstract: Rap1 is a small, Ras-like GTPase that was first identified as a protein that could suppress the oncogenic transformation of cells by Ras. Rap1 is activated by several extracellular stimuli and may be involved in cellular processes such as cell proliferation, cell differentiation, T-cell anergy and platelet activation. At least three different second messengers, namely diacylglycerol, calcium and cyclic AMP, are able to activate Rap1 by promoting its release of the guanine nucleotide GDP and its binding to GTP. Here we report that activation of Rap1 by forskolin and cAMP occurs independently of protein kinase A (also known as cAMP-activated protein kinase). We have cloned the gene encoding a guanine-nucleotide-exchange factor (GEF) which we have named Epac (exchange protein directly activated by cAMP). This protein contains a cAMP-binding site and a domain that is homologous to domains of known GEFs for Ras and Rap1. Epac binds cAMP in vitro and exhibits in vivo and in vitro GEF activity towards Rap1. cAMP strongly induces the GEF activity of Epac towards Rap1 both in vivo and in vitro. We conclude that Epac is a GEF for Rap1 that is regulated directly by cAMP and that Epac is a new target protein for cAMP.

Functional impact of global rare copy number variation in autism spectrum disorders

Abstract: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

Autoantibodies against type I IFNs in patients with life-threatening COVID-19.

Abstract: Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Job resources buffer the impact of job demands on burnout

Abstract: This study tested and refined the job demands–resources model, demonstrating that several job resources play a role in buffering the impact of several job demands on burnout. A total of 1,012 employees of a large institute for higher education participated in the study. Four demanding aspects of the job (e.g., work overload, emotional demands) and 4 job resources (e.g., autonomy, performance feedback) were used to test the central hypothesis that the interaction between (high) demands and (low) resources produces the highest levels of burnout (exhaustion, cynicism, reduced professional efficacy). The hypothesis was rejected for (reduced) professional efficacy but confirmed for exhaustion and cynicism regarding 18 out of 32 possible 2-way interactions (i.e., combinations of specific job demands and resources). During the past three decades, many studies have shown that unfavorable job characteristics may have a profound impact on job stress and burnout. For example, research has revealed that work overload, lack of autonomy, emotional demands, lowsocial support, and role ambiguity can all lead to feelings of exhaustion and negative, callous attitudes toward work (for reviews, see Lee & Ashforth, 1996; Schaufeli & Enzmann, 1998). Although these previous studies have produced a long list of possible antecedents of burnout, theoretical progress has been limited. The present study tries to increase our insight in the causes of burnout by extending the job demands–resources (JD-R) model (Bakker, Demerouti, De Boer, & Schaufeli, 2003; Demerouti, Bakker, Nachreiner, & Schaufeli, 2001). The central hypothesis tested is that burnout is the result of an imbalance between job demands and resources, and that several job resources may compensate for the influence of several job demands on burnout. Evidence for this contention would offer organizations a clear tool for competitive advantage, because proof for such moderating effects implies that employee well-being and productivity may be maintained, even when it is difficult to reduce or redesign job demands.