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Expectation of sickness absence duration: a review on statements and methods used in guidelines in Europe and North America

  • de Boer, Wout E. L.
  • Mousavi, S. Mohsen
  • Delclòs i Clanchet, Jordi, 1956-
  • Benavides, Fernando G. (Fernando García)
  • Lorente, Mercedes
  • Kunz, Regina
Background: Certifying physicians play a key role in the management of sickness absence and are often provided with guidelines. Some of these guidelines contain statements on expected sickness absence duration, according to diagnosis. We were interested in exploring the evidence base of these statements. Methods: We identified guidelines through a survey of EUMASS members and a literature search of the Internet and PubMed. We extracted the statements and methods from the guidelines. We compared: diagnoses that were addressed, expected durations and development processes followed. Next, we presented our findings to the developers, to afford them an opportunity to comment and/or correct any misinterpretations. Results: We identified 4 guidelines from social insurance institutions (France, Serbia, Spain and Sweden) and 4 guidelines from private organisations (1 Netherlands, 3 US). Guidelines addressed between 63 and some 63000 health conditions (ICD 10 codes). Health conditions overlapped among guidelines. Direct comparison is hampered by differences in coding (ICD 9 or 10) and level of aggregation (three or four digit, clustering of diseases and treatment situations). Expectations about duration are defined as minimum, maximum, and optimum or mean or median and percentile distribution, stratified to age and work requirements. In a sample of 5 diagnoses we found overlap in expected duration but also differences. Guidelines are developed differently, pragmatic expert consensus being used most, supplemented with data on sickness absence from different registers, other guidelines and non-systematic literature reviews. The effectiveness of these guidelines has not yet been formally evaluated. Conclusions: Expectations about duration of sickness absence by diagnosis are expressed in several guidelines. The expectations are difficult to compare, their evidence base is unclear and their effectiveness needs to be established.

Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells

  • Chen, Lu
  • Garrido-Martín, Diego
  • Guigó Serra, Roderic
  • Soranzo, Nicole
Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk., This work was predominantly funded by the EU FP7 High Impact Project BLUEPRINT (HEALTH-F5-2011-282510) and the Canadian Institutes of Health Research (CIHR EP1-120608). We thank Simon Dökel, Matthias Linser, Alexander Kovacsovics, and Daniela Balzereit for excellent technical skills on the Illumina platform and Mark Kristiansen (UCL Genomics) for processing the Illumina Infinium HumanMethylation450 BeadChIPs. We gratefully acknowledge the participation of all NIHR Cambridge BioResource volunteers. We thank the Cambridge BioResource staff for their help with volunteer recruitment. We thank members of the Cambridge BioResource SAB and Management Committee for their support of our study and the National Institute for Health Research Cambridge Biomedical Research Centre for funding. The research leading to these results has also received funding from the European Molecular Biology Laboratory, the Max Planck Society, the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa 2013-2017”, SEV-2012-0208 and Spanish National Bioinformatics Institute (INB-ISCIII) PT13/0001/0021 co-funded by FEDER “Una Manera de hacer Europa.” D.G.-M. is supported by a “la Caixa”-Severo Ochoa pre-doctoral fellowship, M.F. was supported by the BHF Cambridge Centre of Excellence (RE/13/6/30180), K.D. is funded as an HSST trainee by NHS Health Education England, S.E. is supported by a fellowship from “La Caixa”, V.P. is supported by an FEBS long-term fellowship, and N.S.’s research is supported by the Wellcome Trust (WT098051 and WT091310), the EU FP7 (EPIGENESYS257082), and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. The Cardiovascular Epidemiology Unit is supported by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), UK National Institute for Health Research Cambridge Biomedical Research Centre. The Blood and Transplant Unit (BTRU) in Donor Health and Genomics is part of, and funded by, the National Institute for Health Research (NIHR) and is a partnership between the University of Cambridge and NHS Blood and Transplant (NHSBT) in collaboration with the University of Oxford and the Wellcome Trust Sanger Institute. The T cell data were produced by the McGill Epigenomics Mapping Centre (EMC McGill). It is funded under the Canadian Epigenetics, Environment, and Health Research Consortium (CEEHRC) by the Canadian Institutes of Health Research and by Genome Quebec (CIHR EP1-120608), with additional support from Genome Canada and FRSQ. T.P. holds a Canada Research Chair. P.F. is a member of the Scientific Advisory Board of Omicia, Inc. S.W. is now an employee of GENOMICS plc, with some minor share options, although all work was conducted when he was an employee of EMBL-EBI.

En recuerdo de Tony McMichael

  • Sunyer Deu, Jordi
  • Antó i Boqué, Josep Maria
  • Kogevinas, Manolis

Thrombin stimulates insulin secretion via protease-activated receptor-3

  • Hänzelmann, Sonja, 1981-
  • Wang, Jinling
  • Güney, Emre, 1983-
  • Tang, Yunzhao
  • Zhang, Enming
  • Axelsson, Annika S.
  • Nenonen, Hannah
  • Salehi, Albert S.
  • Wollheim, Claes B.
  • Zetterberg, Eva
  • Berntorp, Erik
  • Costa, Ivan G.
  • Castelo Valdueza, Robert
  • Rosengren, Anders H.
The disease mechanisms underlying type 2 diabetes (T2D) remain poorly defined. Here we aimed to explore the pathophysiology of T2D by analyzing gene co-expression networks in human islets. Using partial correlation networks we identified a group of co-expressed genes (‘module’) including F2RL2 that was associated with glycated hemoglobin. F2Rl2 is a G-protein-coupled receptor (GPCR) that encodes protease-activated receptor-3 (PAR3). PAR3 is cleaved by thrombin, which exposes a 6-amino acid sequence that acts as a ‘tethered ligand’ to regulate cellular signaling. We have characterized the effect of PAR3 activation on insulin secretion by static insulin secretion measurements, capacitance measurements, studies of diabetic animal models and patient samples. We demonstrate that thrombin stimulates insulin secretion, an effect that was prevented by an antibody that blocks the thrombin cleavage site of PAR3. Treatment with a peptide corresponding to the PAR3 tethered ligand stimulated islet insulin secretion and single β-cell exocytosis by a mechanism that involves activation of phospholipase C and Ca2+ release from intracellular stores. Moreover, we observed that the expression of tissue factor, which regulates thrombin generation, was increased in human islets from T2D donors and associated with enhanced β-cell exocytosis. Finally, we demonstrate that thrombin generation potential in patients with T2D was associated with increased fasting insulin and insulinogenic index. The findings provide a previously unrecognized link between hypercoagulability and hyperinsulinemia and suggest that reducing thrombin activity or blocking PAR3 cleavage could potentially counteract the exaggerated insulin secretion that drives insulin resistance and β-cell exhaustion in T2D., Supported by the NovoNordisk foundation, the Hjelt foundation and the Swedish Research Council. S.H. and R.C. acknowledge support from a Spanish MINECO grant (ref. TIN2011-22826) and S.H. and I.C. acknowledge support from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University.

MACVIA clinical decision algorithm in adolescents and adults with allergic rhinitis

  • Bousquet, Jean
  • MASK study group
  • Antó i Boqué, Josep Maria
  • Sunyer Deu, Jordi
The selection of pharmacotherapy for patients with allergic rhinitis (AR) depends on several factors, including age, prominent symptoms, symptom severity, control of AR, patient preferences, and cost. Allergen exposure and the resulting symptoms vary, and treatment adjustment is required. Clinical decision support systems (CDSSs) might be beneficial for the assessment of disease control. CDSSs should be based on the best evidence and algorithms to aid patients and health care professionals to jointly determine treatment and its step-up or step-down strategy depending on AR control. Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR [fighting chronic diseases for active and healthy ageing]), one of the reference sites of the European Innovation Partnership on Active and Healthy Ageing, has initiated an allergy sentinel network (the MACVIA-ARIA Sentinel Network). A CDSS is currently being developed to optimize AR control. An algorithm developed by consensus is presented in this article. This algorithm should be confirmed by appropriate trials.

Network morphospace

  • Avena-Koenigsberger, Andrea
  • Goñi, Joaquín
  • Solé Vicente, Ricard, 1962-
  • Sporns, Olaf
The structure of complex networks has attracted much attention in recent years. It has been noted that many real-world examples of networked systems share a set of common architectural features. This raises important questions about their origin, for example whether such network attributes reflect common design principles or constraints imposed by selectional forces that have shaped the evolution of network topology. Is it possible to place the many patterns and forms of complex networks into a common space that reveals their relations, and what are the main rules and driving forces that determine which positions in such a space are occupied by systems that have actually evolved? We suggest that these questions can be addressed by combining concepts from two currently relatively unconnected fields. One is theoretical morphology, which has conceptualized the relations between morphological traits defined by mathematical models of biological form. The second is network science, which provides numerous quantitative tools to measure and classify different patterns of local and global network architecture across disparate types of systems. Here, we explore a new theoretical concept that lies at the intersection between both fields, the ‘network morphospace’. Defined by axes that represent specific network traits, each point within such a space represents a location occupied by networks that share a set of common ‘morphological’ characteristics related to aspects of their connectivity. Mapping a network morphospace reveals the extent to which the space is filled by existing networks, thus allowing a distinction between actual and impossible designs and highlighting the generative potential of rules and constraints that pervade the evolution of complex systems.

Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants

  • NCD Risk Factor Collaboration (NCD-RisC)
  • Sunyer Deu, Jordi
Background: Underweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries. Methods: We analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18·5 kg/m2 [underweight], 18·5 kg/m2 to <20 kg/m2, 20 kg/m2 to <25 kg/m2, 25 kg/m2 to <30 kg/m2, 30 kg/m2 to <35 kg/m2, 35 kg/m2 to <40 kg/m2, ≥40 kg/m2 [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue. Findings: We used 1698 population-based data sources, with more than 19·2 million adult participants (9·9 million men and 9·3 million women) in 186 of 200 countries for which estimates were made. Global age-standardised mean BMI increased from 21·7 kg/m2 (95% credible interval 21·3–22·1) in 1975 to 24·2 kg/m2 (24·0–24·4) in 2014 in men, and from 22·1 kg/m2 (21·7–22·5) in 1975 to 24·4 kg/m2 (24·2–24·6) in 2014 in women. Regional mean BMIs in 2014 for men ranged from 21·4 kg/m2 in central Africa and south Asia to 29·2 kg/m2 (28·6–29·8) in Polynesia and Micronesia; for women the range was from 21·8 kg/m2 (21·4–22·3) in south Asia to 32·2 kg/m2 (31·5–32·8) in Polynesia and Micronesia. Over these four decades, age-standardised global prevalence of underweight decreased from 13·8% (10·5–17·4) to 8·8% (7·4–10·3) in men and from 14·6% (11·6–17·9) to 9·7% (8·3–11·1) in women. South Asia had the highest prevalence of underweight in 2014, 23·4% (17·8–29·2) in men and 24·0% (18·9–29·3) in women. Age-standardised prevalence of obesity increased from 3·2% (2·4–4·1) in 1975 to 10·8% (9·7–12·0) in 2014 in men, and from 6·4% (5·1–7·8) to 14·9% (13·6–16·1) in women. 2·3% (2·0–2·7) of the world's men and 5·0% (4·4–5·6) of women were severely obese (ie, have BMI ≥35 kg/m2). Globally, prevalence of morbid obesity was 0·64% (0·46–0·86) in men and 1·6% (1·3–1·9) in women. Interpretation: If post-2000 trends continue, the probability of meeting the global obesity target is virtually zero. Rather, if these trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women. Nonetheless, underweight remains prevalent in the world's poorest regions, especially in south Asia.

The RNA-binding profile of Acinus, a peripheral component of the exon junction complex, reveals its role in splicing regulation

  • Rodor, Julie
  • Pan, Qun
  • Blencowe, Benjamin J.
  • Eyras Jiménez, Eduardo
  • Cáceres, Javier F.
Acinus (apoptotic chromatin condensation inducer in the nucleus) is an RNA-binding protein (RBP) originally identified for its role in apoptosis. It was later found to be an auxiliary component of the exon junction complex (EJC), which is deposited at exon junctions as a consequence of pre-mRNA splicing. To uncover the cellular functions of Acinus and investigate its role in splicing, we mapped its endogenous RNA targets using the cross-linking immunoprecipitation protocol (iCLIP). We observed that Acinus binds to pre-mRNAs, associating specifically to a subset of suboptimal introns, but also to spliced mRNAs. We also confirmed the presence of Acinus as a peripheral factor of the EJC. RNA-seq was used to investigate changes in gene expression and alternative splicing following siRNA-mediated depletion of Acinus in HeLa cells. This analysis revealed that Acinus is preferentially required for the inclusion of specific alternative cassette exons and also controls the faithful splicing of a subset of introns. Moreover, a large number of splicing changes can be related to Acinus binding, suggesting a direct role of Acinus in exon and intron definition. In particular, Acinus regulates the splicing of DFFA/ICAD transcript, a major regulator of DNA fragmentation. Globally, the genome-wide identification of RNA targets of Acinus revealed its role in splicing regulation as well as its involvement in other cellular pathways, including cell cycle progression. Altogether, this study uncovers new cellular functions of an RBP transiently associated with the EJC., J.F.C. was supported by Core funding from the Medical Research Council and by the Wellcome Trust (grant 095518/Z/11/Z). B.J.B. was supported by grants from the CIHR (Canadian Institutes of Health Research). B.J.B. holds the Banbury Chair in Medical Research at the University of Toronto. E.E. was supported by MINECO (Ministerio de Economía y Competitividad) and FEDER (Fondo Europeo de Desarrollo Regional) through grant BIO2014-52566-R, by Sandra Ibarra Foundation for Cancer, and by AGAUR (Agència de Gestió d'Ajuts Universitaris i de Recerca) through grant 2014-SGR1121.

E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing

  • Millán-Uclés, África
  • Zuluaga, Susana
  • Marqués, Marta
  • Vallejo-Díaz, Jesus
  • Sanz, Lorena
  • Cariaga-Martínez, Ariel E.
  • Real, Francisco X.
  • Carrera, Ana C.
Alterations in phosphatidylinositol 3-kinase (PI3K) and in PTEN (phosphatase and tensin homolog), the negative regulator of the PI3K pathway, are found in nearly half of human tumors. As PI3Kβ, the main isoform activated in PTEN-mutant tumors, has kinase-dependent and -independent activities, we compared the effects of depleting vs. drug-inhibiting PI3Kβ kinase activity in a collection of diverse tumor types and in a set of bladder carcinoma cell lines grown as xenografts in mice. PI3Kβ depletion (by intratumor injection of PIK3CB siRNA) induced apoptosis and triggered regression of PTEN-mutant tumors more efficiently than PI3Kβ inhibition. A small proportion of these tumors was resistant to PI3Kβ downregulation; we analyzed what determined resistance in these cases. Using add-back experiments, we show that both PTEN mutation and low E-cadherin expression are necessary for PI3Kβ dependence. In bladder carcinoma, loss of E-cadherin expression coincides with N-cadherin upregulation. We found that PI3Kβ associated with N-cadherin and that PIK3CB depletion selectively disrupted N-cadherin cell adhesions in PTEN-mutant bladder carcinoma. These results support the use of PIK3CB interfering RNA as a therapeutic approach for high-risk bladder cancers that show E-cadherin loss and express mutant PTEN., This work was financed by grants from the Spanish Ministry of Science and Innovation (SAF2011-29530 to FXR, SAF2013-48657 to ACC; Consolider ONCOBIO to FXR, Network of Cooperative Research in Cancer cofinanced by the European Regional Development Fund (RTICC RD12/0036/0059 to ACC and RD12/0036/0034 to FXR), the Madrid regional government (BMD2502 to ACC), and an AECC (Spanish Association against Cancer) grant to FXR.

Aurora-A regulates MCRS1 function during mitosis

  • Meunier, Sylvain
  • Timón Pérez, Krystal
  • Vernos, Isabelle, 1959-
The mitotic spindle is made of microtubules (MTs) nucleated through different pathways involving the centrosomes, the chromosomes or the walls of pre-existing MTs. MCRS1 is a RanGTP target that specifically associates with the chromosome-driven MTs protecting them from MT depolymerases. MCRS1 is also needed for the control of kinetochore fiber (K-fiber) MT minus-ends dynamics in metaphase. Here, we investigated the regulation of MCRS1 activity in M-phase. We show that MCRS1 is phosphorylated by the Aurora-A kinase in mitosis on Ser35/36. Although this phosphorylation has no role on MCRS1 localization to chromosomal MTs and K-fiber minus-ends, we show that it regulates MCRS1 activity in mitosis. We conclude that Aurora-A activity is particularly important in the tuning of K-fiber minus-ends dynamics in mitosis., Work in the Vernos lab is supported by the Spanish Ministry of Economy and Competitiveness grants BFU2012-37163. We acknowledge support of the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa 2013–2017”, SEV-2012-0208.

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