#1 Biological insights from 108 schizophrenia-associated genetic loci Link logo

Ripke, Stephan; Neale, Benjamin M.; Corvin, Aiden; Walters, James T. R.; Farh, Kai-How; Holmans, Peter A.; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Made

Nature Volume 511, Issue 7510, Pages 421–427

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Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.


#2 An atlas of active enhancers across human cell types and tissues Link logo

Andersson, Robin; Gebhard, Claudia; Miguel-Escalada, Irene; Hoof, Ilka; Bornholdt, Jette; Boyd, Mette; Chen, Yun; Zhao, Xiaobei; Schmidl, Christian; Suzuki, Takahiro; Ntini, Evgenia; Arner, Erik; Valen, Eivind; Li, Kang; Schwarzfischer, Lucia; Glatz, Dagm

Nature Volume 507, Issue 7493, Pages 455–461

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Enhancers control the correct temporal and cell-type-specific activation of gene expression in multicellular eukaryotes. Knowing their properties, regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis. Here we use the FANTOM5 panel of samples, covering the majority of human tissues and cell types, to produce an atlas of active, in vivo-transcribed enhancers. We show that enhancers share properties with CpG-poor messenger RNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used to compare regulatory programs between different cells at unprecedented depth, to identify disease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific and ubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents a unique resource for studies on cell-type-specific enhancers and gene regulation.


#3 A promoter-level mammalian expression atlas Link logo

Forrest, Alistair R. R.; Kawaji, Hideya; Rehli, Michael; Baillie, J. Kenneth; de Hoon, Michiel J. L.; Haberle, Vanja; Lassmann, Timo; Kulakovskiy, Ivan V.; Lizio, Marina; Itoh, Masayoshi; Andersson, Robin; Mungall, Christopher J.; Meehan, Terrence F.; Sch

Nature Volume 507, Issue 7493, Pages 462–470

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  • 984 Mendeley readers

Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.


#4 De novo mutations in schizophrenia implicate synaptic networks Link logo

Fromer, Menachem; Pocklington, Andrew J.; Kavanagh, David H.; Williams, Hywel J.; Dwyer, Sarah; Gormley, Padhraig; Georgieva, Lyudmila; Rees, Elliott; Palta, Priit; Ruderfer, Douglas M.; Carrera, Noa; Humphreys, Isla; Johnson, Jessica S.; Roussos, Panos;

Nature Volume 506, Issue 7487, Pages 179–184

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  • 912 Mendeley readers

Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case-control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders.


#5 Defining the role of common variation in the genomic and biological architecture of adult human height Link logo

Wood, Andrew R.; Esko, Tonu; Yang, Jian; Vedantam, Sailaja; Pers, Tune H.; Gustafsson, Stefan; Chun, Audrey Y.; Estrada, Karol; Luan, Jian'an; Kutalik, Zoltan; Amin, Najaf; Buchkovich, Martin L.; Croteau-Chonka, Damien C.; Day, Felix R.; Duan, Yanan; Fall

Nature Genetics Volume 46, Issue 1 1, Pages 1173–1186

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  • 28 news
  • 1 reference in Wikipedia
  • 633 Mendeley readers

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.


#6 Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock Link logo

Holst, Lars B.; Haase, Nicolai; Wetterslev, Jorn; Wernerman, Jan; Guttormsen, Anne B.; Karlsson, Sari; Johansson, Par I.; Aneman, Anders; Vang, Marianne L.; Winding, Robert; Nebrich, Lars; Nibro, Helle L.; Rasmussen, Bodil S.; Lauridsen, Johnny R. M.; Nie

New England Journal of Medicine Volume 371, Issue 15, Pages 1381–1391

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Background Blood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established. Methods In this multicenter, parallel-group trial, we randomly assigned patients in the intensive care unit (ICU) who had septic shock and a hemoglobin concentration of 9 g per deciliter or less to receive 1 unit of leukoreduced red cells when the hemoglobin level was 7 g per deciliter or less (lower threshold) or when the level was 9 g per deciliter or less (higher threshold) during the ICU stay. The primary outcome measure was death by 90 days after randomization. Results We analyzed data from 998 of 1005 patients (99.3%) who underwent randomization. The two intervention groups had similar baseline characteristics. In the ICU, the lower-threshold group received a median of 1 unit of blood (interquartile range, 0 to 3) and the higher-threshold group received a median of 4 units (interquartile range, 2 to 7). At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower-threshold group, as compared with 223 of 496 (45.0%) assigned to the higher-threshold group, had died (relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P=0.44). The results were similar in analyses adjusted for risk factors at baseline and in analyses of the per-protocol populations. The numbers of patients who had ischemic events, who had severe adverse reactions, and who required life support were similar in the two intervention groups. Conclusions Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions. (Funded by the Danish Strategic Research Council and others; TRISS ClinicalTrials.gov number, NCT01485315 .).


#7 Identification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes Link logo

Nielsen, H. Bjorn; Almeida, Mathieu; Juncker, Agnieszka Sierakowska; Rasmussen, Simon; Li, Junhua; Sunagawa, Shinichi; Plichta, Damian R.; Gautier, Laurent; Pedersen, Anders G.; Le Chatelier, Emmanuelle; Pelletier, Eric; Bonde, Ida; Nielsen, Trine; Manich

Nature Biotechnology Volume 32, Issue 8, Pages 822–828

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Most current approaches for analyzing metagenomic data rely on comparisons to reference genomes, but the microbial diversity of many environments extends far beyond what is covered by reference databases. De novo segregation of complex metagenomic data into specific biological entities, such as particular bacterial strains or viruses, remains a largely unsolved problem. Here we present a method, based on binning co-abundant genes across a series of metagenomic samples, that enables comprehensive discovery of new microbial organisms, viruses and co-inherited genetic entities and aids assembly of microbial genomes without the need for reference sequences. We demonstrate the method on data from 396 human gut microbiome samples and identify 7,381 co-abundance gene groups (CAGs), including 741 metagenomic species (MGS). We use these to assemble 238 high-quality microbial genomes and identify affiliations between MGS and hundreds of viruses or genetic entities. Our method provides the means for comprehensive profiling of the diversity within complex metagenomic samples.


#8 The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic

Colin Hill, Francisco Guarner, Gregor Reid, Glenn R. Gibson, Daniel J. Merenstein, Bruno Pot, Lorenzo Morelli, Roberto Berni Canani, Harry J. Flint, Seppo Salminen, Philip C. Calder, Mary Ellen Sanders

Nature Reviews Gastroenterology & Hepatology Volume 11, Issue 8, Pages 506–514

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An expert panel was convened in October 2013 by the International Scientific Association for Probiotics and Prebiotics (ISAPP) to discuss the field of probiotics. It is now 13 years since the definition of probiotics and 12 years after guidelines were published for regulators, scientists and industry by the Food and Agriculture Organization of the United Nations and the WHO (FAO/WHO). The FAO/WHO definition of a probiotic--"live microorganisms which when administered in adequate amounts confer a health benefit on the host"--was reinforced as relevant and sufficiently accommodating for current and anticipated applications. However, inconsistencies between the FAO/WHO Expert Consultation Report and the FAO/WHO Guidelines were clarified to take into account advances in science and applications. A more precise use of the term 'probiotic' will be useful to guide clinicians and consumers in differentiating the diverse products on the market. This document represents the conclusions of the ISAPP consensus meeting on the appropriate use and scope of the term probiotic.


#9 Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. PDF logo

Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, Gibbs JS, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil, P, Vonk Noordegraaf A, Zamorano JL, Zompatori M; ESC Committee for Practice Guidelines (CPG), Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R (Italy), Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, L

European Heart Journal Volume 35, Issue 43, Pages 3033–3073

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  • 458 Mendeley readers


#10 Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes Link logo

Jaiswal, Siddhartha; Fontanillas, Pierre; Flannick, Jason; Manning, Alisa; Grauman, Peter V.; Mar, Brenton G.; Lindsley, R. Coleman; Mermel, Craig H.; Burtt, Noel; Chavez, Alejandro; Higgins, John M.; Moltchanov, Vladislav; Kuo, Frank C.; Kluk, Michael J.

New England Journal of Medicine Volume 371, Issue 26, Pages 2488–2498

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Background The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. Methods We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Results Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Conclusions Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).


#11 Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality:meta-analysis of individual patient data for 8135 women in 22 randomised trials Link logo PDF logo

McGale, P.; Taylor, C.; Correa, C.; Cutter, D.; Duane, F.; Ewertz, M.; Gray, R.; Mannu, G.; Peto, R.; Whelan, T.; Wang, Y.; Wang, Z.; Darby, S.; , ; Joensuu, Heikki

The Lancet Volume 383, Issue 9935, Pages 2127–2135

  • 48 tweets
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  • 4 news
  • 404 Mendeley readers


#12 Quality control and conduct of genome-wide association meta-analyses Link logo

Winkler, Thomas W.; Day, Felix R.; Croteau-Chonka, Damien C.; Wood, Andrew R.; Locke, Adam E.; Maegi, Reedik; Ferreira, Teresa; Fall, Tove; Graff, Mariaelisa; Justice, Anne E.; Luan, Jian'an; Gustafsson, Stefan; Randall, Joshua C.; Vedantam, Sailaja; Work

Nature Protocols Volume 9, Issue 5, Pages 1192–1212

  • 3 tweets
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Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.


#13 Qualitative Content Analysis : a focus on trustworthiness Open access logo Link logo PDF logo

Elo, Satu; Kääriäinen, Maria; Kanste, Outi; Pölkki, Tarja; Utriainen, Kati; Kyngäs, Helvi

SAGE Open Volume 4, Issue 1

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#14 The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling Open access logo Link logo

Van Deun, Jan; Mestdagh, Pieter; Sormunen, Raija; Cocquyt, Veronique; Vermaelen, Karim; Vandesompele, Jo; Bracke, Marc; De Wever, Olivier; Hendrix, An

Journal of Extracellular Vesicles

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Despite an enormous interest in the role of extracellular vesicles, including exosomes, in cancer and their use as biomarkers for diagnosis, prognosis, drug response and recurrence, there is no consensus on dependable isolation protocols. We provide a comparative evaluation of 4 exosome isolation protocols for their usability, yield and purity, and their impact on downstream omics approaches for biomarker discovery. OptiPrep density gradient centrifugation outperforms ultracentrifugation and ExoQuick and Total Exosome Isolation precipitation in terms of purity, as illustrated by the highest number of CD63-positive nanovesicles, the highest enrichment in exosomal marker proteins and a lack of contaminating proteins such as extracellular Argonaute-2 complexes. The purest exosome fractions reveal a unique mRNA profile enriched for translation, ribosome, mitochondrion and nuclear lumen function. Our results demonstrate that implementation of high purification techniques is a prerequisite to obtain reliable omics data and identify exosome-specific functions and biomarkers.



#16 Increasing value and reducing waste in biomedical research regulation and management PDF logo

Salman, Rustam Al-Shahi; Beller, Elaine; Kagan, Jonathan; Hemminki, Elina; Phillips, Robert S.; Savulescu, Julian; Macleod, Malcolm; Wisely, Janet; Chalmers, Iain

The Lancet Volume 383, Issue 9912, Pages 176–185

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After identification of an important research question and selection of an appropriate study design, waste can arise from the regulation, governance, and management of biomedical research. Obtaining regulatory and governance approval has become increasingly burdensome and disproportionate to the conceivable risks to research participants. Regulation and governance involve interventions that are assumed to be justified in the interests of patients and the public, but they can actually compromise these interests. Inefficient management of the procedural conduct of research is wasteful, especially if it results in poor recruitment and retention of participants in well designed studies addressing important questions. These sources of waste can be minimised if the following four recommendations are addressed. First, regulators should use their influence to reduce other causes of waste and inefficiency in research. Second, regulators and policy makers should work with researchers, patients, and health professionals to streamline and harmonise the laws, regulations, guidelines, and processes that govern whether and how research can be done, and ensure that they are proportionate to the plausible risks associated with the research. Third, researchers and research managers should increase the efficiency of recruitment, retention, data monitoring, and data sharing in research through use of research designs known to reduce inefficiencies, and further research should be done to learn how efficiency can be increased. Finally, everyone, particularly those responsible for health-care systems, should promote integration of research into everyday clinical practice. Regulators and researchers should monitor adherence to each of these recommendations and publish metrics.


#17 Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility Link logo

Mahajan, Anubha; Go, Min Jin; Zhang, Weihua; Below, Jennifer E.; Gaulton, Kyle J.; Ferreira, Teresa; Horikoshi, Momoko; Johnson, Andrew D.; Ng, Maggie C. Y.; Prokopenko, Inga; Saleheen, Danish; Wang, Xu; Zeggini, Eleftheria; Abecasis, Goncalo R.; Adair, L

Nature Genetics Volume 46, Issue 3, Pages 234–244

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  • 17 news
  • 338 Mendeley readers

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.


#18 The first 1000 cultured species of the human gastrointestinal microbiota Link logo PDF logo

Rajilic-Stojanovic, Mirjana; de Vos, Willem M.

FEMS Microbiology Reviews Volume 38, Issue 5, Pages 996–1047

  • 65 tweets
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The microorganisms that inhabit the human gastrointestinal tract comprise a complex ecosystem with functions that significantly contribute to our systemic metabolism and have an impact on health and disease. In line with its importance, the human gastrointestinal microbiota has been extensively studied. Despite the fact that a significant part of the intestinal microorganisms has not yet been cultured, presently over 1000 different microbial species that can reside in the human gastrointestinal tract have been identified. This review provides a systematic overview and detailed references of the total of 1057 intestinal species of Eukarya (92), Archaea (8) and Bacteria (957), based on the phylogenetic framework of their small subunit ribosomal RNA gene sequences. Moreover, it unifies knowledge about the prevalence, abundance, stability, physiology, genetics and the association with human health of these gastrointestinal microorganisms, which is currently scattered over a vast amount of literature published in the last 150 years. This detailed physiological and genetic information is expected to be instrumental in advancing our knowledge of the gastrointestinal microbiota. Moreover, it opens avenues for future comparative and functional metagenomic and other high-throughput approaches that need a systematic and physiological basis to have an impact.


#19 Effects of long-term exposure to air pollution on natural-cause mortality: an analysis of 22 European cohorts within the multicentre ESCAPE project PDF logo

Beelen, Rob; Raaschou-Nielsen, Ole; Stafoggia, Massimo; Andersen, Zorana Jovanovic; Weinmayr, Gudrun; Hoffmann, Barbara; Wolf, Kathrin; Samoli, Evangelia; Fischer, Paul; Nieuwenhuijsen, Mark; Vineis, Paolo; Xun, Wei W.; Katsouyanni, Klea; Dimakopoulou, Konstantina; Oudin, Anna; Forsberg, Bertil; Modig, Lars; Havulinna, Aki S.; Lanki, Timo; Turunen, Anu; Oftedal, Bente; Nystad, Wenche; Nafstad, Per; De Faire, Ulf; Pedersen, Nancy L.; Ostenson, Claes-Goeran; Fratiglioni, Laura; Penell, Johanna; Korek, Michal

The Lancet Volume 383, Issue 9919

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Few studies on long-term exposure to air pollution and mortality have been reported from Europe. Within the multicentre European Study of Cohorts for Air Pollution Effects (ESCAPE), we aimed to investigate the association between natural-cause mortality and long-term exposure to several air pollutants.


#20 Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014 PDF logo

Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P, Pani L, Winblad B, Kivipelto M

Journal of Internal Medicine Volume 275, Issue 3, Pages 251–283

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The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or 'mild cognitive impairment due to Alzheimer's disease', for drugs considered to be disease modifying. The duration of trials has remained at 6-12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.


#21 Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke:a meta-analysis of individual patient data from randomised trials Link logo PDF logo

Emberson, Jonathan; Lees, Kennedy R.; Lyden, Patrick; Blackwell, Lisa; Albers, Gregory; Bluhmki, Erich; Brott, Thomas; Cohen, Geoff; Davis, Stephen; Donnan, Geoffrey; Grotta, James; Howard, George; Kaste, Markku; Koga, Masatoshi; von Kummer, Ruediger; Lan

The Lancet Volume 384, Issue 9958, Pages 1929–1935

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#22 An integrated catalog of reference genes in the human gut microbiome Link logo

Li, Junhua; Jia, Huijue; Cai, Xianghang; Zhong, Huanzi; Feng, Qiang; Sunagawa, Shinichi; Arumugam, Manimozhiyan; Kultima, Jens Roat; Prifti, Edi; Nielsen, Trine; Juncker, Agnieszka Sierakowska; Manichanh, Chaysavanh; Chen, Bing; Zhang, Wenwei; Levenez, Fl

Nature Biotechnology Volume 32, Issue 8, Pages 834–841

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Many analyses of the human gut microbiome depend on a catalog of reference genes. Existing catalogs for the human gut microbiome are based on samples from single cohorts or on reference genomes or protein sequences, which limits coverage of global microbiome diversity. Here we combined 249 newly sequenced samples of the Metagenomics of the Human Intestinal Tract (MetaHit) project with 1,018 previously sequenced samples to create a cohort from three continents that is at least threefold larger than cohorts used for previous gene catalogs. From this we established the integrated gene catalog (IGC) comprising 9,879,896 genes. The catalog includes close-to-complete sets of genes for most gut microbes, which are also of considerably higher quality than in previous catalogs. Analyses of a group of samples from Chinese and Danish individuals using the catalog revealed country-specific gut microbial signatures. This expanded catalog should facilitate quantitative characterization of metagenomic, metatranscriptomic and metaproteomic data from the gut microbiome to understand its variation across populations in human health and disease.


#23 Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE--5-a population-based study Link logo PDF logo

De Angelis Roberta; Sant Milena; Coleman Michel P; Francisci Silvia; Baili Paolo; Pierannunzio Daniela; Trama Annalisa; Visser Otto; Brenner Hermann; Ardanaz Eva; Bielska-Lasota Magdalena; Engholm Gerda; Nennecke Alice; Siesling Sabine; Berrino Franco; Ca

Lancet Oncology

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Cancer survival is a key measure of the effectiveness of health-care systems. EUROCARE-the largest cooperative study of population-based cancer survival in Europe-has shown persistent differences between countries for cancer survival, although in general, cancer survival is improving. Major changes in cancer diagnosis, treatment, and rehabilitation occurred in the early 2000s. EUROCARE-5 assesses their effect on cancer survival in 29 European countries.


#24 Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5--a population-based study Link logo PDF logo

Gatta Gemma; Botta Laura; Rossi Silvia; Aareleid Tiiu; Bielska-Lasota Magdalena; Clavel Jacqueline; Dimitrova Nadya; Jakab Zsuzsanna; Kaatsch Peter; Lacour Brigitte; Mallone Sandra; Marcos-Gragera Rafael; Minicozzi Pamela; Sánchez-Pérez Maria-José; Sant M

Lancet Oncology Volume 15, Issue 1

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Survival and cure rates for childhood cancers in Europe have greatly improved over the past 40 years and are mostly good, although not in all European countries. The EUROCARE-5 survival study estimates survival of children diagnosed with cancer between 2000 and 2007, assesses whether survival differences among European countries have changed, and investigates changes from 1999 to 2007.


#25 Diagnosis and management of adult coeliac disease : guidelines from the British Society of Gastroenterology Open access logo Link logo PDF logo

Ludvigsson Jonas; Bai Julio; Biagi Federico; Card Timothy; Ciacci Carolina; Ciclitira Paul; Green Peter; Hadjivassiliou Marios; Holdoway Anne; van Heel David; Kaukinen Katri; Leffler Daniel; Leonard Jonathan; Lundin Knut; McGough Norma; Davidson Mike; Mur

Gut Volume 63, Issue 8, Pages gutjnl-2013-306578–1228

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A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.


#26 Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes Link logo PDF logo

Tubio Jose M C; Li Yilong; Ju Young Seok; Martincorena Inigo; Cooke Susanna L; Tojo Marta; Gundem Gunes; Pipinikas Christodoulos P; Zamora Jorge; Raine Keiran; Menzies Andrew; Roman-Garcia Pablo; Fullam Anthony; Gerstung Moritz; Shlien Adam; Tarpey Patric

Science Volume 345, Issue 6196, Pages 1251343–1251343

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Long interspersed nuclear element-1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. L1 elements propagate through RNA intermediates. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3' transduction. Because 3' transductions are potentially mutagenic, we explored the extent to which they occur somatically during tumorigenesis. Studying cancer genomes from 244 patients, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3' transductions. Fingerprinting of donor L1s revealed that a handful of source L1 elements in a tumor can spawn from tens to hundreds of 3' transductions, which can themselves seed further retrotranspositions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3' transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome.


#27 Loss-of-function mutations in SLC30A8 protect against type 2 diabetes Link logo

Flannick, Jason; Thorleifsson, Gudmar; Beer, Nicola L.; Jacobs, Suzanne B. R.; Grarup, Niels; Burtt, Noel P.; Mahajan, Anubha; Fuchsberger, Christian; Atzmon, Gil; Benediktsson, Rafn; Blangero, John; Bowden, Don W.; Brandslund, Ivan; Brosnan, Julia; Bursl

Nature Genetics Volume 46, Issue 4, Pages 357–363

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Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.


#28 Breast-Cancer Risk in Families with Mutations in PALB2 Link logo

Antoniou, A. C.; Casadei, S.; Heikkinen, T.; Barrowdale, D.; Pylkaes, K.; Roberts, J.; Lee, A.; Subramanian, D.; De Leeneer, K.; Fostira, F.; Tomiak, E.; Neuhausen, S. L.; Teo, Z. L.; Khan, S.; Aittomaki, Kristiina; Moilanen, J. S.; Turnbull, C.; Seal, S.

New England Journal of Medicine Volume 371, Issue 6, Pages 497–506

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Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown.


#29 Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

Perry JR, Day F, Elks CE, Sulem P, Thompson DJ, Ferreira T, He C, Chasman DI, Esko T, Thorleifsson G, Albrecht E, Ang WQ, Corre T, Cousminer DL, Feenstra B, Franceschini N, Ganna A, Johnson AD, Kjellqvist S, Lunetta KL, McMahon G, Nolte IM, Paternoster L, Porcu E, Smith AV, Stolk L, Teumer A, Tšernikova N, Tikkanen E, Ulivi S, Wagner EK, Amin N, Bierut LJ, Byrne EM, Hottenga JJ, Koller DL, Mangino M, Pers TH, Yerges-Armstrong LM, Hua Zhao J, Andrulis IL, Anton-Culver H, Atsma F, Bandinelli S, Beckmann MW, Benitez J, Blomqvist C, Bojesen SE, Bolla MK, Bonanni B, Brauch H, Brenner H, Buring JE, Chang-Claude J, Chanock S, Chen J, Chenevix-Trench G, Collée JM, Couch FJ, Couper D, Coviello AD, Cox A, Czene K, D'adamo AP, Davey Smith G, De Vivo I, Demerath EW, Dennis J, Devilee P, Dieffenbach AK

Nature Volume 514, Issue 7520, Pages 92–97

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Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.


#30 Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity Link logo

Kraus Daniel, Yang Qin, Kong Dong, Banks Alexander S, Zhang Lin, Rodgers Joseph T, Pirinen Eija, Pulinilkunnil Thomas C, Gong Fengying, Wang Ya-chin, Cen Yana, Sauve Anthony A, Asara John M, Peroni Odile D, Monia Brett P, Bhanot Sanjay, Alhonen Leena, Puigserver Pere, Kahn Barbara B

Nature Volume 508, Issue 7495, Pages 258–262

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In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity. Here we show, using DNA array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD(+), an important cofactor linking cellular redox states with energy metabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation. Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine-spermine N(1)-acetyltransferase (SSAT; encoded by Sat1) and by polyamine oxidase (PAO), and has a major role in energy metabolism. We report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD(+) levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and NAD(+)-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.


#31 Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases Open access logo Link logo PDF logo

Gusev, Alexander; Lee, S. Hong; Trynka, Gosia; Finucane, Hilary; Vilhjalmsson, Bjarni J.; Xu, Han; Zang, Chongzhi; Ripke, Stephan; Bulik-Sullivan, Brendan; Stahl, Eli; Kähler, Anna K.; Hultman, Christina M.; Purcell, Shaun M.; McCarroll, Steven A.; Daly, Mark; Pasaniuc, Bogdan; Sullivan, Patrick F.; Neale, Benjamin M.; Wray, Naomi R.; Raychaudhuri, Soumya

American Journal of Human Genetics Volume 95, Issue 5, Pages 535–552

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Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (hg(2)) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg(2) from imputed SNPs (5.1× enrichment; p = 3.7 × 10(-17)) and 38% (SE = 4%) of hg(2) from genotyped SNPs (1.6× enrichment, p = 1.0 × 10(-4)). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of hg(2) despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.


#32 Acute Osteomyelitis in Children Link logo

Peltola, Heikki; Paakkonen, Markus

New England Journal of Medicine Volume 370, Issue 4, Pages 352–360

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#33 Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients Link logo

Landray, Martin J.; Haynes, Richard; Hopewell, Jemma C.; Parish, Sarah; Aung, Theingi; Tomson, Joseph; Wallendszus, Karl; Craig, Martin; Jiang, Lixin; Collins, Rory; Armitage, Jane; , ; Tuomilehto, Jaakko

New England Journal of Medicine Volume 371, Issue 3, Pages 203–212

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Background Patients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low-density lipoprotein (LDL) cholesterol level. Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein (HDL) cholesterol level, but its clinical efficacy and safety are uncertain. Methods After a prerandomization run-in phase to standardize the background statin-based LDL cholesterol-lowering therapy and to establish participants' ability to take extended-release niacin without clinically significant adverse effects, we randomly assigned 25,673 adults with vascular disease to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily. The primary outcome was the first major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization). Results During a median follow-up period of 3.9 years, participants who were assigned to extended-release niacin-laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower and an HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher than the levels in those assigned to placebo. Assignment to niacin-laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29). Niacin-laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P<0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1.0 percentage point; P<0.001), musculoskeletal system (absolute excess, 0.7 percentage points; P<0.001), skin (absolute excess, 0.3 percentage points; P=0.003), and unexpectedly, infection (absolute excess, 1.4 percentage points; P<0.001) and bleeding (absolute excess, 0.7 percentage points; P<0.001). Conclusions Among participants with atherosclerotic vascular disease, the addition of extended-release niacin-laropiprant to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events. (Funded by Merck and others; HPS2-THRIVE ClinicalTrials.gov number, NCT00461630 .).


#34 The many faces of diabetes: a disease with increasing heterogeneity Link logo PDF logo

Tuomi, Tiinamaija; Santoro, Nicola; Caprio, Sonia; Cai, Mengyin; Weng, Jianping; Groop, Leif

The Lancet Volume 383, Issue 9922

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Diabetes is a much more heterogeneous disease than the present subdivision into types 1 and 2 assumes; type 1 and type 2 diabetes probably represent extremes on a range of diabetic disorders. Both type 1 and type 2 diabetes seem to result from a collision between genes and environment. Although genetic predisposition establishes susceptibility, rapid changes in the environment (ie, lifestyle factors) are the most probable explanation for the increase in incidence of both forms of diabetes. Many patients have genetic predispositions to both forms of diabetes, resulting in hybrid forms of diabetes (eg, latent autoimmune diabetes in adults). Obesity is a strong modifier of diabetes risk, and can account for not only a large proportion of the epidemic of type 2 diabetes in Asia but also the ever-increasing number of adolescents with type 2 diabetes. With improved characterisation of patients with diabetes, the range of diabetic subgroups will become even more diverse in the future.


#35 European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage Link logo PDF logo

Steiner, Thorsten; Al-Shahi Salman, Rustam; Beer, Ronnie; Christensen, Hanne; Cordonnier, Charlotte; Csiba, Laszlo; Forsting, Michael; Harnof, Sagi; Klijn, Catharina J. M.; Krieger, Derk; Mendelow, A. David; Molina, Carlos; Montaner, Joan; Overgaard, Kars

International Journal of Stroke Volume 9, Issue 7, Pages 840–855

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Intracerebral hemorrhage (ICH) accounted for 9% to 27% of all strokes worldwide in the last decade, with high early case fatality and poor functional outcome. In view of recent randomized controlled trials (RCTs) of the management of ICH, the European Stroke Organisation (ESO) has updated its evidence-based guidelines for the management of ICH.


#36 Cation-chloride cotransporters in neuronal development, plasticity and disease Link logo

Kaila, Kai; Price, Theodore J.; Payne, John A.; Puskarjov, Martin; Voipio, Juha

Nature Reviews Neuroscience Volume 15, Issue 10, Pages 637–654

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Electrical activity in neurons requires a seamless functional coupling between plasmalemmal ion channels and ion transporters. Although ion channels have been studied intensively for several decades, research on ion transporters is in its infancy. In recent years, it has become evident that one family of ion transporters, cation-chloride cotransporters (CCCs), and in particular K(+)-Cl(-) cotransporter 2 (KCC2), have seminal roles in shaping GABAergic signalling and neuronal connectivity. Studying the functions of these transporters may lead to major paradigm shifts in our understanding of the mechanisms underlying brain development and plasticity in health and disease.


#37 Leveraging Cross- Species Transcription Factor Binding Site Patterns:From Diabetes Risk Loci to Disease Mechanisms Link logo PDF logo

Claussnitzer, Melina; Dankel, Simon N.; Klocke, Bernward; Grallert, Harald; Glunk, Viktoria; Berulava, Tea; Lee, Heekyoung; Oskolkov, Nikolay; Fadista, Joao; Ehlers, Kerstin; Wahl, Simone; Hoffmann, Christoph; Qian, Kun; Ronn, Tina; Riess, Helene; Mueller

Cell Volume 156, Issue 1-2, Pages 343–358

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Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.


#38 Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies Link logo PDF logo

Greving, Jacoba P.; Wermer, Marieke J. H.; Brown, Robert D.; Morita, Akio; Juvela, Seppo; Yonekura, Masahiro; Ishibashi, Toshihiro; Torner, James C.; Nakayama, Takeo; Rinke, Gabriel J. E.; Algra, Ale

Lancet Neurology

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The decision of whether to treat incidental intracranial saccular aneurysms is complicated by limitations in current knowledge of their natural history. We combined individual patient data from prospective cohort studies to determine predictors of aneurysm rupture and to construct a risk prediction chart to estimate 5-year aneurysm rupture risk by risk factor status.


#39 Future directions in Alzheimer's disease from risk factors to prevention Link logo

Imtiaz Bushra, Tolppanen Anna-Maija, Kivipelto Miia, Soininen Hilkka

Biochemical Pharmacology

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The increase in life expectancy has resulted in a high occurrence of dementia and Alzheimer's disease (AD). Research on AD has undergone a paradigm shift from viewing it as a disease of old age to taking a life course perspective. Several vascular, lifestyle, psychological and genetic risk factors influencing this latent period have been recognized and they may act both independently and by potentiating each other. These risk factors have consequently been used to derive risk scores for predicting the likelihood of dementia. Despite population differences, age, low education and vascular risk factors were identified as key factors in all scoring systems. Risk scores can help to identify high-risk individuals who might benefit from different interventions. The European Dementia Prevention Initiative (EDPI), an international collaboration, encourages data sharing between different randomized controlled trials. At the moment, it includes three large ongoing European trials: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), Prevention of Dementia by Intensive Vascular Care (preDIVA), and Multidomain Alzheimer Prevention study (MAPT). Recently EDPI has developed a "Healthy Aging through Internet Counseling in Elderly" (HATICE) program, which intends to manage modifiable risk factors in an aged population through an easily accessible Internet platform. Thus, the focus of dementia research has shifted from identification of potential risk factors to using this information for developing interventions to prevent or delay the onset of dementia as well as identifying special high-risk populations who could be targeted in intervention trials.


#40 Biomarker Profiling by Nuclear Magnetic Resonance Spectroscopy for the Prediction of All-Cause Mortality: An Observational Study of 17,345 Persons Open access logo Link logo PDF logo

Fischer, Krista; Kettunen, Johannes; Wurtz, Peter; Haller, Toomas; Havulinna, Aki S.; Kangas, Antti J.; Soininen, Pasi; Esko, Tonu; Tammesoo, Mari-Liis; Maegi, Reedik; Smit, Steven; Palotie, Aarno; Ripatti, Samuli; Salomaa, Veikko; Ala-Korpela, Mika; Pero

PLoS Medicine Volume 11, Issue 2

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Early identification of ambulatory persons at high short-term risk of death could benefit targeted prevention. To identify biomarkers for all-cause mortality and enhance risk prediction, we conducted high-throughput profiling of blood specimens in two large population-based cohorts.


#41 Role of BDNF epigenetics in activity-dependent neuronal plasticity Link logo

Karpova, Nina N.

Neuropharmacology

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Brain-derived neurotrophic factor (BDNF) is a key mediator of the activity-dependent processes in the brain that have a major impact on neuronal development and plasticity. Impaired control of neuronal activity-induced BDNF expression mediates the pathogenesis of various neurological and psychiatric disorders. Different environmental stimuli, such as the use of pharmacological compounds, physical and learning exercises or stress exposure, lead to activation of specific neuronal networks. These processes entail tight temporal and spatial transcriptional control of numerous BDNF splice variants through epigenetic mechanisms. The present review highlights recent findings on the dynamic and long-term epigenetic programming of BDNF gene expression by the DNA methylation, histone-modifying and microRNA machineries. The review also summarizes the current knowledge on the activity-dependent BDNF mRNA trafficking critical for rapid local regulation of BDNF levels and synaptic plasticity. Current data open novel directions for discovery of new promising therapeutic targets for treatment of neuropsychiatric disorders. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.


#42 The role of red and processed meat in colorectal cancer development:a perspective Link logo

Oostindjer, Marije; Alexander, Jan; Amdam, Gro V.; Andersen, Grethe; Bryan, Nathan S.; Chen, Duan; Corpet, Denis E.; De Smet, Stefaan; Dragsted, Lars Ove; Haug, Anna; Karlsson, Anders H.; Kleter, Gijs; de Kok, Theo M.; Kulseng, Bard; Milkowski, Andrew L.;

Meat Science Volume 97, Issue 4, Pages 583–596

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This paper is based on a workshop held in Oslo, Norway in November 2013, in which experts discussed how to reach consensus on the healthiness of red and processed meat. Recent nutritional recommendations include reducing intake of red and processed meat to reduce cancer risk, in particular colorectal cancer (CRC). Epidemiological and mechanistic data on associations between red and processed meat intake and CRC are inconsistent and underlying mechanisms are unclear. There is a need for further studies on differences between white and red meat, between processed and whole red meat and between different types of processed meats, as potential health risks may not be the same for all products. Better biomarkers of meat intake and of cancer occurrence and updated food composition databases are required for future studies. Modifying meat composition via animal feeding and breeding, improving meat processing by alternative methods such as adding phytochemicals and improving our diets in general are strategies that need to be followed up.


#43 Enzalutamide in metastatic prostate cancer before chemotherapy Link logo

Beer Tomasz;  Armstrong Andrew; Rathkopf Dana; Loriot Yohann; Sternberg Cora; Higano Celestia; Iversen Peter; Bhattacharya Suman; Carles Joan; Chowdhury Simon; Davis Ian; de Bono Johann;  Evans Christopher; Fizazi Karim; Joshua Anthony; Kim Choung-Soo; Ki

New England Journal of Medicine Volume 371, Issue 5, Pages 140601060007009–433

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#44 A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

Al Olama Ali Amin; Kote-Jarai Zsofia; Berndt Sonja I; Conti David V; Schumacher Fredrick; Han Ying; Benlloch Sara; Hazelett Dennis J; Wang Zhaoming; Saunders Ed; Leongamornlert Daniel; Lindstrom Sara; Jugurnauth-Little Sara; Dadaev Tokhir; Tymrakiewicz Ma

Nature Genetics Volume 46, Issue 10, Pages 1103–1109

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Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.


#45 Adenosine activates brown adipose tissue and recruits beige adipocytes via A(2A) receptors

Thorsten Gnad, Saskia Scheibler, Ivar von Kügelgen, Camilla Scheele, Ana Kilić, Anja Glöde, Linda S. Hoffmann, Laia Reverte-Salisa, Philipp Horn, Samet Mutlu, Ali El-Tayeb, Mathias Kranz, Winnie Deuther-Conrad, Peter Brust, Martin E. Lidell, Matthias J. Betz, Sven Enerbäck, Jürgen Schrader, Gennady G. Yegutkin, Christa E. Müller, Alexander Pfeifer

Nature Volume 516, Issue 7531

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Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies. Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of β-adrenergic receptors. Because BAT therapies based on cold exposure or β-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat. However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A2A receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A2A receptors in mice causes a decrease in BAT-dependent thermogenesis, whereas treatment with A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A2A receptors or injection of lentiviral vectors expressing the A2A receptor into white fat induces brown-like cells-so-called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A2A agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.


#46 Plasma proteins predict conversion to dementia from prodromal disease

Hye A, Riddoch-Contreras J, Baird AL, Ashton NJ, Bazenet C, Leung R, Westman E, Simmons A, Dobson R, Sattlecker M, Lupton M, Lunnon K, Keohane A, Ward M, Pike I, Zucht HD, Pepin D, Zheng W, Tunnicliffe A, Richardson J, Gauthier S, Soininen H et.al.

Alzheimer's & Dementia: the Journal of the Alzheimer's Association Volume 10, Issue 6, Pages 799–807.e2

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The study aimed to validate previously discovered plasma biomarkers associated with AD, using a design based on imaging measures as surrogate for disease severity and assess their prognostic value in predicting conversion to dementia.


#47 Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease Link logo PDF logo

Ruemmele, F. M.; Veres, G.; Kolho, K. L.; Griffiths, A.; Levine, A.; Escher, J. C.; Dias, J. Amil; Barabino, A.; Braegger, C. P.; Bronsky, J.; Buderus, S.; Martin-de-Carpi, J.; De Ridder, L.; Fagerberg, U. L.; Hugot, J. P.; Kierkus, J.; Kolacek, S.; Kolet

Journal of Crohn's and Colitis Volume 8, Issue 10, Pages 1179–1207

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Children and adolescents with Crohn's disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohn's and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.


#48 Advances in the prevention of Alzheimer's disease and dementia PDF logo

Solomon A, Mangialasche F, Richard E, Andrieu S, Bennett DA, Breteler B, Fratiglioni L, Hooshmand B, Khachaturian AS, Schneider LS, Skoog I, Kivipelto M

Journal of Internal Medicine Volume 275, Issue 3, Pages 229–250

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Definitions and diagnostic criteria for all medical conditions are regularly subjected to reviews and revisions as knowledge advances. In the field of Alzheimer's disease (AD) research, it has taken almost three decades for diagnostic nomenclature to undergo major re-examination. The shift towards presymptomatic and pre-dementia stages of AD has brought prevention and treatment trials much closer to each other than before.


#49 Clonal culturing of human embryonic stem cells on laminin-521/E-cadherin matrix in defined and xeno-free environment Link logo

Rodin, Sergey; Antonsson, Liselotte; Niaudet, Colin; Simonson, Oscar E.; Salmela, Elina; Hansson, Emil M.; Domogatskaya, Anna; Xiao, Zhijie; Damdimopoulou, Pauliina; Sheikhi, Mona; Inzunza, Jose; Nilsson, Ann-Sofie; Baker, Duncan; Kuiper, Raoul; Sun, Yi;

Nature Communications

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Lack of robust methods for establishment and expansion of pluripotent human embryonic stem (hES) cells still hampers development of cell therapy. Laminins (LN) are a family of highly cell-type specific basement membrane proteins important for cell adhesion, differentiation, migration and phenotype stability. Here we produce and isolate a human recombinant LN-521 isoform and develop a cell culture matrix containing LN-521 and E-cadherin, which both localize to stem cell niches in vivo. This matrix allows clonal derivation, clonal survival and long-term self-renewal of hES cells under completely chemically defined and xeno-free conditions without ROCK inhibitors. Neither LN-521 nor E-cadherin alone enable clonal survival of hES cells. The LN-521/E-cadherin matrix allows hES cell line derivation from blastocyst inner cell mass and single blastomere cells without a need to destroy the embryo. This method can facilitate the generation of hES cell lines for development of different cell types for regenerative medicine purposes.



#51 Homozygous familial hypercholesterolaemia:new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society Link logo PDF logo

Cuchel, Marina; Bruckert, Eric; Ginsberg, Henry N.; Raal, Frederick J.; Santos, Raul D.; Hegele, Robert A.; Kuivenhoven, Jan Albert; Nordestgaard, Borge G.; Descamps, Olivier S.; Steinhagen-Thiessen, Elisabeth; Tybjrg-Hansen, Anne; Watts, Gerald F.; Avern

European Heart Journal Volume 35, Issue 32, Pages 2146–2157

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Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH.


#52 Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer:results from the FinHER trial Link logo PDF logo

Loi, S.; Michiels, S.; Salgado, R.; Sirtaine, N.; Jose, V.; Fumagalli, D.; Kellokumpu-Lehtinen, P-L; Bono, P.; Kataja, V.; Desmedt, C.; Piccart, M. J.; Loibl, S.; Denkert, C.; Smyth, M. J.; Joensuu, H.; Sotiriou, C.

Annals of Oncology Volume 25, Issue 8, Pages 1544–1550

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We have previously shown the prognostic importance of tumor-infiltrating lymphocytes (TILs) in newly diagnosed triple-negative breast cancer (TNBC) using tumor samples from a large clinical trial cohort. In this study, we aimed to validate these findings and also investigate associations with trastuzumab benefit in HER2-overexpressing disease (HER2+).


#53 Infra-Slow EEG Fluctuations Are Correlated with Resting-State Network Dynamics in fMRI Link logo

Hiltunen, Tuija; Kantola, Jussi; Abou Elseoud, Ahmed; Lepola, Pasi; Suominen, Kalervo; Starck, Tuomo; Nikkinen, Juha; Remes, Jukka; Tervonen, Osmo; Palva, Satu; Kiviniemi, Vesa; Palva, J. Matias

Journal of Neuroscience Volume 34, Issue 2

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Ongoing neuronal activity in the CNS waxes and wanes continuously across widespread spatial and temporal scales. In the human brain, these spontaneous fluctuations are salient in blood oxygenation level-dependent (BOLD) signals and correlated within specific brain systems or "intrinsic-connectivity networks." In electrophysiological recordings, both the amplitude dynamics of fast (1-100 Hz) oscillations and the scalp potentials per se exhibit fluctuations in the same infra-slow (0.01-0.1 Hz) frequency range where the BOLD fluctuations are conspicuous. While several lines of evidence show that the BOLD fluctuations are correlated with fast-amplitude dynamics, it has remained unclear whether the infra-slow scalp potential fluctuations in full-band electroencephalography (fbEEG) are related to the resting-state BOLD signals. We used concurrent fbEEG and functional magnetic resonance imaging (fMRI) recordings to address the relationship of infra-slow fluctuations (ISFs) in scalp potentials and BOLD signals. We show here that independent components of fbEEG recordings are selectively correlated with subsets of cortical BOLD signals in specific task-positive and task-negative, fMRI-defined resting-state networks. This brain system-specific association indicates that infra-slow scalp potentials are directly associated with the endogenous fluctuations in neuronal activity levels. fbEEG thus yields a noninvasive, high-temporal resolution window into the dynamics of intrinsic connectivity networks. These results support the view that the slow potentials reflect changes in cortical excitability and shed light on neuronal substrates underlying both electrophysiological and behavioral ISFs.


#54 EHRA/HRS/APHRS expert consensus on ventricular arrhythmias. Link logo

Pedersen, Christian Torp; Kay, G. Neal; Kalman, Jonathan; Borggrefe, Martin; Della-Bella, Paolo; Dickfeld, Timm; Dorian, Paul; Huikuri, Heikki; Kim, Youg-Hoon; Knight, Bradley; Marchlinski, Francis; Ross, David; Sacher, Frederic; Sapp, John; Shivkumar, Kalyanam; Soejima, Kyoko; Tada, Hiroshi; Alexander, Mark E.; Triedman, John K.; Yamada, Takumi

Heart Rhythm Volume 11, Issue 10, Pages e166–e196

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#55 An international atherosclerosis society position pape r: global recommendations for the management of dyslipidemia - full report PDF logo

Grundy, Scott M.; Arai, Hidenori; Barter, Philip; Bersot, Thomas P.; Betteridge, D. John; Carmena, Rafael; Cuevas, Ada; Davidson, Michael H.; Genest, Jacques; Kesäniemi, Y. Antero; Sadikot, Shaukat; Santos, Raul D.; Susekov, Andrey V.; Sy, Rody G.; LaleTokgozoglu, S.; Watts, Gerald F.; Zhao, Dong

Journal of Clinical Lipidology

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An international panel of the International Atherosclerosis Society has developed a new set of recommendations for the management of dyslipidemia. The panel identifies non--high-density lipoprotein cholesterol as the major atherogenic lipoprotein. Primary and secondary prevention are considered separately. Optimal levels for atherogenic lipoproteins are derived for the two forms of prevention. For primary prevention, the recommendations emphasize lifestyle therapies to reduce atherogenic lipoproteins; drug therapy is reserved for subjects at greater risk. Risk assessment is based on estimation of lifetime risk according to differences in baseline population risk in different nations or regions. Secondary prevention emphasizes use of cholesterol-lowering drugs to attain optimal levels of atherogenic lipoproteins.


#56 Association of Bariatric Surgery With Long-term Remission of Type 2 Diabetes and With Microvascular and Macrovascular Complications PDF logo

Sjostrom, Lars; Peltonen, Markku; Jacobson, Peter; Ahlin, Sofie; Andersson-Assarsson, Johanna; Anveden, Asa; Bouchard, Claude; Carlsson, Bjorn; Karason, Kristjan; Lonroth, Hans; Naslund, Ingmar; Sjostrom, Elisabeth; Taube, Magdalena; Wedel, Hans; Svensson, Per-Arne; Sjoholm, Kajsa; Carlsson, Lena M. S.

JAMA: Journal of the American Medical Association Volume 311, Issue 22

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Short-term studies show that bariatric surgery causes remission of diabetes. The long-term outcomes for remission and diabetes-related complications are not known.


#57 Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population Open access logo Link logo

Lim, Elaine T.; Würtz, Peter; Havulinna, Aki S.; Palta, Priit; Tukiainen, Taru; Rehnstrom, Karola; Esko, Tonu; Magi, Reedik; Inouye, Michael; Lappalainen, Tuuli; Chan, Yingleong; Salem, Rany M.; Lek, Monkol; Flannick, Jason; Sim, Xueling; Manning, Alisa;

PLoS Genetics Volume 10, Issue 7

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Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻⁸) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10⁻¹¹⁷). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻⁴), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.


#58 Impact of e-learning on nurses' and student nurses knowledge, skills, and satisfaction: A systematic review and meta-analysis PDF logo

Lahti M, Hatonen H, Valimaki M

International Journal of Nursing Studies

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To review the impact of e-learning on nurses' and nursing student's knowledge, skills and satisfaction related to e-learning.


#59 Break-Induced Replication Repair of Damaged Forks Induces Genomic Duplications in Human Cells Link logo PDF logo

Costantino, Lorenzo; Sotiriou, Sotirios K.; Rantala, Juha K.; Magin, Simon; Mladenov, Emil; Helleday, Thomas; Haber, James E.; Iliakis, George; Kallioniemi, Olli P.; Halazonetis, Thanos D.

Science

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In budding yeast, one-ended DNA double-strand breaks (DSBs) and damaged replication forks are repaired by break-induced replication (BIR), a homologous recombination pathway that requires the Pol32 subunit of DNA polymerase delta. DNA replication stress is prevalent in cancer, but BIR has not been characterized in mammals. In a cyclin E overexpression model of DNA replication stress, POLD3, the human ortholog of POL32, was required for cell cycle progression and processive DNA synthesis. Segmental genomic duplications induced by cyclin E overexpression were also dependent on POLD3, as were BIR-mediated recombination events captured with a specialized DSB repair assay. We propose that BIR repairs damaged replication forks in mammals, accounting for the high frequency of genomic duplications in human cancers.


#60 Overdiagnosis and overtreatment of prostate cancer Link logo PDF logo

Loeb Stacy; Bjurlin Marc; Nicholson Joseph; Tammela Teuvo; Penson David; Carter  H Ballentine; Carroll Peter; Etzioni Ruth

European Urology Volume 65, Issue 6, Pages 1046–1055

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Although prostate cancer (PCa) screening reduces the incidence of advanced disease and mortality, trade-offs include overdiagnosis and resultant overtreatment.


#61 The immune system in children with malnutrition - a systematic review Open access logo PDF logo

Rytter Maren Johanna Heilskov; Kolte Lilian; Briend André; Friis Henrik; Christensen Vibeke Brix

PLoS ONE Volume 9, Issue 8

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Malnourished children have increased risk of dying, with most deaths caused by infectious diseases. One mechanism behind this may be impaired immune function. However, this immune deficiency of malnutrition has not previously been systematically reviewed.


#62 Organizational justice, selection, optimization with compensation, and nurses' work ability PDF logo

Bonsdorff, Monika E. von; Bonsdorff, Mikaela B. von; Zhou, Zhiqing E.; Kauppinen, Markku; Miettinen, Merja; Rantanen, Taina; Vanhala, Sinikka

Journal of Organizational Behavior Volume 24, Issue 1, Pages 89–106

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#63 Synaptic, transcriptional and chromatin genes disrupted in autism Link logo

De Rubeis, Silvia; He, Xin; Goldberg, Arthur P.; Poultney, Christopher S.; Samocha, Kaitlin; Cicek, A. Ercument; Kou, Yan; Liu, Li; Fromer, Menachem; Walker, Susan; Singh, Tarjinder; Klei, Lambertus; Kosmicki, Jack; Fu, Shih-Chen; Aleksic, Branko; Biscald

Nature Volume 515, Issue 7526, Pages 209–215

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The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.


#64 Differential Modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of Host Peripheral Lipid Metabolism and Histone Acetylation in Mouse Gut Organoids Open access logo Link logo PDF logo

Lukovac, Sabina; Belzer, Clara; Pellis, Linette; Keijser, Bart J.; de Vos, Willem M.; Montijn, Roy C.; Roeselers, Guus

mBio Volume 5, Issue 4

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#65 Consensus guidelines for the detection of immunogenic cell death Link logo

Kepp, Oliver; Senovilla, Laura; Vitale, Ilio; Vacchelli, Erika; Adjemian, Sandy; Agostinis, Patrizia; Apetoh, Lionel; Aranda, Fernando; Barnaba, Vincenzo; Bloy, Norma; Bracci, Laura; Breckpot, Karine; Brough, David; Buque, Aitziber; Castro, Maria G.; Ciro

Transactions of the Institute of Measurement and Control, with Measurement + Control Volume 3, Issue 9

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Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named "immunogenic cell death" (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.


#66 Crossing the Interspecies Barrier: Opening the Door to Zoonotic Pathogens. Open access logo PDF logo

Gortazar, C., Reperant, L.A., Kuiken, T., de la Fuente, J., Boadella, M., Martínez-Lopez, B., Ruiz-Fons , F., Estrada-Peña, A., Drosten, C., Medley, G., Ostfeld, R., Peterson, T.,VerCauteren, K.C., Menge, C., Artois, M., Schultsz, C., Delahay, R., Serra-Cobo, J., Poulin, R., Keck, F., Aguirre, A.A., Henttonen, H., Dobson, A.P., Kutz, S. Lubroth, J. and Mysterud, A.

PLoS Pathogens Volume 10, Issue 6

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#67 Long term exposure to ambient air pollution and incidence of acute coronary events: prospective cohort study and meta-analysis in 11 European cohorts from the ESCAPE Project PDF logo

Cesaroni, Giulia; Forastiere, Francesco; Stafoggia, Massimo; Andersen, Zorana J.; Badaloni, Chiara; Beelen, Rob; Caracciolo, Barbara; de Faire, Ulf; Erbel, Raimund; Eriksen, Kirsten T.; Fratiglioni, Laura; Galassi, Claudia; Hampel, Regina; Heier, Margit; Hennig, Frauke; Hilding, Agneta; Hoffmann, Barbara; Houthuijs, Danny; Joeckel, Karl-Heinz; Korek, Michal; Lanki, Timo; Leander, Karin; Magnusson, Patrik K. E.; Migliore, Enrica; Ostenson, Caes-Goeran; Overvad, Kim; Pedersen, Nancy L.; Pekkanen, Juha J.; Pe

British Medical Journal Volume 348, Issue jan21 3, Pages f7412–f7412

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To study the effect of long term exposure to airborne pollutants on the incidence of acute coronary events in 11 cohorts participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE).


#68 EAACI Food Allergy and Anaphylaxis Guidelines: diagnosis and management of food allergy Link logo PDF logo

Muraro A; Werfel T; Hoffmann-Sommergruber K; Roberts G; Beyer K; Bindslev-Jensen C; Cardona V; Dubois A; duToit G; Eigenmann P; Fernandez Rivas M; Halken S; Hickstein L; Høst A; Knol E; Lack G; Marchisotto MJ; Niggemann B; Nwaru BI; Papadopoulos N et al

Allergy Volume 69, Issue 8, Pages 1008–1025

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Food allergy can result in considerable morbidity, impact negatively on quality of life, and prove costly in terms of medical care. These guidelines have been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Guidelines for Food Allergy and Anaphylaxis Group, building on previous EAACI position papers on adverse reaction to foods and three recent systematic reviews on the epidemiology, diagnosis, and management of food allergy, and provide evidence-based recommendations for the diagnosis and management of food allergy. While the primary audience is allergists, this document is relevant for all other healthcare professionals, including primary care physicians, and pediatric and adult specialists, dieticians, pharmacists and paramedics. Our current understanding of the manifestations of food allergy, the role of diagnostic tests, and the effective management of patients of all ages with food allergy is presented. The acute management of non-life-threatening reactions is covered in these guidelines, but for guidance on the emergency management of anaphylaxis, readers are referred to the related EAACI Anaphylaxis Guidelines.


#69 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC) PDF logo

Authors/Task Force members, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H, ESC Committee for Practice Guidelines (CPG): Zamorano JL, Achenbach S, Baumgartner H, Bax JJ , Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P), Linhart A , Nihoyannopoulos

European Heart Journal Volume 35, Issue 39

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#70 The epidemiology of food allergy in Europe: a systematic review and meta-analysis Link logo PDF logo

Nwaru BI; Hickstein L; Panesar SS; Muraro A; Werfel T; Cardona V; Dubois AE; Halken S; Hoffmann-Sommergruber K; Poulsen LK; Roberts G; Van Ree R; Vlieg-Boerstra BJ; Sheikh A;  EAACI Food Allergy and Anaphylaxis Guidelines Group

Allergy Volume 69, Issue 1, Pages n/a–n/a

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Food allergy (FA) is an important atopic disease although its precise burden is unclear. This systematic review aimed to provide recent, up-to-date data on the incidence, prevalence, time trends, and risk and prognostic factors for FA in Europe. We searched four electronic databases, covering studies published from 1 January 2000 to 30 September 2012. Two independent reviewers appraised the studies and qualified the risk of bias using the Critical Appraisal Skills Programme tool. Seventy-five eligible articles (comprising 56 primary studies) were included in a narrative synthesis, and 30 studies in a random-effects meta-analysis. Most of the studies were graded as at moderate risk of bias. The pooled lifetime and point prevalence of self-reported FA were 17.3% (95% CI: 17.0-17.6) and 5.9% (95% CI: 5.7-6.1), respectively. The point prevalence of sensitization to ≥1 food as assessed by specific IgE was 10.1% (95% CI: 9.4-10.8) and skin prick test 2.7% (95% CI: 2.4-3.0), food challenge positivity 0.9% (95% CI: 0.8-1.1). While the incidence of FA appeared stable over time, there was some evidence that the prevalence may be increasing. There were no consistent risk or prognostic factors for the development or resolution of FA identified, but sex, age, country of residence, familial atopic history, and the presence of other allergic diseases seem to be important. Food allergy is a significant clinical problem in Europe. The evidence base in this area would benefit from additional studies using standardized, rigorous methodology; data are particularly required from Eastern and Southern Europe.


#71 Best practices interventions to improve quality of care of people with dementia living at home PDF logo

Zabalegui A, Hamers J, Karlsson S, Leino-Kilpi H, Renom-Guiteras A, Saks K, Soto M, Sutcliffe C, Cabrera E

Patient Education & Counseling Volume 95, Issue 2, Pages 175–184

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To identify effective interventions which improve quality of care for people with dementia (PwD) living at home.


#72 Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease Link logo

Gylling, Helena; Plat, Jogchum; Turley, Stephen; Ginsberg, Henry N.; Ellegard, Lars; Jessup, Wendy; Jones, Peter J.; Luetjohann, Dieter; Maerz, Winfried; Masana, Luis; Silbernagel, Guenther; Staels, Bart; Boren, Jan; Catapano, Alberico L.; De Backer, Guy;

Atherosclerosis (00219150) Volume 232, Issue 2, Pages 346–360

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This EAS Consensus Panel critically appraised evidence relevant to the benefit to risk relationship of functional foods with added plant sterols and/or plant stanols, as components of a healthy lifestyle, to reduce plasma low-density lipoprotein-cholesterol (LDL-C) levels, and thereby lower cardiovascular risk.


#73 Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer Open access logo PDF logo

Ju Young Seok; Alexandrov Ludmil B; Gerstung Moritz; Martincorena Inigo; Nik-Zainal Serene; Ramakrishna Manasa; Davies Helen R; Papaemmanuil Elli; Gundem Gunes; Shlien Adam; Bolli Niccolo; Behjati Sam; Tarpey Patrick S; Nangalia Jyoti; Massie Charles E; B

eLife

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#74 Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

The Coffee and Caffeine Genetics Consortium; Cornelis MC; Byrne EM; Esko T; Nalls MA; Ganna A; Paynter N; Monda KL; Amin N; Fischer K; Renstrom F; Ngwa JS; Huikari V; Cavadino A; Nolte IM; Teumer A; Yu K; Marques-Vidal P; Rawal R; Manichaikul A; Wojczynsk

Molecular Psychiatry Volume 20, Issue 5, Pages 647–656

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Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91 462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.Molecular Psychiatry advance online publication, 7 October 2014; doi:10.1038/mp.2014.107.


#75 NAD+-Dependent Activation of Sirt1 Corrects the Phenotype in a Mouse Model of Mitochondrial Disease Open access logo

Cerutti R, Pirinen E, Lamperti C, Marchet S, Sauve AA, Li W, Leoni V, Schon EA, Dantzer F, Auwerx J, Viscomi C, Zeviani M

Cell Metabolism (Science Direct) Volume 19, Issue 6, Pages 1042–1049

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Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways related to mitochondrial biogenesis are targets of Sirtuin1, a NAD(+)-dependent protein deacetylase. As NAD(+) boosts the activity of Sirtuin1 and other sirtuins, intracellular levels of NAD(+) play a key role in the homeostatic control of mitochondrial function by the metabolic status of the cell. We show here that supplementation with nicotinamide riboside, a natural NAD(+) precursor, or reduction of NAD(+) consumption by inhibiting the poly(ADP-ribose) polymerases, leads to marked improvement of the respiratory chain defect and exercise intolerance of the Sco2 knockout/knockin mouse, a mitochondrial disease model characterized by impaired cytochrome c oxidase biogenesis. This strategy is potentially translatable into therapy of mitochondrial disorders in humans.


#76 Prevalence of common food allergies in Europe: a systematic review and meta-analysis. PDF logo

Nwaru BI; Hickstein L; Panesar SS; Roberts G; Muraro A; Sheikh A; EAACI Food Allergy and Anaphylaxis Guidelines Group.

Allergy Volume 69, Issue 8, Pages 992–1007

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Allergy to cow's milk, egg, wheat, soy, peanut, tree nuts, fish, and shellfish constitutes the majority of food allergy reactions, but reliable estimates of their prevalence are lacking. This systematic review aimed to provide up-to-date estimates of their prevalence in Europe.Studies published in Europe from January 1, 2000, to September 30, 2012, were identified from searches of four electronic databases. Two independent reviewers appraised the studies and extracted the estimates of interest. Data were pooled using random-effects meta-analyses. Fifty studies were included in a narrative synthesis and 42 studies in the meta-analyses. Although there were significant heterogeneity between the studies, the overall pooled estimates for all age groups of self-reported lifetime prevalence of allergy to cow's milk, egg, wheat, soy, peanut, tree nuts, fish, and shellfish were 6.0% (95% confidence interval: 5.7-6.4), 2.5% (2.3-2.7), 3.6% (3.0-4.2), 0.4% (0.3-0.6), 1.3% (1.2-1.5), 2.2% (1.8-2.5), and 1.3% (0.9-1.7), respectively. The prevalence of food-challenge-defined allergy to cow's milk, egg, wheat, soy, peanut, tree nuts, fish, and shellfish was 0.6% (0.5-0.8), 0.2% (0.2-0.3), 0.1% (0.01-0.2), 0.3% (0.1-0.4), 0.2% (0.2-0.3), 0.5% (0.08-0.8), 0.1% (0.02-0.2), and 0.1% (0.06-0.3), respectively. Allergy to cow's milk and egg was more common among younger children, while allergy to peanut, tree nuts, fish, and shellfish was more common among the older ones. There were insufficient data to compare the estimates of soy and wheat allergy between the age groups. Allergy to most foods, except soy and peanut, appeared to be more common in Northern Europe. In summary, the lifetime self-reported prevalence of allergy to common foods in Europe ranged from 0.1 to 6.0%. The heterogeneity between studies was high, and participation rates varied across studies reaching as low as <20% in some studies. Standardizing the methods of assessment of food allergies and initiating strategies to increase participation will advance this evidence base.


#77 Stress-related eating, obesity and associated behavioural traits in adolescents : a prospective population-based cohort study Open access logo Link logo PDF logo

Jääskeläinen, Anne; Nevanperä, Nina; Remes, Jouko; Rahkonen, Fanni; Järvelin, Marjo-Riitta; Laitinen, Jaana

BMC Public Health Volume 14, Issue 1

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Stress-related eating is associated with unhealthy eating and drinking habits and an increased risk of obesity among adults, but less is known about factors related to stress-driven eating behaviour among children and adolescents. We studied the prevalence of stress-related eating and its association with overweight, obesity, abdominal obesity, dietary and other health behaviours at the age of 16. Furthermore, we examined whether stress-related eating is predicted by early-life factors including birth size and maternal gestational health.


#78 Phase transfer entropy: A novel phase-based measure for directed connectivity in networks coupled by oscillatory interactions.

Lobier, Muriel; Siebenhuhner, Felix; Palva, Satu; Palva, J. Matias

NeuroImage

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We introduce here phase transfer entropy (Phase TE) as a measure of directed connectivity among neuronal oscillations. Phase TE quantifies the transfer entropy between phase time-series extracted from neuronal signals by filtering for instance. To validate the measure, we used coupled Neuronal Mass Models to both evaluate the characteristics of Phase TE and compare its performance with that of a real-valued TE implementation. We showed that Phase TE detects the strength and direction of connectivity even in the presence of such amounts of noise and linear mixing that typically characterize MEG and EEG recordings. Phase TE performed well across a wide range of analysis lags and sample sizes. Comparisons between Phase TE and real-valued TE estimates showed that Phase TE is more robust to nuisance parameters and considerably more efficient computationally. In addition, Phase TE accurately untangled bidirectional frequency band specific interaction patterns that confounded real-valued TE. Finally, we found that surrogate data can be used to construct appropriate null-hypothesis distributions and to estimate statistical significance of Phase TE. These results hence suggest that Phase TE is well suited for the estimation of directed phase-based connectivity in large-scale investigations of the human functional connectome.


#79 Indoor environmental quality in school buildings, and the health and well-being of students

Turunen M, Toyinbo O, Putus T, Nevalainen A, Shaughnessy R, Haverinen-Shaughnessy U.

International Journal of Hygiene & Environmental Health

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Poor indoor environmental quality (IEQ) in classrooms may be a risk for health symptoms and cause absence from school. We conducted a comprehensive study in order to assess the connection between IEQ in Finnish elementary school buildings and the health and academic performance of sixth grade students. The specific aim of the present paper was to study the school- or grade-level prevalence of symptoms in relation to IEQ. The school- or grade-level (i.e. group level) prevalence of self-reported symptoms and perceived IEQ was studied using data collected by a health questionnaire comprising 37 questions. The health questionnaire was sent to all 6th grade students in a stratified random sample of 355 elementary schools in Finland. Indoor environmental conditions were assessed with measurements of ventilation rate and thermal conditions of classrooms in a subsample of 56 schools. Altogether 297 elementary schools participated in the health questionnaire study and a total of 4248 questionnaires were returned (estimated response rate 62.6%). The most common weekly symptoms in the spring semester were fatigue (7.7%), stuffy nose (7.3%), and headache (5.5%). However, both mean prevalence values for different symptoms among all 6th grade students and group-level prevalence values for specific symptoms varied considerably. On the group level, the prevalence values most frequently found above 95% CI (calculated for N=15) were wheezing, cough with wheezing, and fever over 37°C. The most frequently reported IEQ factors causing daily inconvenience in classrooms were noise (11.0%) and stuffy air/poor indoor air quality (IAQ) (7.0%), which were also found most frequently above 95% CI on the group level (calculated for N=15), together with self-reported high indoor temperature and dust or dirtiness. Self-reported daily stuffiness/poor IAQ was significantly correlated with measured mean temperatures and ventilation rates in classrooms. High prevalence of students' self-reported stuffiness/poor IAQ may indicate high indoor temperature or low ventilation rate in classrooms. Also high group level prevalence of other IEQ factors and certain symptoms may be indicative of IEQ problems that should be further studied. The results of this study can be used as a reference for assessing the questionnaire-based prevalence of self-reported symptoms among 6th graders, and their association with IEQ in classrooms. For such assessment, the number of students responding to the questionnaire must be carefully considered, also bearing in mind that prevalence values are symptom specific.


#80 Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration

Smith, Colette J.; Ryom, Lene; Weber, Rainer; Morlat, Philippe; Pradier, Christian; Reiss, Peter; Kowalska, Justyna D.; de Wit, Stephane; Law, Matthew; el Sadr, Wafaa; Kirk, Ole; Friis-Moller, Nina; Monforte, Antonella d'Arminio; Phillips, Andrew N.; Sabi

The Lancet Volume 384, Issue 9939, Pages 241–248

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#81 Gut Microbiota Signatures Predict Host and Microbiota Responses to Dietary Interventions in Obese Individuals Open access logo Link logo PDF logo

Korpela, Katri; Flint, Harry J.; Johnstone, Alexandra M.; Lappi, Jenni; Poutanen, Kaisa; Dewulf, Evelyne; Delzenne, Nathalie; de Vos, Willem M.; Salonen, Anne

PLoS ONE Volume 9, Issue 3

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Interactions between the diet and intestinal microbiota play a role in health and disease, including obesity and related metabolic complications. There is great interest to use dietary means to manipulate the microbiota to promote health. Currently, the impact of dietary change on the microbiota and the host metabolism is poorly predictable and highly individual. We propose that the responsiveness of the gut microbiota may depend on its composition, and associate with metabolic changes in the host.


#82 Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data Link logo PDF logo

Muthuri, Stella G.; Venkatesan, Sudhir; Myles, Puja R.; Leonardi-Bee, Jo; Al Khuwaitir, Tarig S. A.; Al Mamun, Adbullah; Anovadiya, Ashish P.; Azziz-Baumgartner, Eduardo; Baez, Clarisa; Bassetti, Matteo; Beovic, Bojana; Bertisch, Barbara; Bonmarin, Isabel

The Lancet Respiratory Medicine Volume 2, Issue 5, Pages 395–404

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#83 GABA actions and ionic plasticity in epilepsy Link logo

Kaila, Kai; Ruusuvuori, Eva; Seja, Patricia; Voipio, Juha; Puskarjov, Martin

Current Opinion in Neurobiology

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Concepts of epilepsy, based on a simple change in neuronal excitation/inhibition balance, have subsided in face of recent insights into the large diversity and context-dependence of signaling mechanisms at the molecular, cellular and neuronal network level. GABAergic transmission exerts both seizure-suppressing and seizure-promoting actions. These two roles are prone to short-term and long-term alterations, evident both during epileptogenesis and during individual epileptiform events. The driving force of GABAergic currents is controlled by ion-regulatory molecules such as the neuronal K-Cl cotransporter KCC2 and cytosolic carbonic anhydrases. Accumulating evidence suggests that neuronal ion regulation is highly plastic, thereby contributing to the multiple roles ascribed to GABAergic signaling during epileptogenesis and epilepsy.


#84 Gene-Lifestyle Interaction and Type 2 Diabetes:The EPIC InterAct Case-Cohort Study Open access logo Link logo PDF logo

Langenberg, Claudia; Sharp, Stephen J.; Franks, Paul W.; Scott, Robert A.; Deloukas, Panos; Forouhi, Nita G.; Froguel, Philippe; Groop, Leif C.; Hansen, Torben; Palla, Luigi; Pedersen, Oluf; Schulze, Matthias B.; Tormo, Maria-Jose; Wheeler, Eleanor; Agnol

PLoS Medicine Volume 11, Issue 5

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Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention.


#85 Expert consensus and recommendations on safety criteria for active mobilization of mechanically ventilated critically ill adults Open access logo Link logo PDF logo

Hodgson, Carol L.; Stiller, Kathy; Needham, Dale M.; Tipping, Claire J.; Harrold, Megan; Baldwin, Claire E.; Bradley, Scott; Berney, Sue; Caruana, Lawrence R.; Elliott, Doug; Green, Margot; Haines, Kimberley; Higgins, Alisa M.; Kaukonen, Kirsi-Maija; Ledi

Critical Care Volume 18, Issue 6

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IntroductionTo develop consensus recommendations on safety parameters for mobilizing adult, mechanically ventilated, intensive care unit (ICU) patients.MethodsA systematic literature review followed by a meeting of 23 multidisciplinary ICU experts to seek consensus regarding the safe mobilization of mechanically ventilated patients.ResultsSafety considerations were summarized in four categories: respiratory, cardiovascular, neurological and other. Consensus was achieved on all criteria for safe mobilization, with the exception being levels of vasoactive agents. Intubation via an endotracheal tube was not a contraindication to early mobilization and a fraction of inspired oxygen less than 0.6 with a percutaneous oxygen saturation more than 90% and a respiratory rate less than 30 breaths/minute were considered safe criteria for in- and out-of-bed mobilization if there were no other contraindications. At an international meeting, 94 multidisciplinary ICU clinicians concurred with the proposed recommendations.ConclusionConsensus recommendations regarding safety criteria for mobilization of adult, mechanically ventilated patients in ICU have the potential to guide ICU rehabilitation whilst minimizing the risk of adverse events.


#86 Mortality Related to Severe Sepsis and Septic Shock Among Critically III Patients in Australia and New Zealand, 2000-2012 Link logo PDF logo

Kaukonen, Maija; Bailey, Michael; Suzuki, Satoshi; Pilcher, David; Bellomo, Rinaldo

JAMA: Journal of the American Medical Association Volume 311, Issue 13

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Severe sepsis and septic shock are major causes of mortality in intensive care unit (ICU) patients. It is unknown whether progress has been made in decreasing their mortality rate.


#87 Internet-based peer support for parents: a systematic integrative review

Hannakaisa Niela-Vilén; Anna Axelin; Sanna Salanterä; Hanna-Leena Melender

International Journal of Nursing Studies Volume 51, Issue 11, Pages 1524–1537

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The Internet and social media provide various possibilities for online peer support. The aim of this review was to explore Internet-based peer-support interventions and their outcomes for parents.


#88 Efficacy and Safety of Apixaban in Patients After Cardioversion for Atrial Fibrillation Link logo PDF logo

Flaker, Greg; Lopes, Renato D.; Al-Khatib, Sana M.; Hermosillo, Antonio G.; Hohnloser, Stefan H.; Tinga, Brian; Zhu, Jun; Mohan, Puneet; Garcia, David; Bartunek, Jozef; Vinereanu, Dragos; Husted, Steen; Harjola, Veli Pekka; Rosenqvist, Marten; Alexander,

Journal of the American College of Cardiology (JACC) Volume 63, Issue 11, Pages 1082–1087

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The aim of this study was to determine the risk of major clinical and thromboembolic events after cardioversion for atrial fibrillation in subjects treated with apixaban, an oral factor Xa inhibitor, compared with warfarin.


#89 DALI: Defining Antibiotic Levels in Intensive Care Unit Patients: Are Current beta-Lactam Antibiotic Doses Sufficient for Critically Ill Patients? Link logo PDF logo

Roberts, Jason A.; Paul, Sanjoy K.; Akova, Murat; Bassetti, Matteo; De Waele, Jan J.; Dimopoulos, George; Kaukonen, Kirsi-Maija; Koulenti, Despoina; Martin, Claude; Montravers, Philippe; Rello, Jordi; Rhodes, Andrew; Starr, Therese; Wallis, Steven C.; Lip

Clinical Infectious Diseases Volume 58, Issue 8, Pages 1072–1083

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Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether β-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome.


#90 Regularized Machine Learning in the Genetic Prediction of Complex Traits Open access logo Link logo PDF logo

Okser, Sebastian; Pahikkala, Tapio; Airola, Antti; Salakoski, Tapio; Ripatti, Samuli; Aittokallio, Tero

PLoS Genetics Volume 10, Issue 11

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#91 Common variant at 16p11.2 conferring risk of psychosis Link logo

Steinberg, S.; de Jong, S.; Mattheisen, M.; Costas, J.; Demontis, D.; Jamain, S.; Pietiläinen, O. P. H.; Lin, K.; Papiol, S.; Huttenlocher, J.; Sigurdsson, E.; Vassos, E.; Giegling, I.; Breuer, R.; Fraser, G.; Walker, N.; Melle, I.; Djurovic, S.; Agartz,

Molecular Psychiatry Volume 19, Issue 1, Pages 108–114

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Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).


#92 Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling Link logo

Logan, Clare V.; Szabadkai, Gyoergy; Sharpe, Jenny A.; Parry, David A.; Torelli, Silvia; Childs, Anne-Marie; Kriek, Marjolein; Phadke, Rahul; Johnson, Colin A.; Roberts, Nicola Y.; Bonthron, David T.; Pysden, Karen A.; Whyte, Tamieka; Munteanu, Iulia; Fol

Nature Genetics Volume 46, Issue 2

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Mitochondrial Ca(2+) uptake has key roles in cell life and death. Physiological Ca(2+) signaling regulates aerobic metabolism, whereas pathological Ca(2+) overload triggers cell death. Mitochondrial Ca(2+) uptake is mediated by the Ca(2+) uniporter complex in the inner mitochondrial membrane, which comprises MCU, a Ca(2+)-selective ion channel, and its regulator, MICU1. Here we report mutations of MICU1 in individuals with a disease phenotype characterized by proximal myopathy, learning difficulties and a progressive extrapyramidal movement disorder. In fibroblasts from subjects with MICU1 mutations, agonist-induced mitochondrial Ca(2+) uptake at low cytosolic Ca(2+) concentrations was increased, and cytosolic Ca(2+) signals were reduced. Although resting mitochondrial membrane potential was unchanged in MICU1-deficient cells, the mitochondrial network was severely fragmented. Whereas the pathophysiology of muscular dystrophy and the core myopathies involves abnormal mitochondrial Ca(2+) handling, the phenotype associated with MICU1 deficiency is caused by a primary defect in mitochondrial Ca(2+) signaling, demonstrating the crucial role of mitochondrial Ca(2+) uptake in humans.


#93 Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer. Open access logo

Saunders Edward J; Dadaev Tokhir; Leongamornlert Daniel A; Jugurnauth-Little Sarah; Tymrakiewicz Malgorzata; Wiklund Fredrik; Al Olama Ali Amin; Benlloch Sara; Neal David E; Hamdy Freddie C; Donovan Jenny L; Giles Graham G; Severi Gianluca; Gronberg Henri

PLoS Genetics Volume 10, Issue 2

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The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.


#94 Parallel independent evolution of pathogenicity within the genus Yersinia Link logo PDF logo

Reuter, Sandra; Connor, Thomas R.; Barquist, Lars; Walker, Danielle; Feltwell, Theresa; Harris, Simon R.; Fookes, Maria; Hall, Miquette E.; Petty, Nicola K.; Fuchs, Thilo M.; Corander, Jukka; Dufour, Muriel; Ringwood, Tamara; Savin, Cyril; Bouchier, Chris

Proceedings of the National Academy of Sciences of the United States of America Volume 111, Issue 18, Pages 201317161–6773

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The genus Yersinia has been used as a model system to study pathogen evolution. Using whole-genome sequencing of all Yersinia species, we delineate the gene complement of the whole genus and define patterns of virulence evolution. Multiple distinct ecological specializations appear to have split pathogenic strains from environmental, nonpathogenic lineages. This split demonstrates that contrary to hypotheses that all pathogenic Yersinia species share a recent common pathogenic ancestor, they have evolved independently but followed parallel evolutionary paths in acquiring the same virulence determinants as well as becoming progressively more limited metabolically. Shared virulence determinants are limited to the virulence plasmid pYV and the attachment invasion locus ail. These acquisitions, together with genomic variations in metabolic pathways, have resulted in the parallel emergence of related pathogens displaying an increasingly specialized lifestyle with a spectrum of virulence potential, an emerging theme in the evolution of other important human pathogens.


#95 The Impact of the FIFA 11+Training Program on Injury Prevention in Football Players:A Systematic Review Open access logo Link logo

Barengo, Noel; Francisco Meneses-Echavez, Jose; Ramirez-Velez, Robinson; Dylan Cohen, Daniel; Tovar, Gustavo; Correa Bautista, Jorge Enrique

International Journal of Environmental Research and Public Health Volume 11, Issue 11, Pages 11986–12000

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The FIFA 11+ is a simple, and easy to implement, sports injury prevention program comprising a warm up of 10 conditioning exercises. The aim of this systematic review was to evaluate the impact of the FIFA 11+ on injury incidence, compliance and cost effectiveness when implemented among football players. MEDLINE, EMBASE and Scopus databases were searched using the search terms "FIFA 11+", "football", "soccer", "injury prevention", and "The 11". The titles and abstracts were screened by two independent reviewers and the data were filtered by one reviewer using a standardized extraction form and thereafter checked by another one. The risk of bias and the methodological quality of the studies were evaluated through the PEDro score and Critical Appraisal Skills Programme (CASP). A total of 911 studies were identified, of which 12 met the inclusion criteria of the review. The FIFA 11+ has demonstrated how a simple exercise program completed as part of warm-up can decrease the incidence of injuries in amateur football players. In general, considerable reductions in the number of injured players, ranging between 30% and 70%, have been observed among the teams that implemented the FIFA 11+. In addition, players with high compliance to the FIFA 11+ program had an estimated risk reduction of all injuries by 35% and show significant improvements in components of neuromuscular and motor performance when participating in structured warm-up sessions at least 1.5 times/week. Most studies had high methodological quality and a low risk of bias. Given the large number of people who play football at amateur level and the detrimental impact of sports injuries on a personal and societal level, the FIFA 11+ can be considered as a fundamental tool to minimize the risks of participation in a sport with substantial health benefits.


#96 A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding Link logo

Huang, Qilai; Whitington, Thomas; Gao, Ping; Lindberg, Johan F.; Yang, Yuehong; Sun, Jielin; Vaisanen, Marja-Riitta; Szulkin, Robert; Annala, Matti; Yan, Jian; Egevad, Lars A.; Zhang, Kai; Lin, Ruizhu; Jolma, Arttu; Nykter, Matti; Manninen, Aki; Wiklund,

Nature Genetics

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Genome-wide association studies have identified thousands of SNPs associated with predisposition to various diseases, including prostate cancer. However, the mechanistic roles of these SNPs remain poorly defined, particularly for noncoding polymorphisms. Here we find that the prostate cancer risk-associated SNP rs339331 at 6q22 lies within a functional HOXB13-binding site. The risk-associated T allele at rs339331 increases binding of HOXB13 to a transcriptional enhancer, conferring allele-specific upregulation of the rs339331-associated gene RFX6. Suppression of RFX6 diminishes prostate cancer cell proliferation, migration and invasion. Clinical data indicate that RFX6 upregulation in human prostate cancers correlates with tumor progression, metastasis and risk of biochemical relapse. Finally, we observe a significant association between the risk-associated T allele at rs339331 and increased RFX6 mRNA levels in human prostate tumors. Together, our results suggest that rs339331 affects prostate cancer risk by altering RFX6 expression through a functional interaction with the prostate cancer susceptibility gene HOXB13.


#97 Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) PDF logo

Jean-Pascal Lefaucheur, Nathalie André-Obadia, Andrea Antal, Samar S. Ayache, Chris Baeken, David H. Benninger, Roberto M. Cantello, Massimo Cincotta, Mamede de Carvalho, Dirk De Ridder, Hervé Devanne, Vincenzo Di Lazzaro, Saša R. Filipovic´, Friedhelm C. Hummel, Satu K. Jääskeläinen, Vasilios K. Kimiskidis, Giacomo Koch, Berthold Langguth, Thomas Nyffeler, Antonio Oliviero, Frank Padberg, Emmanuel Poulet, Simone Rossi, Paolo Maria Rossini, C. Rothwell, Carlos Schönfeldt-Lecuona, Hartwig R. Siebner, Christi

Clinical Neurophysiology Volume 125, Issue 11, Pages 2150–2206

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A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.


#98 De novo mutations in HCN1 cause early infantile epileptic encephalopathy Link logo

Nava, Caroline; Dalle, Carine; Rastetter, Agnes; Striano, Pasquale; de Kovel, Carolien G. F.; Nabbout, Rima; Cances, Claude; Ville, Dorothee; Brilstra, Eva H.; Gobbi, Giuseppe; Raffo, Emmanuel; Bouteiller, Delphine; Marie, Yannick; Trouillard, Oriane; Rob

Nature Genetics Volume 46, Issue 6

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Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels contribute to cationic Ih current in neurons and regulate the excitability of neuronal networks. Studies in rat models have shown that the Hcn1 gene has a key role in epilepsy, but clinical evidence implicating HCN1 mutations in human epilepsy is lacking. We carried out exome sequencing for parent-offspring trios with fever-sensitive, intractable epileptic encephalopathy, leading to the discovery of two de novo missense HCN1 mutations. Screening of follow-up cohorts comprising 157 cases in total identified 4 additional amino acid substitutions. Patch-clamp recordings of Ih currents in cells expressing wild-type or mutant human HCN1 channels showed that the mutations had striking but divergent effects on homomeric channels. Individuals with mutations had clinical features resembling those of Dravet syndrome with progression toward atypical absences, intellectual disability and autistic traits. These findings provide clear evidence that de novo HCN1 point mutations cause a recognizable early-onset epileptic encephalopathy in humans.


#99 Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico

SIGMA Type 2 Diabetes Consortium, Williams AL, Jacobs SB, Moreno-Macías H, Huerta-Chagoya A, Churchhouse C, Márquez-Luna C, García-Ortíz H, Gómez-Vázquez MJ, Burtt NP, Aguilar-Salinas CA, González-Villalpando C, Florez JC, Orozco L, Haiman CA, Tusié-Luna T, Altshuler D (including Laakso M)

Nature Volume 506, Issue 7486, Pages 97–101

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Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10(-13); odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10(-4); OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.


#100 Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3 Open access logo Link logo PDF logo

Khan, Nahid A.; Auranen, Mari; Paetau, Ilse; Pirinen, Eija; Euro, Liliya; Forsström, Saara; Pasila, Lotta; Velagapudi, Vidya; Carroll, Christopher J.; Auwerx, Johan; Suomalainen, Anu

EMBO Molecular Medicine Volume 6, Issue 6, Pages 721–731

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Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD(+)/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD(+) precursor, was previously shown to boost NAD(+) levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD(+) levels are a promising treatment strategy for mitochondrial myopathy.


#101 Impact of Diet on Human Intestinal Microbiota and Health Link logo

Salonen, Anne; de Vos, Willem M.

Annual Review of Food Science and Technology

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Our intestinal microbiota is involved in the breakdown and bioconversion of dietary and host components that are not degraded and taken up by our own digestive system. The end products generated by our microbiota fuel our enterocytes and support growth but also have signaling functions that generate systemic immune and metabolic responses. Due to the immense metabolic capacity of the intestinal microbiota and its relatively high plasticity, there is great interest in identifying dietary approaches that allow intentional and predictable modulation of the microbiota. In this article, we review the current insights on dietary influence on the human intestinal microbiota based on recent high-throughput molecular studies and interconnections with health. We focus especially on the emerging data that identify the amount and type of dietary fat as significant modulators of the colonic microbiota and its metabolic output.


#102 Structural changes induced by daily music listening in the recovering brain after middle cerebral artery stroke: a voxel-based morphometry study Open access logo Link logo PDF logo

Sarkamo, Teppo; Ripolles, Pablo; Vepsalainen, Henna; Autti, Taina; Silvennoinen, Heli M.; Salli, Eero; Laitinen, Sari; Forsblom, Anita; Soinila, Seppo; Rodriguez-Fornells, Antoni

Frontiers in Human Neuroscience

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Music is a highly complex and versatile stimulus for the brain that engages many temporal, frontal, parietal, cerebellar, and subcortical areas involved in auditory, cognitive, emotional, and motor processing. Regular musical activities have been shown to effectively enhance the structure and function of many brain areas, making music a potential tool also in neurological rehabilitation. In our previous randomized controlled study, we found that listening to music on a daily basis can improve cognitive recovery and improve mood after an acute middle cerebral artery stroke. Extending this study, a voxel-based morphometry (VBM) analysis utilizing cost function masking was performed on the acute and 6-month post-stroke stage structural magnetic resonance imaging data of the patients (n = 49) who either listened to their favorite music [music group (MG), n = 16] or verbal material [audio book group (ABG), n = 18] or did not receive any listening material [control group (CG), n = 15] during the 6-month recovery period. Although all groups showed significant gray matter volume (GMV) increases from the acute to the 6-month stage, there was a specific network of frontal areas [left and right superior frontal gyrus (SFG), right medial SFG] and limbic areas [left ventral/subgenual anterior cingulate cortex (SACC) and right ventral striatum (VS)] in patients with left hemisphere damage in which the GMV increases were larger in the MG than in the ABG and in the CG. Moreover, the GM reorganization in the frontal areas correlated with enhanced recovery of verbal memory, focused attention, and language skills, whereas the GM reorganization in the SACC correlated with reduced negative mood. This study adds on previous results, showing that music listening after stroke not only enhances behavioral recovery, but also induces fine-grained neuroanatomical changes in the recovering brain.


#103 The role of central sensitization in shoulder pain : a systematic literature review Open access logo Link logo PDF logo

Sanchis, Marc N.; Lluch, Enrique; Nijs, Jo; Struyf, Filip; Kangasperko, Maija

Seminars in Arthritis & Rheumatism Volume 44, Issue 6, Pages 710–716

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Hyperexcitability of the central nervous system has been suggested to play an important role in pain experienced by patients with unilateral shoulder pain. A systematic literature review following the PRISMA guidelines was performed to evaluate the existing evidence related to the presence of central sensitization in patients with unilateral shoulder pain of different etiologies including those with chronic subacromial impingement syndrome. Studies addressing neuropathic pain (e.g., post-stroke shoulder pain) were not considered.


#104 Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease Open access logo PDF logo

Mäkinen Ville-Petteri; Civelek Mete; Meng Quinying; Zhang Bin; Zhu Jun; Levian Candace; Huan Tianxiao; Segrè Ayellet V; Ghosh Sujoy; Vivar Juan; Nikpay Majid; Stewart Alexandre FR; Nelson Christopher P; Willenborg Christina; Erdmann Jeanette; Blakenberg S

PLoS Genetics Volume 10, Issue 7

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The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions.


#105 How do somatosensory deficits in the arm and hand relate to upper limb impairment, activity, and participation problems after stroke? a systematic review Link logo

Meyer, Sarah;Karttunen, Auli;Thijs, Vincent;Feys, Hilde;Verheyden, Geert

Physical Therapy Volume 94, Issue 9, Pages 1220–1231

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BackgroundThe association between somatosensory impairments and outcome after stroke remains unclear.PurposeTo systematically review the available literature on the relation between somatosensory impairments in the upper limb and outcome after stroke.Data SourcesWe systematically searched PubMed, CINAHL, EMBASE, Cochrane Library, PsycINFO and Web of Science from inception until July 2013.Study SelectionStudies were included if adult patients with stroke (minimum n=10) were examined with reliable and/or valid measures of somatosensation in the upper limb to investigate the relation with upper limb impairment, activity and participation measures. Exclusion criteria included measures of somatosensation involving an overall score for upper and lower limb outcome and papers including only lower limb outcomes.Data ExtractionEligibility assessment, data extraction and quality evaluation was completed by two independent reviewers. A cut-off score of ≥65% of the maximal quality score was used for further inclusion in this review.Data SynthesisSix papers met all inclusion criteria. Two-point discrimination showed to be predictive for upper limb dexterity and somatosensory evoked potentials showed to have predictive value in upper limb motor recovery. Proprioception was significantly correlated with perceived level of physical activity and social isolation and had some predictive value in functional movements of the upper limb. Finally, the combination of light touch and proprioception impairment showed to be significantly related to upper limb motor recovery, as well as to handicap situations during activities of daily living.LimitationsHeterogeneity of included studies warrants caution when interpreting results.ConclusionsLarge variation in results was found due to heterogeneity of studies. However, somatosensory deficits showed to have an important role in upper limb motor and functional performance after stroke.


#106 Gene-wide analysis detects two new susceptibility genes for Alzheimer's Disease Open access logo

Escott-Price V, Bellenguez C, Wang L-S, Choi S-H, Harold D, Jones L, Holmans P, Gerrish A, Vedernikov A, Richards A, DeStefano AL, Lambert J-C, Ibrahim-Verbaas CA, Naj AC, Sims R, Jun G, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thornton-Wells TA et.al.

PLoS ONE Volume 9, Issue 6

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Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.


#107 Innate immune evasion of microbes

Amdahl, Hanne

Immunological Reviews Volume 245, Issue 1, Pages 113–131

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#108 Miswiring the brain: Delta(9)-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway PDF logo

Tortoriello Giuseppe, Morris Claudia V, Alpar Alan, Fuzik Janos, Shirran Sally L, Calvigioni Daniela, Keimpema Erik, Botting Catherine H, Reinecke Kirstin, Herdegen Thomas, Courtney Michael, Hurd Yasmin L, Harkany Tibor

EMBO Journal Volume 33, Issue 7, Pages 668–685

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Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Δ(9)-tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid receptor-driven molecular cascade to disrupt neuronal specification. Here, we show that repeated THC exposure disrupts endocannabinoid signaling, particularly the temporal dynamics of CB1 cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC-sensitive neuronal proteome we identify Superior Cervical Ganglion 10 (SCG10)/stathmin-2, a microtubule-binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis-exposed fetuses, defining SCG10 as the first cannabis-driven molecular effector in the developing cerebrum. CB1 cannabinoid receptor activation recruits c-Jun N-terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring.


#109 Standard method for detecting upper respiratory carriage of Streptococcus pneumoniae: Updated recommendations from the World Health Organization Pneumococcal Carriage Working Group

Satzke, Catherine; Turner, Paul; Virolainen-Julkunen, Anni; Adrian, Peter V.; Antonio, Martin; Hare, Kim M.; Henao-Restrepo, Ana Maria; Leach, Amanda J.; Klugman, Keith P.; Porter, Barbara D.; Sa-Leao, Raquel; Scott, J. Anthony; Nohynek, Hanna; O'Brien, Katherine L.

Vaccine Volume 32, Issue 1, Pages 165–179

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#110 Group-PCA for very large fMRI datasets Link logo

Smith, Stephen M.; Hyvärinen, Aapo; Varoquaux, Gael; Miller, Karla L.; Beckmann, Christian F.

NeuroImage

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Increasingly-large datasets (for example, the resting-state fMRI data from the Human Connectome Project) are demanding analyses that are problematic because of the sheer scale of the aggregate data. We present two approaches for applying group-level PCA; both give a close approximation to the output of PCA applied to full concatenation of all individual datasets, while having very low memory requirements regardless of the number of datasets being combined. Across a range of realistic simulations, we find that in most situations, both methods are more accurate than current popular approaches for analysis of multi-subject resting-state fMRI studies. The group-PCA output can be used to feed into a range of further analyses that are then rendered practical, such as the estimation of group-averaged voxelwise connectivity, group-level parcellation, and group-ICA.


#111 A global analysis of Y-chromosomal haplotype diversity for 23 STR loci Link logo

Purps, Josephine; Siegert, Sabine; Willuweit, Sascha; Nagy, Marion; Alves, Cintia; Salazar, Renato; Angustia, Sheila M. T.; Santos, Lorna H.; Anslinger, Katja; Bayer, Birgit; Ayub, Qasim; Wei, Wei; Xue, Yali; Tyler-Smith, Chris; Bafalluy, Miriam Baeta; Ma

Forensic Science International: Genetics

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In a worldwide collaborative effort, 19,630 Y-chromosomes were sampled from 129 different populations in 51 countries. These chromosomes were typed for 23 short-tandem repeat (STR) loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, GATAH4, DYS481, DYS533, DYS549, DYS570, DYS576, and DYS643) and using the PowerPlex Y23 System (PPY23, Promega Corporation, Madison, WI). Locus-specific allelic spectra of these markers were determined and a consistently high level of allelic diversity was observed. A considerable number of null, duplicate and off-ladder alleles were revealed. Standard single-locus and haplotype-based parameters were calculated and compared between subsets of Y-STR markers established for forensic casework. The PPY23 marker set provides substantially stronger discriminatory power than other available kits but at the same time reveals the same general patterns of population structure as other marker sets. A strong correlation was observed between the number of Y-STRs included in a marker set and some of the forensic parameters under study. Interestingly a weak but consistent trend toward smaller genetic distances resulting from larger numbers of markers became apparent.


#112 International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies PDF logo

Agmon-Levin, Nancy; Damoiseaux, Jan; Kallenberg, Cees; Sack, Ulrich; Witte, Torsten; Herold, Manfred; Bossuyt, Xavier; Musset, Lucille; Cervera, Ricard; Plaza-Lopez, Aresio; Dias, Carlos; Sousa, Maria Jose; Radice, Antonella; Eriksson, Catharina; Hultgren, Olof; Viander, Markku; Khamashta, Munther; Regenass, Stephan; Andrade, Luis Eduardo; Wiik, Allan; Vainio, Olli

Annals of the Rheumatic Diseases Volume 73, Issue 1

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Anti-nuclear antibodies (ANA) are fundamental for the diagnosis of autoimmune diseases, and have been determined by indirect immunofluorescence assay (IIFA) for decades. As the demand for ANA testing increased, alternative techniques were developed challenging the classic IIFA. These alternative platforms differ in their antigen profiles, sensitivity and specificity, raising uncertainties regarding standardisation and interpretation of incongruent results. Therefore, an international group of experts has created recommendations for ANA testing by different methods. Two groups of experts participated in this initiative. The European autoimmunity standardization initiative representing 15 European countries and the International Union of Immunologic Societies/World Health Organization/Arthritis Foundation/Centers for Disease Control and Prevention autoantibody standardising committee. A three-step process followed by a Delphi exercise with closed voting was applied. Twenty-five recommendations for determining ANA (1-13), anti-double stranded DNA antibodies (14-18), specific antibodies (19-23) and validation of methods (24-25) were created. Significant differences between experts were observed regarding recommendations 24-25 (p<0.03). Here, we formulated recommendations for the assessment and interpretation of ANA and associated antibodies. Notably, the roles of IIFA as a reference method, and the importance of defining nuclear and cytoplasmic staining, were emphasised, while the need to incorporate alternative automated methods was acknowledged. Various approaches to overcome discrepancies between methods were suggested of which an improved bench-to-bedside communication is of the utmost importance. These recommendations are based on current knowledge and can enable harmonisation of local algorithms for testing and evaluation of ANA and related autoantibodies. Last but not least, new more appropriate terminologies have been suggested.


#113 Physical Activity of Children : A Global Matrix of Grades Comparing 15 Countries Link logo

Tremblay, Mark S.;Gray, Casey E.;Akinroye, Kingsley K.;Harrington, Deirdre M.;Katzmarzyk, Peter T.;Lambert, Estelle V.;Liukkonen, Jarmo;Maddison, Ralph;Ocansey, Reginald T.;Onywera, Vincent O.;Prista, Antonio;Reilly, John J.;Martinez, Maria del Pilar Rodriguez;Sarmiento, Olga L.;Standage, Martyn;Tomkinson, Grant R.

Journal of Physical Activity and Health Volume 11, Issue 4 Suppl 1, Pages S113–S125

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The Active Healthy Kids Canada (AHKC) Report Card on Physical Activity for Children and Youth has been effective in powering the movement to get kids moving by influencing priorities, policies, and practice in Canada. The AHKC Report Card process was replicated in 14 additional countries from 5 continents using 9 common indicators (Overall Physical Activity, Organized Sport Participation, Active Play, Active Transportation, Sedentary Behavior, Family and Peers, School, Community and Built Environment, and Government Strategies and Investments), a harmonized process and a standardized grading framework. The 15 Report Cards were presented at the Global Summit on the Physical Activity of Children in Toronto on May 20, 2014. The consolidated findings are summarized here in the form of a global matrix of grades. There is a large spread in grades across countries for most indicators. Countries that lead in certain indicators lag in others. Overall, the grades for indicators of physical activity (PA) around the world are low/poor. Many countries have insufficient information to assign a grade, particularly for the Active Play and Family and Peers indicators. Grades for Sedentary Behaviors are, in general, better in low income countries. The Community and Built Environment indicator received high grades in high income countries and notably lower grades in low income countries. There was a pattern of higher PA and lower sedentary behavior in countries reporting poorer infrastructure, and lower PA and higher sedentary behavior in countries reporting better infrastructure, which presents an interesting paradox. Many surveillance and research gaps and weaknesses were apparent. International cooperation and cross-fertilization is encouraged to tackle existing challenges, understand underlying mechanisms, derive innovative solutions, and overcome the expanding childhood inactivity crisis.


#114 Nurses' Shift Length and Overtime Working in 12 European Countries Open access logo Link logo PDF logo

Griffiths Peter, Dall'Ora Chiara, Simon Michael, Ball Jane, Lindqvist Rikard, Rafferty Anne-Marie, Schoonhoven Lisette, Tishelman Carol, Aiken H. Linda, Sermeus Walter, Van den Heede Koen, Bruyneel Luk, Lesaffre Emmanuel, Diya Luwis, Smith Herbert, Sloane Douglas, Jones Simon, Kinnunen Juha, Ensio Anneli, Jylhä Virpi

Medical care Volume 52, Issue 11, Pages 975–981

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Despite concerns as to whether nurses can perform reliably and effectively when working longer shifts, a pattern of two 12- to 13-hour shifts per day is becoming common in many hospitals to reduce shift to shift handovers, staffing overlap, and hence costs.


#115 Too Fit To Fracture: exercise recommendations for individuals with osteoporosis or osteoporotic vertebral fracture Link logo PDF logo

Giangregorio, L. M.;Papaioannou, A.;MacIntyre, N. J.;Ashe, M. C.;Heinonen, Ari;Shipp, K.;Wark, J.;McGill, S.;Keller, H.;Jain, R.;Laprade, J.;Cheung, A. M.

Osteoporosis International Volume 25, Issue 3, Pages 821–835

  • 32 tweets
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A consensus process was conducted to develop exercise recommendations for individuals with osteoporosis or vertebral fractures. A multicomponent exercise program that includes balance and resistance training is recommended.


#116 "The cerebrospinal fluid ""Alzheimer profile"": Easily said, but what does it mean?" Link logo PDF logo

Duits FH, Teunissen CE, Bouwman FH, Visser PJ, Mattsson N, Zetterberg H, Blennow K, Hansson O, Minthon L, Andreasen N, Marcusson J, Wallin A, Rikkert MO, Tsolaki M, Parnetti L, Herukka SK, Hampel H, De Leon MJ, Schröder J, Aarsland D, Blankenstein MA, Scheltens P, van der Flier WM

Alzheimer's & Dementia: the Journal of the Alzheimer's Association

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We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-ß1-42 (Aβ42), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimer's disease (AD).


#117 The microRNAs in the blood vessel endothelial cells Open access logo Link logo

Pulkkinen Kati

Blood Volume 105, Issue 7, Pages 2783–2786

  • 1 tweet
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#118 Alzheimer's disease biomarker discovery using SOMAscan multiplexed protein technology PDF logo

Sattlecker Martina, Kiddle Steven J, Newhouse Stephen, Proitsi Petroula, Nelson Sally, Williams Stephen, Johnston Caroline, Killick Richard, Simmons Andrew, Westman Eric, Hodges Angela, Soininen Hilkka, Kloszewska Iwona, Mecocci Patrizia, Tsolaki Magda, Vellas Bruno, Lovestone Simon, Dobson Richard JB

Alzheimer's & Dementia: the Journal of the Alzheimer's Association

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Blood proteins and their complexes have become the focus of a great deal of interest in the context of their potential as biomarkers of Alzheimer's disease (AD). We used a SOMAscan assay for quantifying 1001 proteins in blood samples from 331 AD, 211 controls, and 149 mild cognitive impaired (MCI) subjects. The strongest associations of protein levels with AD outcomes were prostate-specific antigen complexed to α1-antichymotrypsin (AD diagnosis), pancreatic prohormone (AD diagnosis, left entorhinal cortex atrophy, and left hippocampus atrophy), clusterin (rate of cognitive decline), and fetuin B (left entorhinal atrophy). Multivariate analysis found that a subset of 13 proteins predicted AD with an accuracy of area under the curve of 0.70. Our replication of previous findings provides further evidence that levels of these proteins in plasma are truly associated with AD. The newly identified proteins could be potential biomarkers and are worthy of further investigation.


#119 Treatment of non-traumatic rotator cuff tears: A randomised controlled trial with one-year clinical results Link logo

Kukkonen J, Joukainen A, Lehtinen J, Mattila KT, Tuominen EK, Kauko T, Äärimaa V

The Bone & Joint Journal Volume 96, Issue 1

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We have compared three different methods of treating symptomatic non-traumatic tears of the supraspinatus tendon in patients above 55 years of age. A total of 180 shoulders (173 patients) with supraspinatus tendon tears were randomly allocated into one of three groups (each of 60 shoulders); physiotherapy (group 1), acromioplasty and physiotherapy (group 2) and rotator cuff repair, acromioplasty and physiotherapy (group 3). The Constant score was assessed and followed up by an independent observer pre-operatively and at three, six and twelve months after the intervention. Of these, 167 shoulders were available for assessment at one year (follow-up rate of 92.8%). There were 55 shoulders in group 1 (24 in males and 31 in females, mean age 65 years (55 to 79)), 57 in group 2 (29 male and 28 female, mean age 65 years (55 to 79)) and 55 shoulders in group 3 (26 male and 29 female, mean age 65 years (55 to 81)). There were no between-group differences in the Constant score at final follow-up: 74.1 (sd 14.2), 77.2 (sd 13.0) and 77.9 (sd 12.1) in groups 1, 2 and 3, respectively (p = 0.34). The mean change in the Constant score was 17.0, 17.5, and 19.8, respectively (p = 0.34). These results suggest that at one-year follow-up, operative treatment is no better than conservative treatment with regard to non-traumatic supraspinatus tears, and that conservative treatment should be considered as the primary method of treatment for this condition.


#120 Comparing land use regression and dispersion modelling to assess residential exposure to ambient air pollution for epidemiological studies

de Hoogh, Kees; Korek, Michal; Vienneau, Danielle; Keuken, Menno; Kukkonen, Jaakko; Nieuwenhuijsen, Mark J.; Badaloni, Chiara; Beelen, Rob; Bolignano, Andrea; Cesaroni, Giulia; Pradas, Marta Cirach; Cyrys, Josef; Douros, John; Eeftens, Marloes; Forastiere, Francesco; Forsberg, Bertil; Fuks, Kateryna; Gehring, Ulrike; Gryparis, Alexandros; Gulliver, John; Hansell, Anna L.; Hoffmann, Barbara; Johansson, Christer; Jonkers, Sander; Kangas, Leena; Katsouyanni, Klea; Kuenzli, Nino; Lanki, Timo; Memmesheimer, Mic

Environment International

  • 3 tweets
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Land-use regression (LUR) and dispersion models (DM) are commonly used for estimating individual air pollution exposure in population studies. Few comparisons have however been made of the performance of these methods.


#121 The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples An NTM-NET collaborative study PDF logo

Hoefsloot, Wouter; Van Ingen, Jakko; Andrejak, Claire; Angeby, Kristian; Bauriaud, Rosine; Bemer, Pascale; Beylis, Natalie; Boeree, Martin J.; Cacho, Juana; Chihota, Violet; Chimara, Erica; Churchyard, Gavin; Cias, Raquel; Daza, Rosa; Daley, Charles L.; Dekhuijzen, P. N. Richard; Domingo, Diego; Drobniewski, Francis; Esteban, Jaime; Fauvilte-Dufaux, Maryse; Folkvardsen, Dorte Bek; Gibbons, Noel; Gomez-Mampaso, Enrique; Gonzalez, Rosa; Hoffmann, Harald; Hsueh, Po-Ren; Indra, Alexander; Jagielski, Tomasz; Ja

European Respiratory Journal

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A significant knowledge gap exists concerning the geographical distribution of nontuberculous mycobacteria (NTM) isolation worldwide. To provide a snapshot of NTM species distribution, global partners in the NTM-Network European Trials Group (NET) framework (www.ntm-net.org), a branch of the Tuberculosis Network European Trials Group (TB-NET), provided identification results of the total number of patients in 2008 in whom NTM were isolated from pulmonary samples. From these data, we visualised the relative distribution of the different NTM found per continent and per country. We received species identification data for 20 182 patients, from 62 laboratories in 30 countries across six continents. 91 different NTM species were isolated. Mycobacterium avium complex (MAC) bacteria predominated in most countries, followed by M. gordonae and M. xenopi. Important differences in geographical distribution of MAC species as well as M. xenopi, M. kansasii and rapid-growing mycobacteria were observed. This snapshot demonstrates that the species distribution among NTM isolates from pulmonary specimens in the year 2008 differed by continent and differed by country within these continents. These differences in species distribution may partly determine the frequency and manifestations of pulmonary NTM disease in each geographical location.


#122 Matrix metalloproteinases in inflammation

Liisa Nissinen, Veli-Matti Kähäri

Biochimica et Biophysica Acta (BBA)

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Matrix metalloproteinases (MMPs) are a family of ubiquitously expressed zinc-dependent endopeptidases with broad substrate specificity and strictly regulated tissue specific expression. They are expressed in physiological situations and pathological conditions involving inflammation. MMPs regulate several functions related to inflammation including bioavailability and activity of inflammatory cytokines and chemokines. There is also evidence that MMPs regulate inflammation in tumor microenvironment, which plays an important role in cancer progression.


#123 ESPGHAN Revised Porto Criteria for the Diagnosis of Inflammatory Bowel Disease in Children and Adolescents Link logo PDF logo

Levine, Arie; Koletzko, Sibylle; Turner, Dan; Escher, Johanna C.; Cucchiara, Salvatore; de Ridder, Lissy; Kolho, Kaija-Leena; Veres, Gabor; Russell, Richard K.; Paerregaard, Anders; Buderus, Stephan; Greer, Mary-Louise C.; Dias, Jorge A.; Veereman-Wauters

Journal of Pediatric Gastroenterology & Nutrition Volume Publish Ahead of Print, Issue 6

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The diagnosis of pediatric-onset inflammatory bowel disease (PIBD) can be challenging in choosing the most informative diagnostic tests and correctly classifying PIBD into its different subtypes. Recent advances in our understanding of the natural history and phenotype of PIBD, increasing availability of serological and fecal biomarkers, and the emergence of novel endoscopic and imaging technologies taken together have made the previous Porto criteria for the diagnosis of PIBD obsolete.


#124 Metabolic Signatures of Adiposity in Young Adults:Mendelian Randomization Analysis and Effects of Weight Change Open access logo Link logo PDF logo

Würtz, Peter; Wang, Qin; Kangas, Antti J.; Richmond, Rebecca C.; Skarp, Joni; Tiainen, Mika; Tynkkynen, Tuulia; Soininen, Pasi; Havulinna, Aki S.; Kaakinen, Marika; Viikari, Jorma S.; Savolainen, Markku J.; Kahonen, Mika; Lehtimaki, Terho; Mannisto, Satu;

PLoS Medicine Volume 11, Issue 12

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Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood.


#125 De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies Link logo PDF logo

Appenzeller, Silke; Balling, Rudi; Barisic, Nina; Baulac, Stephanie; Caglayan, Hande; Craiu, Dana; De Jonghe, Peter; Depienne, Christel; Dimova, Petia; Djemie, Tania; Gormley, Padhraig; Guerrini, Renzo; Helbig, Ingo; Hjalgrim, Helle; Hoffman-Zacharska, Do

American Journal of Human Genetics Volume 95, Issue 4, Pages 360–370

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Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.


#126 The effects of health coaching on adult patients with chronic diseases: A systematic review PDF logo

Kivela, Kirsi; Elo, Satu; Kyngas, Helvi; Kääriäinen, Maria

Patient Education & Counseling Volume 97, Issue 2, Pages 147–157

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The aim of this systematic review was to describe the effects of health coaching on adult patients with chronic diseases.


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