Showing papers by "Charité published in 2018"
Christina Fitzmaurice1, Christina Fitzmaurice2, Christina Fitzmaurice3, Tomi Akinyemiju4 +177 more•Institutions (102)
TL;DR: In this paper, the authors assess the burden of 29 cancer groups over time to provide a framework for policy discussion, resource allocation, and research focus, and evaluate cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs) for 195 countries and territories by age and sex using the Global Burden of Disease study estimation methods.
Abstract: Importance The increasing burden due to cancer and other noncommunicable diseases poses a threat to human development, which has resulted in global political commitments reflected in the Sustainable Development Goals as well as the World Health Organization (WHO) Global Action Plan on Non-Communicable Diseases. To determine if these commitments have resulted in improved cancer control, quantitative assessments of the cancer burden are required. Objective To assess the burden for 29 cancer groups over time to provide a framework for policy discussion, resource allocation, and research focus. Evidence Review Cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs) were evaluated for 195 countries and territories by age and sex using the Global Burden of Disease study estimation methods. Levels and trends were analyzed over time, as well as by the Sociodemographic Index (SDI). Changes in incident cases were categorized by changes due to epidemiological vs demographic transition. Findings In 2016, there were 17.2 million cancer cases worldwide and 8.9 million deaths. Cancer cases increased by 28% between 2006 and 2016. The smallest increase was seen in high SDI countries. Globally, population aging contributed 17%; population growth, 12%; and changes in age-specific rates, −1% to this change. The most common incident cancer globally for men was prostate cancer (1.4 million cases). The leading cause of cancer deaths and DALYs was tracheal, bronchus, and lung cancer (1.2 million deaths and 25.4 million DALYs). For women, the most common incident cancer and the leading cause of cancer deaths and DALYs was breast cancer (1.7 million incident cases, 535 000 deaths, and 14.9 million DALYs). In 2016, cancer caused 213.2 million DALYs globally for both sexes combined. Between 2006 and 2016, the average annual age-standardized incidence rates for all cancers combined increased in 130 of 195 countries or territories, and the average annual age-standardized death rates decreased within that timeframe in 143 of 195 countries or territories. Conclusions and Relevance Large disparities exist between countries in cancer incidence, deaths, and associated disability. Scaling up cancer prevention and ensuring universal access to cancer care are required for health equity and to fulfill the global commitments for noncommunicable disease and cancer control.
4,621 citations
TL;DR: Intensified research efforts and global initiatives are clearly needed to address the burden of low back pain as a public health problem, where health and other systems are often fragile and not equipped to cope with this growing burden.
2,114 citations
TL;DR: A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent and significant loci and finds important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia.
Abstract: Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.
1,898 citations
TL;DR: This work presents a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and shows that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods.
Abstract: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
1,620 citations
TL;DR: Non-vitamin K antagonist oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with atrial fibrillation (AF) and have emerged as the preferred choice, particularly in patients newly started on antICOagulation.
Abstract: The current manuscript is the second update of the original Practical Guide, published in 2013 [Heidbuchel et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-651; Heidbuchel et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17:1467-1507]. Non-vitamin K antagonist oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with atrial fibrillation (AF) and have emerged as the preferred choice, particularly in patients newly started on anticoagulation. Both physicians and patients are becoming more accustomed to the use of these drugs in clinical practice. However, many unresolved questions on how to optimally use these agents in specific clinical situations remain. The European Heart Rhythm Association (EHRA) set out to coordinate a unified way of informing physicians on the use of the different NOACs. A writing group identified 20 topics of concrete clinical scenarios for which practical answers were formulated, based on available evidence. The 20 topics are as follows i.e., (1) Eligibility for NOACs; (2) Practical start-up and follow-up scheme for patients on NOACs; (3) Ensuring adherence to prescribed oral anticoagulant intake; (4) Switching between anticoagulant regimens; (5) Pharmacokinetics and drug-drug interactions of NOACs; (6) NOACs in patients with chronic kidney or advanced liver disease; (7) How to measure the anticoagulant effect of NOACs; (8) NOAC plasma level measurement: rare indications, precautions, and potential pitfalls; (9) How to deal with dosing errors; (10) What to do if there is a (suspected) overdose without bleeding, or a clotting test is indicating a potential risk of bleeding; (11) Management of bleeding under NOAC therapy; (12) Patients undergoing a planned invasive procedure, surgery or ablation; (13) Patients requiring an urgent surgical intervention; (14) Patients with AF and coronary artery disease; (15) Avoiding confusion with NOAC dosing across indications; (16) Cardioversion in a NOAC-treated patient; (17) AF patients presenting with acute stroke while on NOACs; (18) NOACs in special situations; (19) Anticoagulation in AF patients with a malignancy; and (20) Optimizing dose adjustments of VKA. Additional information and downloads of the text and anticoagulation cards in different languages can be found on an EHRA website (www.NOACforAF.eu).
1,499 citations
Verneri Anttila1, Verneri Anttila2, Brendan Bulik-Sullivan2, Brendan Bulik-Sullivan1 +717 more•Institutions (270)
TL;DR: It is demonstrated that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine, and it is shown that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures.
Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
1,357 citations
Cardiff University1, Harvard University2, Charité3, King's College London4, Broad Institute5, University of Adelaide6, Centre for Mental Health7, University of Queensland8, University of Münster9, University of Edinburgh10, QIMR Berghofer Medical Research Institute11, University of Vigo12, University of California, Los Angeles13, Icahn School of Medicine at Mount Sinai14, University of Oviedo15, Lundbeck16, Aarhus University17, University of Oslo18, Oslo University Hospital19, Statens Serum Institut20, University of Bergen21, Aarhus University Hospital22, University of Copenhagen23, University of Belgrade24, Tbilisi State Medical University25, deCODE genetics26, University of Verona27, Mental Health Services28, Eli Lilly and Company29, Ludwig Maximilian University of Munich30, Martin Luther University of Halle-Wittenberg31
TL;DR: A new genome-wide association study of schizophrenia is reported, and through meta-analysis with existing data and integrating genomic fine-mapping with brain expression and chromosome conformation data, 50 novel associated loci and 145 loci are identified.
Abstract: Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.
1,259 citations
Aix-Marseille University1, Cornell University2, Washington University in St. Louis3, Charité4, Pasteur Institute5, French Institute of Health and Medical Research6, Keio University7, University of California, San Francisco8, Laboratory of Molecular Biology9, VU University Amsterdam10, University of Oxford11, University of Amsterdam12
TL;DR: The advances in ILC biology over the past decade are distill the advances to refine the nomenclature of ILCs and highlight the importance of I LCs in tissue homeostasis, morphogenesis, metabolism, repair, and regeneration.
1,252 citations
1,238 citations
TL;DR: The hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies is supported and increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed.
Abstract: Summary Background Tumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2-positive breast cancer, and luminal–HER2-negative breast cancer. Methods Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0–10% immune cells in stromal tissue within the tumour), intermediate (11–59%), and high TILs (≥60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts. Findings In the luminal–HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p 2 test for trend). In the univariable analysis, a 10% increase in TILs was associated with longer disease-free survival in TNBC (hazard ratio [HR] 0·93 [95% CI 0·87–0·98], p=0·011) and HER2-positive breast cancer (0·94 [0·89–0·99], p=0·017), but not in luminal–HER2-negative tumours (1·02 [0·96–1·09], p=0·46). The increase in TILs was also associated with longer overall survival in TNBC (0·92 [0·86–0·99], p=0·032), but had no association in HER2-positive breast cancer (0·94 [0·86–1·02], p=0·11), and was associated with shorter overall survival in luminal–HER2-negative tumours (1·10 [1·02–1·19], p=0·011). Interpretation Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed, and was also associated with a survival benefit in HER2-positive breast cancer and TNBC. By contrast, increased TILs were an adverse prognostic factor for survival in luminal–HER2-negative breast cancer, suggesting a different biology of the immunological infiltrate in this subtype. Our data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results in luminal breast cancer, further research investigating the interaction of the immune system with different types of endocrine therapy is warranted. Funding Deutsche Krebshilfe and European Commission.
1,154 citations
University of Oxford1, University of Michigan2, Wellcome Trust Sanger Institute3, Amgen4, University of Cambridge5, University of Copenhagen6, University of Liverpool7, University of Freiburg8, Boston University9, University of Tartu10, Erasmus University Medical Center11, Leiden University Medical Center12, Pasteur Institute13, Icahn School of Medicine at Mount Sinai14, UCLA Medical Center15, Vanderbilt University Medical Center16, Wake Forest University17, National University of Singapore18, Imperial College London19, London North West Healthcare NHS Trust20, Charité21, Innsbruck Medical University22, Washington University in St. Louis23, Queen Mary University of London24, University of Southern Denmark25, National and Kapodistrian University of Athens26, Robertson Centre for Biostatistics27, University of Exeter28, Uppsala University29, University of Düsseldorf30, Steno Diabetes Center31, Aalborg University32, University of Eastern Finland33, Broad Institute34, Frederiksberg Hospital35, University of Bergen36, Lund University37, Technische Universität München38, University of North Carolina at Chapel Hill39, Ninewells Hospital40, University of Edinburgh41, University of Minnesota42, University of Glasgow43, Ludwig Maximilian University of Munich44, University of Iceland45, Aarhus University46, Science for Life Laboratory47, Stanford University48, University of Helsinki49, National Institutes of Health50, University of Dundee51, Harvard University52
TL;DR: Combining 32 genome-wide association studies with high-density imputation provides a comprehensive view of the genetic contribution to type 2 diabetes in individuals of European ancestry with respect to locus discovery, causal-variant resolution, and mechanistic insight.
Abstract: We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
Swedish University of Agricultural Sciences1, University of Tartu2, Uppsala University3, Max Delbrück Center for Molecular Medicine4, Charité5, Leiden University6, University of Wisconsin-Madison7, Braunschweig University of Technology8, Technical University of Madrid9, Wageningen University and Research Centre10, University of California, Riverside11, University of Oslo12, Lund University13, ETH Zurich14, American Museum of Natural History15, University of Würzburg16
TL;DR: It is shown that bacterial, but not fungal, genetic diversity is highest in temperate habitats and that microbial gene composition varies more strongly with environmental variables than with geographic distance, and that the relative contributions of these microorganisms to global nutrient cycling varies spatially.
Abstract: Soils harbour some of the most diverse microbiomes on Earth and are essential for both nutrient cycling and carbon storage. To understand soil functioning, it is necessary to model the global distribution patterns and functional gene repertoires of soil microorganisms, as well as the biotic and environmental associations between the diversity and structure of both bacterial and fungal soil communities1–4. Here we show, by leveraging metagenomics and metabarcoding of global topsoil samples (189 sites, 7,560 subsamples), that bacterial, but not fungal, genetic diversity is highest in temperate habitats and that microbial gene composition varies more strongly with environmental variables than with geographic distance. We demonstrate that fungi and bacteria show global niche differentiation that is associated with contrasting diversity responses to precipitation and soil pH. Furthermore, we provide evidence for strong bacterial–fungal antagonism, inferred from antibiotic-resistance genes, in topsoil and ocean habitats, indicating the substantial role of biotic interactions in shaping microbial communities. Our results suggest that both competition and environmental filtering affect the abundance, composition and encoded gene functions of bacterial and fungal communities, indicating that the relative contributions of these microorganisms to global nutrient cycling varies spatially.
TL;DR: This JACC Scientific Expert Panel provides consensus recommendations for an update of the cardiovascular magnetic resonance (CMR) diagnostic criteria for myocardial inflammation in patients with suspected acute or active myocardian inflammation (Lake Louise Criteria) that include options to use parametric mapping techniques.
Susanne Gröbner1, Barbara C. Worst, Joachim Weischenfeldt2, Joachim Weischenfeldt3 +182 more•Institutions (23)
TL;DR: The data suggest that 7–8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
Abstract: Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
TL;DR: ProTox-II is presented, a freely available webserver for in silico toxicity prediction for toxicologists, regulatory agencies, computational and medicinal chemists, and all users without login at http://tox.charite.de/protox_II.
Abstract: Advancement in the field of computational research has made it possible for the in silico methods to offer significant benefits to both regulatory needs and requirements for risk assessments, and pharmaceutical industry to assess the safety profile of a chemical. Here, we present ProTox-II that incorporates molecular similarity, pharmacophores, fragment propensities and machine-learning models for the prediction of various toxicity endpoints; such as acute toxicity, hepatotoxicity, cytotoxicity, carcinogenicity, mutagenicity, immunotoxicity, adverse outcomes pathways (Tox21) and toxicity targets. The predictive models are built on data from both in vitro assays (e.g. Tox21 assays, Ames bacterial mutation assays, hepG2 cytotoxicity assays, Immunotoxicity assays) and in vivo cases (e.g. carcinogenicity, hepatotoxicity). The models have been validated on independent external sets and have shown strong performance. ProTox-II provides a freely available webserver for in silico toxicity prediction for toxicologists, regulatory agencies, computational and medicinal chemists, and all users without login at http://tox.charite.de/protox_II. The webserver takes a two-dimensional chemical structure as an input and reports the possible toxicity profile of the chemical for 33 models with confidence scores, and an overall toxicity radar chart along with three most similar compounds with known acute toxicity.
Christina Fitzmaurice1, Christina Fitzmaurice2, Tomi Akinyemiju3, Faris Lami4 +172 more•Institutions (95)
Humboldt University of Berlin1, Medical University of Graz2, Hospital Kuala Lumpur3, University of Zurich4, University of Cincinnati5, University of Southern Denmark6, Medical University of Silesia7, Humanitas University8, Charité9, Penn State Milton S. Hershey Medical Center10, Federal University of São Paulo11, Autonomous University of Barcelona12, St Thomas' Hospital13, Laval University14, Hiroshima University15, Medical University of South Carolina16, Hannover Medical School17, Campbelltown Hospital18, Mahidol University19, Royal Free Hospital20, University of Bari21, University Medical Center Groningen22, Johns Hopkins University23, University of Toronto24, Technion – Israel Institute of Technology25, Aarhus University Hospital26, Peking University27
TL;DR: In this paper, an evidence-and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group.
Abstract: This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Sectionof the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA(2)LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.
VU University Amsterdam1, Erasmus University Rotterdam2, Karolinska Institutet3, Charité4, Virginia Commonwealth University5, South London and Maudsley NHS Foundation Trust6, QIMR Berghofer Medical Research Institute7, King's College London8, University of Southern Denmark9, University of California, Riverside10, University of Southern California11, University of Minnesota12, University of Queensland13, University College London14, Johns Hopkins University15, University of California, Los Angeles16, University of Crete17, Icahn School of Medicine at Mount Sinai18, Harvard University19, Veterans Health Administration20, Yale University21, Haukeland University Hospital22, Trinity College, Dublin23, University of Edinburgh24, North Shore-LIJ Health System25, Hofstra University26, National Institutes of Health27, Oslo University Hospital28, University of Bergen29, National University of Ireland, Galway30, University of Helsinki31, University of Oslo32, Martin Luther University of Halle-Wittenberg33, Duke University34, National and Kapodistrian University of Athens35, Mental Health Research Institute36, University of Colorado Boulder37, Imperial College London38, University of Manchester39, Wellcome Trust40, Manchester Academic Health Science Centre41, Stanford University42, University of Oregon43, University of Toronto44, University of Michigan45, Erasmus University Medical Center46, Broad Institute47, University of North Carolina at Chapel Hill48
TL;DR: A large-scale genetic association study of intelligence identifies 190 new loci and implicates 939 new genes related to neurogenesis, neuron differentiation and synaptic structure, a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Abstract: Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Catholic University of the Sacred Heart1, Memorial Sloan Kettering Cancer Center2, International Agency for Research on Cancer3, University Health Network4, University of Lausanne5, Centre Hospitalier Universitaire de Grenoble6, Utrecht University7, Charité8, University of Texas MD Anderson Cancer Center9, Technische Universität München10, Belfast Health and Social Care Trust11, University of Zurich12, University of Nottingham13, Beatson West of Scotland Cancer Centre14, Tohoku University15, University of Verona16, Institut Gustave Roussy17, University of Bologna18, Radboud University Nijmegen19
TL;DR: This work believes this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.
TL;DR: This review highlights the current knowledge about the roles of ANG-(1–7) in physiology and disease, with particular emphasis on the brain.
Abstract: The renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1-7)/MAS, whose end point is the metabolite ANG-(1-7). ACE2 and other enzymes can form ANG-(1-7) directly or indirectly from either the decapeptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1-7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1-7) in physiology and disease, with particular emphasis on the brain.
TL;DR: High‐dimensional cytometry reveals that microglia, several subsets of border‐associated macrophages and dendritic cells coexist in the CNS at steady state and exhibit disease‐specific transformations in the immune microenvironment during aging and in models of Alzheimer’s disease and multiple sclerosis.
TL;DR: Senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours.
Abstract: Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16INK4a, p21CIP1 and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness'). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from Eμ-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells.
University of Birmingham1, University of Texas Health Science Center at San Antonio2, The Forsyth Institute3, University of Adelaide4, Charité5, Goethe University Frankfurt6, University of Alabama at Birmingham7, University at Buffalo8, University of Toronto9, Hadassah Medical Center10, Tufts University11, University of Copenhagen12, University of Iowa13, University of California, San Francisco14, University of Bern15, University of Giessen16, Osaka University17, Texas A&M University18, University of São Paulo19, Ohio State University20, Katholieke Universiteit Leuven21, University of Ferrara22, University of Basel23, University of Graz24, Niigata University25
TL;DR: While gingival health and gingivitis have many clinical features, case definitions are primarily predicated on presence or absence of bleeding on probing, which creates differences in the way in which a "case" of gedival health or gingIVitis is defined for clinical practice as opposed to epidemiologically in population prevalence surveys.
Abstract: Periodontal health is defined by absence of clinically detectable inflammation. There is a biological level of immune surveillance that is consistent with clinical gingival health and homeostasis. Clinical gingival health may be found in a periodontium that is intact, i.e. without clinical attachment loss or bone loss, and on a reduced periodontium in either a non-periodontitis patient (e.g. in patients with some form of gingival recession or following crown lengthening surgery) or in a patient with a history of periodontitis who is currently periodontally stable. Clinical gingival health can be restored following treatment of gingivitis and periodontitis. However, the treated and stable periodontitis patient with current gingival health remains at increased risk of recurrent periodontitis, and accordingly, must be closely monitored. Two broad categories of gingival diseases include non-dental plaque biofilm-induced gingival diseases and dental plaque-induced gingivitis. Non-dental plaque biofilm-induced gingival diseases include a variety of conditions that are not caused by plaque and usually do not resolve following plaque removal. Such lesions may be manifestations of a systemic condition or may be localized to the oral cavity. Dental plaque-induced gingivitis has a variety of clinical signs and symptoms, and both local predisposing factors and systemic modifying factors can affect its extent, severity, and progression. Dental plaque-induced gingivitis may arise on an intact periodontium or on a reduced periodontium in either a non-periodontitis patient or in a currently stable "periodontitis patient" i.e. successfully treated, in whom clinical inflammation has been eliminated (or substantially reduced). A periodontitis patient with gingival inflammation remains a periodontitis patient (Figure 1), and comprehensive risk assessment and management are imperative to ensure early prevention and/or treatment of recurrent/progressive periodontitis. Precision dental medicine defines a patient-centered approach to care, and therefore, creates differences in the way in which a "case" of gingival health or gingivitis is defined for clinical practice as opposed to epidemiologically in population prevalence surveys. Thus, case definitions of gingival health and gingivitis are presented for both purposes. While gingival health and gingivitis have many clinical features, case definitions are primarily predicated on presence or absence of bleeding on probing. Here we classify gingival health and gingival diseases/conditions, along with a summary table of diagnostic features for defining health and gingivitis in various clinical situations.
TL;DR: For the first time, specific loci that distinguish between BD and SCZ are discovered and polygenic components underlying multiple symptom dimensions are identified that point to the utility of genetics to inform symptomology and potential treatment.
German Center for Neurodegenerative Diseases1, Salk Institute for Biological Studies2, Paracelsus Private Medical University of Salzburg3, University of Pennsylvania4, University of Auckland5, King's College London6, University of Gothenburg7, Charité8, University of Zurich9, National Institutes of Health10, Princeton University11, Columbia University12, French Institute of Health and Medical Research13, University of Lausanne14, Fundación Instituto Leloir15, University of Wisconsin-Madison16, University of Amsterdam17, Karolinska Institutet18
TL;DR: It is argued that there is currently no reason to abandon the idea that adult-generated neurons make important functional contributions to neural plasticity and cognition across the human lifespan.
University Hospital Heidelberg1, Humboldt University of Berlin2, Charité3, University of Düsseldorf4, University of Southern Denmark5, Children's Hospital at Westmead6, Tohoku University7, Walton Centre8, Ruhr University Bochum9, Ludwig Maximilian University of Munich10, Johns Hopkins University11, John Radcliffe Hospital12, University of Barcelona13, Hannover Medical School14, Mayo Clinic15
TL;DR: In this article, the authors proposed indications for MOG-IgG testing based on expert consensus, and gave a list of conditions atypical for MG-EM (red flags) that should prompt physicians to challenge a positive MOG IgG test result, and provided recommendations regarding assay methodology, specimen sampling and data interpretation.
Abstract: Over the past few years, new-generation cell-based assays have demonstrated a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations. Most experts now consider MOG-IgG-associated encephalomyelitis (MOG-EM) a disease entity in its own right, immunopathogenetically distinct from both classic multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD). Owing to a substantial overlap in clinicoradiological presentation, MOG-EM was often unwittingly misdiagnosed as MS in the past. Accordingly, increasing numbers of patients with suspected or established MS are currently being tested for MOG-IgG. However, screening of large unselected cohorts for rare biomarkers can significantly reduce the positive predictive value of a test. To lessen the hazard of overdiagnosing MOG-EM, which may lead to inappropriate treatment, more selective criteria for MOG-IgG testing are urgently needed. In this paper, we propose indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions atypical for MOG-EM (“red flags”) that should prompt physicians to challenge a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling and data interpretation.
Goethe University Frankfurt1, Charité2, Ural Federal University3, French Institute of Health and Medical Research4, Charles University in Prague5, Pierre-and-Marie-Curie University6, University of Western Brittany7, University of Milano-Bicocca8, Erasmus University Rotterdam9, Kyung Hee University10, Inje University11, University of Turku12, University of Queensland13, Newcastle University14, Newcastle upon Tyne Hospitals NHS Foundation Trust15, University of Barcelona16, Catalan Institution for Research and Advanced Studies17, University of Hamburg18, Hannover Medical School19, Boston Children's Hospital20, Paris Diderot University21, Sheba Medical Center22, Tel Aviv University23, North Bristol NHS Trust24, University of Kiel25, Medical University of Vienna26, Medical University of Silesia27
TL;DR: This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.
Abstract: Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.
Ruhr University Bochum1, Paris Descartes University2, University of Toronto3, University of California, San Diego4, University of Washington5, Charité6, Medical University of Vienna7, VU University Amsterdam8, Ghent University Hospital9, University of Oxford10, University of California, San Francisco11, University of Leeds12, University Health Network13, University of Glasgow14, University College London15, University of Pennsylvania16, University of Rochester Medical Center17, Erasmus University Rotterdam18, Katholieke Universiteit Leuven19, Leiden University Medical Center20
TL;DR: There was broad agreement, now better supported by data than in 2012, that remission/inactive disease and, alternatively, low/minimal disease activity are the principal targets for the treatment of PsA.
Abstract: Therapeutic targets have been defined for axial and peripheral spondyloarthritis (SpA) in 2012, but the evidence for these recommendations was only of indirect nature. These recommendations were re-evaluated in light of new insights. Based on the results of a systematic literature review and expert opinion, a task force of rheumatologists, dermatologists, patients and a health professional developed an update of the 2012 recommendations. These underwent intensive discussions, on site voting and subsequent anonymous electronic voting on levels of agreement with each item. A set of 5 overarching principles and 11 recommendations were developed and voted on. Some items were present in the previous recommendations, while others were significantly changed or newly formulated. The 2017 task force arrived at a single set of recommendations for axial and peripheral SpA, including psoriatic arthritis (PsA). The most exhaustive discussions related to whether PsA should be assessed using unidimensional composite scores for its different domains or multidimensional scores that comprise multiple domains. This question was not resolved and constitutes an important research agenda. There was broad agreement, now better supported by data than in 2012, that remission/inactive disease and, alternatively, low/minimal disease activity are the principal targets for the treatment of PsA. As instruments to assess the patients on the path to the target, the Ankylosing Spondylitis Disease Activity Score (ASDAS) for axial SpA and the Disease Activity index for PSoriatic Arthritis (DAPSA) and Minimal Disease Activity (MDA) for PsA were recommended, although not supported by all. Shared decision-making between the clinician and the patient was seen as pivotal to the process. The task force defined the treatment target for SpA as remission or low disease activity and developed a large research agenda to further advance the field.
TL;DR: The use of VX‐445–tezacaftor–ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe48del alleles.
Abstract: Background VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and ivacaftor (VX-445–tezacaftor–ivacaftor). Methods We evaluated the effects of VX-445–tezacaftor–ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445–tezacaftor–ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del–MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del) after tezacaftor–ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline. Results In vitro, VX-445–tezacaftor–i...
Hofstra University1, Charité2, University of Verona3, King's College London4, Lundbeck5, Copenhagen University Hospital6, Yale University7, Maastricht University8, University of Hong Kong9, The Feinstein Institute for Medical Research10, SUNY Downstate Medical Center11, Dartmouth College12, Boston University13, University of Calgary14, University of North Carolina at Chapel Hill15, Nathan Kline Institute for Psychiatric Research16, National Institutes of Health17
TL;DR: In this paper, the authors compared early intervention services (EIS) with treatment as usual (TAU) for early-phase psychosis and found that EIS was associated with better outcomes than TAU at the end of treatment for all 13 meta-analyzable outcomes.
Abstract: Importance The value of early intervention in psychosis and allocation of public resources has long been debated because outcomes in people with schizophrenia spectrum disorders have remained suboptimal. Objective To compare early intervention services (EIS) with treatment as usual (TAU) for early-phase psychosis. Data Sources Systematic literature search of PubMed, PsycINFO, EMBASE, and ClinicalTrials.gov without language restrictions through June 6, 2017. Study Selection Randomized trials comparing EIS vs TAU in first-episode psychosis or early-phase schizophrenia spectrum disorders. Data Extraction and Synthesis This systematic review was conducted according to PRISMA guidelines. Three independent investigators extracted data for a random-effects meta-analysis and prespecified subgroup and meta-regression analyses. Main Outcomes and Measures The coprimary outcomes were all-cause treatment discontinuation and at least 1 psychiatric hospitalization during the treatment period. Results Across 10 randomized clinical trials (mean [SD] trial duration, 16.2 [7.4] months; range, 9-24 months) among 2176 patients (mean [SD] age, 27.5 [4.6] years; 1355 [62.3%] male), EIS was associated with better outcomes than TAU at the end of treatment for all 13 meta-analyzable outcomes. These outcomes included the following: all-cause treatment discontinuation (risk ratio [RR], 0.70; 95% CI, 0.61-0.80; P P = .003), involvement in school or work (RR, 1.13; 95% CI, 1.03-1.24; P = .01), total symptom severity (standardized mean difference [SMD], −0.32; 95% CI, −0.47 to −0.17; P P P Conclusions and Relevance In early-phase psychosis, EIS are superior to TAU across all meta-analyzable outcomes. These results support the need for funding and use of EIS in patients with early-phase psychosis.