Showing papers by "University of Düsseldorf published in 2017"
University College London1, Children's Hospital of Philadelphia2, VU University Medical Center3, Sir Charles Gairdner Hospital4, National Multiple Sclerosis Society5, Vita-Salute San Raffaele University6, Medical University of Graz7, Ottawa Hospital Research Institute8, Fukushima Medical University9, New York University10, University of Düsseldorf11, University of Basel12, Corinne Goldsmith Dickinson Center for Multiple Sclerosis13, University of Manitoba14, St. Michael's Hospital15, Hebron University16, Johns Hopkins University17, University of Copenhagen18, University of British Columbia19, University of Bari20, French Institute of Health and Medical Research21, Claude Bernard University Lyon 122, University of California, San Francisco23, Mayo Clinic24, Salisbury University25, Cleveland Clinic26
TL;DR: The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation.
Abstract: The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.
3,945 citations
TL;DR: Although screening for rarer atypical forms of diabetic neuropathy may be warranted, DSPN and autonomic neuropathy are the most common forms encountered in practice and the strongest available evidence regarding treatment pertains to these forms.
Abstract: Diabetic neuropathies are the most prevalent chronic complications of diabetes. This heterogeneous group of conditions affects different parts of the nervous system and presents with diverse clinical manifestations. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons:
1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable by specific measures.
2. A number of treatment options exist for symptomatic diabetic neuropathy.
3. Up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet.
4. Recognition and treatment of autonomic neuropathy may improve symptoms, reduce sequelae, and improve quality of life.
Among the various forms of diabetic neuropathy, distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathies, particularly cardiovascular autonomic neuropathy (CAN), are by far the most studied (1–4). There are several atypical forms of diabetic neuropathy as well (1–4). Patients with prediabetes may also develop neuropathies that are similar to diabetic neuropathies (5–10). Table 1 provides a comprehensive classification scheme for the diabetic neuropathies.
View this table:
Table 1
Classification for diabetic neuropathies
Due to a lack of treatments that target the underlying nerve damage, prevention is the key component of diabetes care. Screening for symptoms and signs of diabetic neuropathy is also critical in clinical practice, as it may detect the earliest stages of neuropathy, enabling early intervention. Although screening for rarer atypical forms of diabetic neuropathy may be warranted, DSPN and autonomic neuropathy are the most common forms encountered in practice. The strongest available evidence regarding treatment pertains to these forms.
This Position Statement is based on several recent technical reviews, to which the reader is referred for detailed discussion …
1,306 citations
TL;DR: The present overview focuses on recent progress on metabolic sources and sinks of H 2O2 and on the role of H2O2 in redox signaling under physiological conditions, denoted as oxidative eustress.
Abstract: Hydrogen peroxide emerged as major redox metabolite operative in redox sensing, signaling and redox regulation. Generation, transport and capture of H2O2 in biological settings as well as their biological consequences can now be addressed. The present overview focuses on recent progress on metabolic sources and sinks of H2O2 and on the role of H2O2 in redox signaling under physiological conditions (1–10 nM), denoted as oxidative eustress. Higher concentrations lead to adaptive stress responses via master switches such as Nrf2/Keap1 or NF-κB. Supraphysiological concentrations of H2O2 (>100 nM) lead to damage of biomolecules, denoted as oxidative distress. Three questions are addressed: How can H2O2 be assayed in the biological setting? What are the metabolic sources and sinks of H2O2? What is the role of H2O2 in redox signaling and oxidative stress?
1,242 citations
University of California, San Francisco1, University of Basel2, University of British Columbia3, McGill University4, Vita-Salute San Raffaele University5, Queen Mary University of London6, University of Düsseldorf7, Icahn School of Medicine at Mount Sinai8, University of Miami9, Hoffmann-La Roche10, Genentech11, Baylor College of Medicine12
TL;DR: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections.
Abstract: BackgroundAn evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. MethodsIn this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. ResultsThe percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression w...
1,220 citations
University of California, San Francisco1, University of British Columbia2, Vita-Salute San Raffaele University3, Queen Mary University of London4, University of Düsseldorf5, Icahn School of Medicine at Mount Sinai6, University of Barcelona7, Autonomous University of Barcelona8, Medical University of Łódź9, University of Texas Health Science Center at Houston10, University Hospital of Basel11, McGill University12, Hoffmann-La Roche13, Genentech14, University of Basel15
TL;DR: Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta‐1a over a period of 96 weeks.
Abstract: BackgroundB cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. MethodsIn two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. ResultsThe annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disabilit...
1,198 citations
TL;DR: A systematic evaluation of 14 participant‐level confound regression methods for functional connectivity highlights the heterogeneous efficacy of existing methods, and suggests that different confounding regression strategies may be appropriate in the context of specific scientific goals.
790 citations
University of Waterloo1, University of Melbourne2, Complutense University of Madrid3, Massachusetts Eye and Ear Infirmary4, University of California, Los Angeles5, University of Düsseldorf6, University of São Paulo7, Yonsei University8, Federal University of São Paulo9, Fudan University Shanghai Medical College10, Aston University11, University of Auckland12
TL;DR: It became clear that many of the treatments available for the management of dry eye disease lack the necessary Level 1 evidence to support their recommendation, often due to a lack of appropriate masking, randomization or controls and in some cases due to issues with selection bias or inadequate sample size.
Abstract: The members of the Management and Therapy Subcommittee undertook an evidence-based review of current dry eye therapies and management options. Management options reviewed in detail included treatments for tear insufficiency and lid abnormalities, as well as anti-inflammatory medications, surgical approaches, dietary modifications, environmental considerations and complementary therapies. Following this extensive review it became clear that many of the treatments available for the management of dry eye disease lack the necessary Level 1 evidence to support their recommendation, often due to a lack of appropriate masking, randomization or controls and in some cases due to issues with selection bias or inadequate sample size. Reflecting on all available evidence, a staged management algorithm was derived that presents a step-wise approach to implementing the various management and therapeutic options according to disease severity. While this exercise indicated that differentiating between aqueous-deficient and evaporative dry eye disease was critical in selecting the most appropriate management strategy, it also highlighted challenges, based on the limited evidence currently available, in predicting relative benefits of specific management options, in managing the two dry eye disease subtypes. Further evidence is required to support the introduction, and continued use, of many of the treatment options currently available to manage dry eye disease, as well as to inform appropriate treatment starting points and understand treatment specificity in relation to dry eye disease subtype.
785 citations
University of Zurich1, Erasmus University Rotterdam2, Ludwig Maximilian University of Munich3, Medical University of Vienna4, Umeå University5, Aix-Marseille University6, University Hospital Heidelberg7, VU University Amsterdam8, Institut Gustave Roussy9, University of Cambridge10, University of Portsmouth11, University of Bonn12, Leiden University13, University of Lausanne14, University of Hamburg15, University of Düsseldorf16, German Cancer Research Center17
TL;DR: The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas, based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline.
Abstract: The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas. The guideline is based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline. The recommendations focus on pathological and radiological diagnostics, and the main treatment modalities of surgery, radiotherapy, and pharmacotherapy. In this guideline we have also integrated the results from contemporary clinical trials that have changed clinical practice. The guideline aims to provide guidance for diagnostic and management decisions, while limiting unnecessary treatments and costs. The recommendations are a resource for professionals involved in the management of patients with glioma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.
773 citations
TL;DR: It is demonstrated that selenolate-based catalysis of the essential mammalian selenoprotein GPX4 is unexpectedly dispensable for normal embryogenesis and the survival of a specific type of interneurons emerges to exclusively depend on selenocysteine-containing GPX 4, thereby preventing fatal epileptic seizures.
759 citations
University of Toronto1, German Cancer Research Center2, University of Düsseldorf3, University of Pittsburgh4, Ontario Institute for Cancer Research5, Seoul National University6, University of Warsaw7, University of Lyon8, Mayo Clinic9, The Chinese University of Hong Kong10, Johns Hopkins University11, University of Alabama at Birmingham12, University of Washington13, Fred Hutchinson Cancer Research Center14, University of California, San Francisco15, Hamilton Health Sciences16, McMaster University17, Vanderbilt University18, University of Colorado Denver19, Semmelweis University20, Erasmus University Rotterdam21, University of Ulsan22, Kitasato University23, Mexican Social Security Institute24, Masaryk University25, Emory University26, University of Debrecen27, University of Naples Federico II28, Washington University in St. Louis29, McGill University30, Montreal Children's Hospital31, Virginia Commonwealth University32, Chonnam National University33, University of Queensland34, University of Calgary35, University of São Paulo36, University of Cincinnati37, University of Arkansas for Medical Sciences38, The Catholic University of America39, University of California, Los Angeles40, University of Sydney41, Kumamoto University42, Saint Louis University43, Case Western Reserve University44
TL;DR: Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes.
737 citations
TL;DR: The complete structure of an Aβ(1–42) fibril composed of two intertwined protofilaments determined by cryo–electron microscopy (cryo-EM) and provides a structural basis for understanding the effect of several disease-causing and disease-preventing mutations.
Abstract: Amyloids are implicated in neurodegenerative diseases. Fibrillar aggregates of the amyloid-β protein (Aβ) are the main component of the senile plaques found in brains of Alzheimer’s disease patients. We present the structure of an Aβ(1–42) fibril composed of two intertwined protofilaments determined by cryo–electron microscopy (cryo-EM) to 4.0-angstrom resolution, complemented by solid-state nuclear magnetic resonance experiments. The backbone of all 42 residues and nearly all side chains are well resolved in the EM density map, including the entire N terminus, which is part of the cross-β structure resulting in an overall “LS”-shaped topology of individual subunits. The dimer interface protects the hydrophobic C termini from the solvent. The characteristic staggering of the nonplanar subunits results in markedly different fibril ends, termed “groove” and “ridge,” leading to different binding pathways on both fibril ends, which has implications for fibril growth.
TL;DR: The results suggest that gwMRF parcellations reveal neurobiologically meaningful features of brain organization and are potentially useful for future applications requiring dimensionality reduction of voxel-wise fMRI data.
Abstract: A central goal in systems neuroscience is the parcellation of the cerebral cortex into discrete neurobiological “atoms”. Resting-state functional magnetic resonance imaging (rs-fMRI) offers the possibility of in-vivo human cortical parcellation. Almost all previous parcellations relied on one of two approaches. The local gradient approach detects abrupt transitions in functional connectivity patterns. These transitions potentially reflect cortical areal boundaries defined by histology or visuotopic fMRI. By contrast, the global similarity approach clusters similar functional connectivity patterns regardless of spatial proximity, resulting in parcels with homogeneous (similar) rs-fMRI signals. Here we propose a gradient-weighted Markov Random Field (gwMRF) model integrating local gradient and global similarity approaches. Using task-fMRI and rs-fMRI across diverse acquisition protocols, we found gwMRF parcellations to be more homogeneous than four previously published parcellations. Furthermore, gwMRF parcellations agreed with the boundaries of certain cortical areas defined using histology and visuotopic fMRI. Some parcels captured sub-areal (somatotopic and visuotopic) features that likely reflect distinct computational units within known cortical areas. These results suggest that gwMRF parcellations reveal neurobiologically meaningful features of brain organization and are potentially useful for future applications requiring dimensionality reduction of voxel-wise fMRI data. Multi-resolution parcellations generated from 1489 participants are available at FREESURFER_WIKI LINK_TO_BE_ADDED.
Wellcome Trust Centre for Human Genetics1, Imperial College London2, University of Oulu3, Agency for Science, Technology and Research4, National Institutes of Health5, King's College London6, Ealing Hospital7, National University of Singapore8, University of Turin9, University Medical Center Groningen10, University of Tartu11, University of Bristol12, University College London13, University of Eastern Finland14, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico15, University of Kiel16, Leiden University Medical Center17, Dresden University of Technology18, University of Düsseldorf19, University of Surrey20, Erasmus University Rotterdam21, Max Healthcare22, Technische Universität München23, University of Naples Federico II24, Wellcome Trust Sanger Institute25, Science for Life Laboratory26, University of Ulm27, Ludwig Maximilian University of Munich28, University of Kelaniya29, Institute of Cancer Research30, Queen Mary University of London31, King Abdulaziz University32, Massachusetts Institute of Technology33, Health Protection Agency34, Churchill Hospital35, University of Oxford36, Imperial College Healthcare37
TL;DR: In this article, the authors used epigenome-wide association to show that body mass index (BMI), a key measure of adiposity, is associated with widespread changes in DNA methylation.
Abstract: Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances1,2. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation3,4,5,6, a key regulator of gene expression and molecular phenotype7. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10−7, range P = 9.2 × 10−8 to 6.0 × 10−46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10−6, range P = 5.5 × 10−6 to 6.1 × 10−35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07–2.56); P = 1.1 × 10−54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.
TL;DR: The multifaceted and complex interactions between the liver and T2DM are described, which show some efficacy in the treatment of NASH.
Abstract: The association between NAFLD and diabetes mellitus has garnered increasing attention in the past few years. In this Review, Tilg and colleagues explore in detail the molecular mechanisms linking NAFLD and diabetes mellitus, and discuss clinical aspects arising from the interaction of both diseases. The liver constitutes a key organ in systemic metabolism, contributing substantially to the development of insulin resistance and type 2 diabetes mellitus (T2DM). The mechanisms underlying these processes are not entirely understood, but involve hepatic fat accumulation, alterations of energy metabolism and inflammatory signals derived from various cell types including immune cells. Lipotoxins, mitochondrial function, cytokines and adipocytokines have been proposed to play a major part in both NAFLD and T2DM. Patients with NAFLD are commonly insulin resistant. On the other hand, a large number of patients with T2DM develop NAFLD with its inflammatory complication, NASH. The high incidence of NASH in patients with T2DM leads to further complications, such as liver cirrhosis and hepatocellular carcinoma, which are increasingly recognized. Therapeutic concepts such as thiazolidinediones (glitazones) for treating T2DM also show some efficacy in the treatment of NASH. This Review will describe the multifaceted and complex interactions between the liver and T2DM.
TL;DR: This article conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel.
Abstract: To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects) We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology
Bielefeld University1, BRICS2, University of Düsseldorf3, Oregon State University4, University of California, San Diego5, Aarhus University6, University of Copenhagen7, Roskilde University8, Joint Genome Institute9, Pittsburgh Supercomputing Center10, Saint Petersburg State University11, Max Planck Society12, University of Vienna13, University of Technology, Sydney14, Centre national de la recherche scientifique15, Genome Institute of Singapore16, University of Warwick17, University of Tübingen18, Intel19, French Institute for Research in Computer Science and Automation20, Joint BioEnergy Institute21, Taipei Medical University22, Lawrence Berkeley National Laboratory23, Georgia Institute of Technology24, University of Calgary25, University of Göttingen26, National Health Research Institutes27, San Diego State University28, Boyce Thompson Institute for Plant Research29, Robert Koch Institute30, Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior31, University of Maryland, College Park32, Newcastle University33, Leibniz Association34, ETH Zurich35
TL;DR: The Critical Assessment of Metagenome Interpretation (CAMI) challenge has engaged the global developer community to benchmark their programs on highly complex and realistic data sets, generated from ∼700 newly sequenced microorganisms and ∼600 novel viruses and plasmids and representing common experimental setups as discussed by the authors.
Abstract: Methods for assembly, taxonomic profiling and binning are key to interpreting metagenome data, but a lack of consensus about benchmarking complicates performance assessment. The Critical Assessment of Metagenome Interpretation (CAMI) challenge has engaged the global developer community to benchmark their programs on highly complex and realistic data sets, generated from ∼700 newly sequenced microorganisms and ∼600 novel viruses and plasmids and representing common experimental setups. Assembly and genome binning programs performed well for species represented by individual genomes but were substantially affected by the presence of related strains. Taxonomic profiling and binning programs were proficient at high taxonomic ranks, with a notable performance decrease below family level. Parameter settings markedly affected performance, underscoring their importance for program reproducibility. The CAMI results highlight current challenges but also provide a roadmap for software selection to answer specific research questions.
TL;DR: In this article, the authors proposed scalable quantum computers composed of qubits encoded in aggregates of four or more Majorana zero modes, realized at the ends of topological superconducting wire segments that are assembled into super-conducting islands with significant charging energy.
Abstract: We present designs for scalable quantum computers composed of qubits encoded in aggregates of four or more Majorana zero modes, realized at the ends of topological superconducting wire segments that are assembled into superconducting islands with significant charging energy. Quantum information can be manipulated according to a measurement-only protocol, which is facilitated by tunable couplings between Majorana zero modes and nearby semiconductor quantum dots. Our proposed architecture designs have the following principal virtues: (1) the magnetic field can be aligned in the direction of all of the topological superconducting wires since they are all parallel; (2) topological T junctions are not used, obviating possible difficulties in their fabrication and utilization; (3) quasiparticle poisoning is abated by the charging energy; (4) Clifford operations are executed by a relatively standard measurement: detection of corrections to quantum dot energy, charge, or differential capacitance induced by quantum fluctuations; (5) it is compatible with strategies for producing good approximate magic states.
University of Warwick1, Montreal Neurological Institute and Hospital2, McGill University3, University of Düsseldorf4, Forschungszentrum Jülich5, Concordia University6, Otto-von-Guericke University Magdeburg7, Cognition and Brain Sciences Unit8, MIND Institute9, Nathan Kline Institute for Psychiatric Research10, Stanford University11, University of California, Berkeley12, French Institute for Research in Computer Science and Automation13, Washington University in St. Louis14, Erasmus University Medical Center15, National University of Singapore16
TL;DR: Intentions from developing a set of recommendations on behalf of the Organization for Human Brain Mapping are described and barriers that impede these practices are identified, including how the discipline must change to fully exploit the potential of the world's neuroimaging data.
Abstract: Given concerns about the reproducibility of scientific findings, neuroimaging must define best practices for data analysis, results reporting, and algorithm and data sharing to promote transparency, reliability and collaboration. We describe insights from developing a set of recommendations on behalf of the Organization for Human Brain Mapping and identify barriers that impede these practices, including how the discipline must change to fully exploit the potential of the world's neuroimaging data.
TL;DR: The state-of-the-art in MOF-MMM fabrication, and the more recent use of POFs and molecular additives are outlined.
Abstract: Research into extended porous materials such as metal-organic frameworks (MOFs) and porous organic frameworks (POFs), as well as the analogous metal-organic polyhedra (MOPs) and porous organic cages (POCs), has blossomed over the last decade. Given their chemical and structural variability and notable porosity, MOFs have been proposed as adsorbents for industrial gas separations and also as promising filler components for high-performance mixed-matrix membranes (MMMs). Research in this area has focused on enhancing the chemical compatibility of the MOF and polymer phases by judiciously functionalizing the organic linkers of the MOF, modifying the MOF surface chemistry, and, more recently, exploring how particle size, morphology, and distribution enhance separation performance. Other filler materials, including POFs, MOPs, and POCs, are also being explored as additives for MMMs and have shown remarkable anti-aging performance and excellent chemical compatibility with commercially available polymers. This Review briefly outlines the state-of-the-art in MOF-MMM fabrication, and the more recent use of POFs and molecular additives.
Hannover Medical School1, University of Cologne2, University Hospital Heidelberg3, University of Düsseldorf4, Sapienza University of Rome5, VU University Medical Center6, University of Zurich7, National Institutes of Health8, Katholieke Universiteit Leuven9, Leibniz Association10, Dresden University of Technology11
TL;DR: An abbreviated version of the risk assessment strategy proposed by the current European PH guidelines provides accurate mortality estimates in patients with PAH and proved valid at follow-up and in major PAH subgroups.
Abstract: The 2015 European pulmonary hypertension (PH) guidelines propose a risk stratification strategy for patients with pulmonary arterial hypertension (PAH). Low-, intermediate- and high-risk strata are defined by estimated 1-year mortality risks of 10%, respectively. This risk assessment strategy awaits validation. We analysed data from patients with newly diagnosed PAH enrolled into COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension), a European-based PH registry. An abbreviated version of the risk assessment strategy proposed by the European PH guidelines was applied, using the following variables: World Health Organization functional class, 6-min walking distance, brain natriuretic peptide or its N-terminal fragment, right atrial pressure, cardiac index and mixed venous oxygen saturation. Data from 1588 patients were analysed. Mortality rates were significantly different between the three risk strata (p An abbreviated version of the risk assessment strategy proposed by the current European PH guidelines provides accurate mortality estimates in patients with PAH.
TL;DR: It is illustrated how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology.
Abstract: Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of gliomas. These molecular characteristics can be used to refine glioma classification, to improve prediction of patient outcomes, and to guide individualized treatment. Thus, the WHO Classification of Tumours of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers - together with classic histological features - in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. This paradigm shift is markedly changing how glioma is diagnosed, and has important implications for future clinical trials and patient management in daily practice. Herein, we highlight the developments in our understanding of the molecular genetics of gliomas, and review the current landscape of clinically relevant molecular biomarkers for use in classification of the disease subtypes. Novel approaches to the genetic characterization of gliomas based on large-scale DNA-methylation profiling and next-generation sequencing are also discussed. In addition, we illustrate how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology.
University of California, Berkeley1, World Health Organization2, Johns Hopkins University3, Centre for Mental Health4, VU University Amsterdam5, Emory University6, National Institutes of Health7, University of Düsseldorf8, University of Haifa9, Aarhus University10, University of Naples Federico II11, University of Copenhagen12, Public Health Foundation of India13, King's College London14, Schizophrenia Research Foundation15, Columbia University16, Addis Ababa University17
TL;DR: A comprehensive framework that may be useful for designing, implementing and evaluating interventions and programmes to reduce excess mortality in persons with SMD is described, incorporating lessons learned from the multilevel model of risk and the comprehensive intervention framework.
Technische Universität München1, Ludwig Maximilian University of Munich2, Max Planck Society3, University of Tübingen4, Paris Descartes University5, Boston Children's Hospital6, French Institute of Health and Medical Research7, University of Paris8, Centre national de la recherche scientifique9, Newcastle University10, Paracelsus Private Medical University of Salzburg11, University of Düsseldorf12
TL;DR: The power of transcriptome sequencing is demonstrated to molecularly diagnose 10% of mitochondriopathy patients and identify candidate genes for the remainder, and examples of intronic loss-of-function variants with pathological relevance are provided.
Abstract: Across a variety of Mendelian disorders, ∼50-75% of patients do not receive a genetic diagnosis by exome sequencing indicating disease-causing variants in non-coding regions. Although genome sequencing in principle reveals all genetic variants, their sizeable number and poorer annotation make prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to molecularly diagnose 10% (5 of 48) of mitochondriopathy patients and identify candidate genes for the remainder. We find a median of one aberrantly expressed gene, five aberrant splicing events and six mono-allelically expressed rare variants in patient-derived fibroblasts and establish disease-causing roles for each kind. Private exons often arise from cryptic splice sites providing an important clue for variant prioritization. One such event is found in the complex I assembly factor TIMMDC1 establishing a novel disease-associated gene. In conclusion, our study expands the diagnostic tools for detecting non-exonic variants and provides examples of intronic loss-of-function variants with pathological relevance.
TL;DR: A comprehensive overview of factors contributing to diabetes risk, including aspects of diet quality and quantity, little physical activity, increased monitor viewing time or sitting in general, exposure to noise or fine dust, short or disturbed sleep, smoking, stress and depression, and a low socioeconomic status are presented.
Abstract: Environmental and lifestyle changes, in addition to the ageing of populations, are generally believed to account for the rapid global increase in type 2 diabetes prevalence and incidence in recent decades. In this review, we present a comprehensive overview of factors contributing to diabetes risk, including aspects of diet quality and quantity, little physical activity, increased monitor viewing time or sitting in general, exposure to noise or fine dust, short or disturbed sleep, smoking, stress and depression, and a low socioeconomic status. In general, these factors promote an increase in body mass index. Since loss of β-cell function is the ultimate cause of developing overt type 2 diabetes, environmental and lifestyle changes must have resulted in a higher risk of β-cell damage in those at genetic risk. Multiple mechanistic pathways may come into play. Strategies of diabetes prevention should aim at promoting a ‘diabetes-protective lifestyle’ whilst simultaneously enhancing the resistance of the human organism to pro-diabetic environmental and lifestyle factors. More research on diabetes-protective mechanisms seems warranted.
TL;DR: A common pattern of disruption across major psychiatric disorders that parallels the "multiple-demand network" observed in intact cognition is demonstrated, demonstrated to be transdiagnostically vulnerable to gray matter reduction.
Abstract: Objective:Cognitive deficits are a common feature of psychiatric disorders. The authors investigated the nature of disruptions in neural circuitry underlying cognitive control capacities across psychiatric disorders through a transdiagnostic neuroimaging meta-analysis.Method:A PubMed search was conducted for whole-brain functional neuroimaging articles published through June 2015 that compared activation in patients with axis I disorders and matched healthy control participants during cognitive control tasks. Tasks that probed performance or conflict monitoring, response inhibition or selection, set shifting, verbal fluency, and recognition or working memory were included. Activation likelihood estimation meta-analyses were conducted on peak voxel coordinates.Results:The 283 experiments submitted to meta-analysis included 5,728 control participants and 5,493 patients with various disorders (schizophrenia, bipolar or unipolar depression, anxiety disorders, and substance use disorders). Transdiagnostically ...
TL;DR: Selecting specific optimal intakes of the investigated food groups can lead to a considerable change in the risk of premature death, whereas consumption of risk-increasing foods is associated with a 2-fold increased risk of all-cause mortality.
TL;DR: Primary analyses demonstrated that behaviour-changing interventions compared to no treatment/usual care control at longest follow-up reduced BMI, BMI z score and weight.
Abstract: Background: Child and adolescent overweight and obesity has increased globally, and can be associated with significant short- and longterm health consequences This is an update of a Cochrane Review published first in 2003, and updated previously in 2009 However, the update has now been split into six reviews addressing different childhood obesity treatments at different ages Objectives: To assess the effects of diet, physical activity and behavioural interventions (behaviour-changing interventions) for the treatment of overweight or obese children aged 6 to 11 years Search methods: We searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS as well as trial registers ClinicalTrialsgov and RsdI1401 Diet, physical activity and behavioural interventions for the treatment of overweight or obese children from th 2 / 499 ICTRP Search Portal We checked references of studies and systematic reviews We did not apply any language restrictions The date of the last search was July 2016 for all databases Selection criteria: We selected randomised controlled trials (RCTs) of diet, physical activity, and behavioural interventions (behaviour-changing interventions) for treating overweight or obese children aged 6 to 11 years, with a minimum of six months' follow-up We excluded interventions that specifically dealt with the treatment of eating disorders or type 2 diabetes, or included participants with a secondary or syndromic cause of obesity Data collection and analysis Two review authors independently screened references, extracted data, assessed risk of bias, and evaluated the quality of the evidence using the GRADE instrument We contacted study authors for additional information We carried out metaanalyses according to the statistical guidelines in the Cochrane Handbook for Systematic Reviews of Interventions Main results: We included 70 RCTs with a total of 8461 participants randomised to either the intervention or control groups The number of participants per trial ranged from 16 to 686 Fifty-five trials compared a behaviour-changing intervention with no treatment/usual care control and 15 evaluated the effectiveness of adding an additional component to a behaviour-changing intervention Sixty-four trials were parallel RCTs, and four were cluster RCTs Sixty-four trials were multicomponent, two were diet only and four were physical activity only interventions Ten trials had more than two arms The overall quality of the evidence was low or very low and 62 trials had a high risk of bias for at least one criterion Total duration of trials ranged from six months to three years The median age of participants was 10 years old and the median BMI z score was 22 Primary analyses demonstrated that behaviour-changing interventions compared to no treatment/usual care control at longest follow-up reduced BMI, BMI z score and weight Mean difference (MD) in BMI was -053 kg/m2 (95% confidence interval (CI) -082 to -024); P < 000001; 24 trials; 2785 participants; low-quality evidence MD in BMI z score was -006 units (95% CI -010 to -002); P = 0001; 37 trials; 4019 participants; low-quality evidence and MD in weight was -145 kg (95% CI -188 to -102); P < 000001; 17 trials; 1774 participants; low-quality evidence Thirty-one trials reported on serious adverse events, with 29 trials reporting zero occurrences RR 057 (95% CI 017 to 193); P = 037; 4/2105 participants in the behaviour-changing intervention groups compared with 7/1991 participants in the comparator groups) Few trials reported health-related quality of life or behaviour change outcomes, and none of the analyses demonstrated a substantial difference in these outcomes between intervention and control In two trials reporting on minutes per day of TV viewing, a small reduction of 66 minutes per day (95% CI -1288 to -031), P = 004; 2 trials; 55 participants) was found in favour of the intervention No trials reported on all-cause mortality, morbidity or socioeconomic effects, and few trials reported on participant views; none of which could be meta-analysed As the meta-analyses revealed substantial heterogeneity, we conducted subgroup analyses to examine the impact of type of comparator, type of intervention, risk of attrition bias, setting, duration of post-intervention follow-up period, parental involvement and baseline BMI z score No subgroup effects were shown for any of the subgroups on any of the outcomes Some data indicated that a reduction in BMI immediately post-intervention was no longer evident at follow-up at less than six months, which has to be investigated in further trials Authors' conclusions: Multi-component behaviour-changing interventions that incorporate diet, physical activity and behaviour change may be beneficial in achieving small, short-term reductions in BMI, BMI z score and weight in children aged 6 to 11 years The evidence suggests a very low occurrence of adverse events The quality of the evidence was low or very low The heterogeneity observed across all outcomes was not explained by subgrouping Further research is required of behaviourchanging interventions in lower income countries and in children from different ethnic groups; also on the impact of behaviour-changing interventions on health-related quality of life and comorbidities The sustainability of reduction in BMI/BMI z score and weight is a key consideration and there is a need for longer-term follow-up and further research on the most appropriate forms of post-intervention maintenance in order to ensure intervention benefits are sustained over the longer term
TL;DR: In this paper, a zero-dead-time optical clock based on interleaved interrogation of two cold-atom ensembles has been proposed to overcome the Dick effect, which results in an aliasing of frequency noise from the laser interrogating the atomic transition.
Abstract: Optical clocks with a record low zero-dead-time instability of 6 × 10–17 at 1 second are demonstrated in two cold-ytterbium systems. The two systems are interrogated by a shared optical local oscillator to nearly eliminate the Dick effect. Atomic clocks based on optical transitions are the most stable, and therefore precise, timekeepers available. These clocks operate by alternating intervals of atomic interrogation with the ‘dead’ time required for quantum state preparation and readout. This non-continuous interrogation of the atom system results in the Dick effect, an aliasing of frequency noise from the laser interrogating the atomic transition1,2. Despite recent advances in optical clock stability that have been achieved by improving laser coherence, the Dick effect has continually limited the performance of optical clocks. Here we implement a robust solution to overcome this limitation: a zero-dead-time optical clock that is based on the interleaved interrogation of two cold-atom ensembles3. This clock exhibits vanishingly small Dick noise, thereby achieving an unprecedented fractional frequency instability assessed to be for an averaging time τ in seconds. We also consider alternate dual-atom-ensemble schemes to extend laser coherence and reduce the standard quantum limit of clock stability, achieving a spectroscopy line quality factor of Q > 4 × 1015.
TL;DR: The studies contributing most information to outcomes of weight and body mass index (BMI) were from studies at a low risk of bias, but studies with a highrisk of bias provided data on adverse events and quality of life.
Abstract: Background
Adolescent overweight and obesity has increased globally, and can be associated with short- and long-term health consequences. Modifying known dietary and behavioural risk factors through behaviour changing interventions (BCI) may help to reduce childhood overweight and obesity. This is an update of a review published in 2009.
Objectives
To assess the effects of diet, physical activity and behavioural interventions for the treatment of overweight or obese adolescents aged 12 to 17 years.
Search methods
We performed a systematic literature search in: CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, and the trial registers ClinicalTrials.gov and ICTRP Search Portal. We checked references of identified studies and systematic reviews. There were no language restrictions. The date of the last search was July 2016 for all databases.
Selection criteria
We selected randomised controlled trials (RCTs) of diet, physical activity and behavioural interventions for treating overweight or obesity in adolescents aged 12 to 17 years.
Data collection and analysis
Two review authors independently assessed risk of bias, evaluated the overall quality of the evidence using the GRADE instrument and extracted data following the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We contacted trial authors for additional information.
Main results
We included 44 completed RCTs (4781 participants) and 50 ongoing studies. The number of participants in each trial varied (10 to 521) as did the length of follow-up (6 to 24 months). Participants ages ranged from 12 to 17.5 years in all trials that reported mean age at baseline. Most of the trials used a multidisciplinary intervention with a combination of diet, physical activity and behavioural components. The content and duration of the intervention, its delivery and the comparators varied across trials. The studies contributing most information to outcomes of weight and body mass index (BMI) were from studies at a low risk of bias, but studies with a high risk of bias provided data on adverse events and quality of life.
The mean difference (MD) of the change in BMI at the longest follow-up period in favour of BCI was -1.18 kg/m2 (95% confidence interval (CI) -1.67 to -0.69); 2774 participants; 28 trials; low quality evidence. BCI lowered the change in BMI z score by -0.13 units (95% CI -0.21 to -0.05); 2399 participants; 20 trials; low quality evidence. BCI lowered body weight by -3.67 kg (95% CI -5.21 to -2.13); 1993 participants; 20 trials; moderate quality evidence. The effect on weight measures persisted in trials with 18 to 24 months' follow-up for both BMI (MD -1.49 kg/m2 (95% CI -2.56 to -0.41); 760 participants; 6 trials and BMI z score MD -0.34 (95% CI -0.66 to -0.02); 602 participants; 5 trials).
There were subgroup differences showing larger effects for both BMI and BMI z score in studies comparing interventions with no intervention/wait list control or usual care, compared with those testing concomitant interventions delivered to both the intervention and control group. There were no subgroup differences between interventions with and without parental involvement or by intervention type or setting (health care, community, school) or mode of delivery (individual versus group).
The rate of adverse events in intervention and control groups was unclear with only five trials reporting harms, and of these, details were provided in only one (low quality evidence). None of the included studies reported on all-cause mortality, morbidity or socioeconomic effects.
BCIs at the longest follow-up moderately improved adolescent's health-related quality of life (standardised mean difference 0.44 ((95% CI 0.09 to 0.79); P = 0.01; 972 participants; 7 trials; 8 comparisons; low quality of evidence) but not self-esteem.
Trials were inconsistent in how they measured dietary intake, dietary behaviours, physical activity and behaviour.
Authors' conclusions
We found low quality evidence that multidisciplinary interventions involving a combination of diet, physical activity and behavioural components reduce measures of BMI and moderate quality evidence that they reduce weight in overweight or obese adolescents, mainly when compared with no treatment or waiting list controls. Inconsistent results, risk of bias or indirectness of outcome measures used mean that the evidence should be interpreted with caution. We have identified a large number of ongoing trials (50) which we will include in future updates of this review.
Catherine M. Phelan, Karoline Kuchenbaecker1, Karoline Kuchenbaecker2, Jonathan Tyrer1 +440 more•Institutions (156)
TL;DR: Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Abstract: To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.