Showing papers by "Karolinska Institutet published in 2019"
TL;DR: Together, rational deployment of prevention, attainment of global goals for viral hepatitis eradication, and improvements in HCC surveillance and therapy hold promise for achieving a substantial reduction in the worldwide HCC burden within the next few decades.
Abstract: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Risk factors for HCC include chronic hepatitis B and hepatitis C, alcohol addiction, metabolic liver disease (particularly nonalcoholic fatty liver disease) and exposure to dietary toxins such as aflatoxins and aristolochic acid. All these risk factors are potentially preventable, highlighting the considerable potential of risk prevention for decreasing the global burden of HCC. HCC surveillance and early detection increase the chance of potentially curative treatment; however, HCC surveillance is substantially underutilized, even in countries with sufficient medical resources. Early-stage HCC can be treated curatively by local ablation, surgical resection or liver transplantation. Treatment selection depends on tumour characteristics, the severity of underlying liver dysfunction, age, other medical comorbidities, and available medical resources and local expertise. Catheter-based locoregional treatment is used in patients with intermediate-stage cancer. Kinase and immune checkpoint inhibitors have been shown to be effective treatment options in patients with advanced-stage HCC. Together, rational deployment of prevention, attainment of global goals for viral hepatitis eradication, and improvements in HCC surveillance and therapy hold promise for achieving a substantial reduction in the worldwide HCC burden within the next few decades.
2,122 citations
University of Pennsylvania1, University of Chicago2, University of Melbourne3, Emory University4, University of Cologne5, University of Kansas6, Medical University of Vienna7, Ohio State University8, University of California, San Francisco9, University of Texas MD Anderson Cancer Center10, Université de Montréal11, University of Minnesota12, McMaster University13, Royal Prince Alfred Hospital14, University of Würzburg15, Karolinska Institutet16, University of Michigan17, University of Oslo18, Novartis19, University of Lyon20
TL;DR: The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study.
Abstract: Background Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study. Methods We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee. Results A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 ...
2,086 citations
VU University Amsterdam1, Karolinska Institutet2, deCODE genetics3, Vanderbilt University4, Jönköping University5, Oslo University Hospital6, University of Oslo7, King's College London8, Stavanger University Hospital9, Akershus University Hospital10, University of Tromsø11, Innlandet Hospital Trust12, Norwegian University of Science and Technology13, University of California, San Francisco14, Vanderbilt University Medical Center15, University of Iceland16, University of Cambridge17, University of Bergen18, University College London19, Namsos Hospital20, University of North Carolina at Chapel Hill21, Charité22, Broad Institute23, Harvard University24, VU University Medical Center25
TL;DR: A large genome-wide association study of clinically diagnosed AD and AD-by-proxy identifies new loci and functional pathways that contribute to AD risk and adds novel insights into the neurobiology of AD.
Abstract: Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.
1,460 citations
Lundbeck1, Aarhus University2, Harvard University3, Broad Institute4, Karolinska Institutet5, Cardiff University6, Statens Serum Institut7, QIMR Berghofer Medical Research Institute8, University of Iceland9, deCODE genetics10, Mental Health Services11, Charité12, Semel Institute for Neuroscience and Human Behavior13, University of California, Los Angeles14, University of Queensland15, Oslo University Hospital16, King's College London17, University of Toronto18, VU University Amsterdam19, Radboud University Nijmegen20, Veterans Health Administration21, Yale University22, Children's Hospital of Philadelphia23, Haukeland University Hospital24, University of Bergen25, University of Pennsylvania26, I.M. Sechenov First Moscow State Medical University27, University of Würzburg28, Maastricht University29, Goethe University Frankfurt30, Universidade Federal do Rio Grande do Sul31, Icahn School of Medicine at Mount Sinai32, University of North Carolina at Chapel Hill33, Emory University34, University of Copenhagen35, Aarhus University Hospital36, State University of New York Upstate Medical University37
TL;DR: A genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls identifies variants surpassing genome- wide significance in 12 independent loci and implicates neurodevelopmental pathways and conserved regions of the genome as being involved in underlying ADHD biology.
Abstract: Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
1,436 citations
Royal Edinburgh Hospital1, King's College London2, Centre for Mental Health3, University of Glasgow4, University of Edinburgh5, Medical Research Council6, University of Münster7, University of Melbourne8, University of Freiburg9, University of Queensland10, Charité11, Broad Institute12, Harvard University13, University of North Carolina at Chapel Hill14, Karolinska Institutet15
TL;DR: A genetic meta-analysis of depression found 269 associated genes that highlight several potential drug repositioning opportunities, and relationships with depression were found for neuroticism and smoking.
Abstract: Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.
1,312 citations
Heidelberg University1, University of Marburg2, Queen Mary University of London3, University of Leeds4, Rutgers University5, University of New South Wales6, University of Münster7, Aarhus University8, Columbia University9, University of Chieti-Pescara10, University of Oslo11, Karolinska Institutet12, Université catholique de Louvain13, University of Sydney14, Paris Descartes University15, Royal Perth Hospital16, University of Western Australia17, University of Dundee18, Maastricht University19, Katholieke Universiteit Leuven20, National Yang-Ming University21, Taipei Veterans General Hospital22
TL;DR: In conditions such as fibromyalgia or nonspecific low-back pain, chronic pain may be conceived as a disease in its own right; in this proposal, this subgroup is called “chronic primary pain,” and in 6 other subgroups, pain is secondary to an underlying disease.
Abstract: Chronic pain is a major source of suffering. It interferes with daily functioning and often is accompanied by distress. Yet, in the International Classification of Diseases, chronic pain diagnoses are not represented systematically. The lack of appropriate codes renders accurate epidemiological investigations difficult and impedes health policy decisions regarding chronic pain such as adequate financing of access to multimodal pain management. In cooperation with the WHO, an IASP Working Group has developed a classification system that is applicable in a wide range of contexts, including pain medicine, primary care, and low-resource environments. Chronic pain is defined as pain that persists or recurs for more than 3 months. In chronic pain syndromes, pain can be the sole or a leading complaint and requires special treatment and care. In conditions such as fibromyalgia or nonspecific low-back pain, chronic pain may be conceived as a disease in its own right; in our proposal, we call this subgroup "chronic primary pain." In 6 other subgroups, pain is secondary to an underlying disease: chronic cancer-related pain, chronic neuropathic pain, chronic secondary visceral pain, chronic posttraumatic and postsurgical pain, chronic secondary headache and orofacial pain, and chronic secondary musculoskeletal pain. These conditions are summarized as "chronic secondary pain" where pain may at least initially be conceived as a symptom. Implementation of these codes in the upcoming 11th edition of International Classification of Diseases will lead to improved classification and diagnostic coding, thereby advancing the recognition of chronic pain as a health condition in its own right.
1,311 citations
TL;DR: Genome-wide analysis identifies 30 loci associated with bipolar disorder, allowing for comparisons of shared genes and pathways with other psychiatric disorders, including schizophrenia and depression.
Abstract: Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
1,090 citations
Norwegian School of Sport Sciences1, University College London2, Oslo University Hospital3, St George's, University of London4, Columbia University Medical Center5, San Diego State University6, Boston University7, Karolinska Institutet8, Karolinska University Hospital9, University of Leicester10, University Hospitals of Leicester NHS Trust11, National Institutes of Health12, Harvard University13, Brigham and Women's Hospital14
TL;DR: Higher levels of total physical activity, at any intensity, and less time spent sedentary, are associated with substantially reduced risk for premature mortality, with evidence of a non-linear dose-response pattern in middle aged and older adults.
Abstract: Objective To examine the dose-response associations between accelerometer assessed total physical activity, different intensities of physical activity, and sedentary time and all cause mortality. Design Systematic review and harmonised meta-analysis. Data sources PubMed, PsycINFO, Embase, Web of Science, Sport Discus from inception to 31 July 2018. Eligibility criteria Prospective cohort studies assessing physical activity and sedentary time by accelerometry and associations with all cause mortality and reported effect estimates as hazard ratios, odds ratios, or relative risks with 95% confidence intervals. Data extraction and analysis Guidelines for meta-analyses and systematic reviews for observational studies and PRISMA guidelines were followed. Two authors independently screened the titles and abstracts. One author performed a full text review and another extracted the data. Two authors independently assessed the risk of bias. Individual level participant data were harmonised and analysed at study level. Data on physical activity were categorised by quarters at study level, and study specific associations with all cause mortality were analysed using Cox proportional hazards regression analyses. Study specific results were summarised using random effects meta-analysis. Main outcome measure All cause mortality. Results 39 studies were retrieved for full text review; 10 were eligible for inclusion, three were excluded owing to harmonisation challenges (eg, wrist placement of the accelerometer), and one study did not participate. Two additional studies with unpublished mortality data were also included. Thus, individual level data from eight studies (n=36 383; mean age 62.6 years; 72.8% women), with median follow-up of 5.8 years (range 3.0-14.5 years) and 2149 (5.9%) deaths were analysed. Any physical activity, regardless of intensity, was associated with lower risk of mortality, with a non-linear dose-response. Hazards ratios for mortality were 1.00 (referent) in the first quarter (least active), 0.48 (95% confidence interval 0.43 to 0.54) in the second quarter, 0.34 (0.26 to 0.45) in the third quarter, and 0.27 (0.23 to 0.32) in the fourth quarter (most active). Corresponding hazards ratios for light physical activity were 1.00, 0.60 (0.54 to 0.68), 0.44 (0.38 to 0.51), and 0.38 (0.28 to 0.51), and for moderate-to-vigorous physical activity were 1.00, 0.64 (0.55 to 0.74), 0.55 (0.40 to 0.74), and 0.52 (0.43 to 0.61). For sedentary time, hazards ratios were 1.00 (referent; least sedentary), 1.28 (1.09 to 1.51), 1.71 (1.36 to 2.15), and 2.63 (1.94 to 3.56). Conclusion Higher levels of total physical activity, at any intensity, and less time spent sedentary, are associated with substantially reduced risk for premature mortality, with evidence of a non-linear dose-response pattern in middle aged and older adults. Systematic review registration PROSPERO CRD42018091808.
805 citations
TL;DR: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community providing the theory and key practical aspects offlow cytometry enabling immunologists to avoid the common errors that often undermine immunological data.
Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
698 citations
Karolinska Institutet1, Ghent University2, Eastern Virginia Medical School3, Université de Montréal4, Katholieke Universiteit Leuven5, Regeneron6, University of Pittsburgh7, University of Barcelona8, University of Pennsylvania9, Brigham and Women's Hospital10, Royal Brisbane and Women's Hospital11, St Thomas' Hospital12, Charité13, Humanitas University14, University of Pisa15, University of South Florida16, University of Amsterdam17, University of Fukui18
TL;DR: Dupilumab significantly improved the coprimary endpoints in both studies and was added to standard of care in adults with severe CRSwNP despite previous treatment with systemic corticosteroids, surgery, or both.
676 citations
Nasim Mavaddat1, Kyriaki Michailidou2, Kyriaki Michailidou1, Joe Dennis1 +307 more•Institutions (105)
TL;DR: This PRS, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset is developed and empirically validated and is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
Abstract: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
TL;DR: This review focuses on the aging-related structural changes and mechanisms at cellular and subcellular levels underlying changes in the individual motor unit: specifically, the perikaryon of the α-motoneuron, its neuromuscular junction(s), and the muscle fibers that it innervates.
Abstract: Sarcopenia is a loss of muscle mass and function in the elderly that reduces mobility, diminishes quality of life, and can lead to fall-related injuries, which require costly hospitalization and ex...
TL;DR: This article analyzes the interaction of nanoparticle surface and ligands with different chemical groups, the types of bonding, the final dispersibility of ligand-coated nanoparticles in complex media, their reactivity, and their performance in biomedicine, photodetectors, photovoltaic devices, light-emitting devices, sensors, memory devices, thermoelectric applications, and catalysis.
Abstract: The design of nanoparticles is critical for their efficient use in many applications ranging from biomedicine to sensing and energy. While shape and size are responsible for the properties of the inorganic nanoparticle core, the choice of ligands is of utmost importance for the colloidal stability and function of the nanoparticles. Moreover, the selection of ligands employed in nanoparticle synthesis can determine their final size and shape. Ligands added after nanoparticle synthesis infer both new properties as well as provide enhanced colloidal stability. In this article, we provide a comprehensive review on the role of the ligands with respect to the nanoparticle morphology, stability, and function. We analyze the interaction of nanoparticle surface and ligands with different chemical groups, the types of bonding, the final dispersibility of ligand-coated nanoparticles in complex media, their reactivity, and their performance in biomedicine, photodetectors, photovoltaic devices, light-emitting devices, sensors, memory devices, thermoelectric applications, and catalysis.
TL;DR: An online database, PanglaoDB, accessible through a user-friendly interface that can be used to explore published mouse and human single cell RNA sequencing studies, and establishes a community-curated cell-type marker compendium, containing more than 6000 gene-cell-type associations, as a resource for automatic annotation of cell types.
Abstract: Single-cell RNA sequencing is an increasingly used method to measure gene expression at the single cell level and build cell-type atlases of tissues. Hundreds of single-cell sequencing datasets have already been published. However, studies are frequently deposited as raw data, a format difficult to access for biological researchers due to the need for data processing using complex computational pipelines. We have implemented an online database, PanglaoDB, accessible through a user-friendly interface that can be used to explore published mouse and human single cell RNA sequencing studies. PanglaoDB contains pre-processed and pre-computed analyses from more than 1054 single-cell experiments covering most major single cell platforms and protocols, based on more than 4 million cells from a wide range of tissues and organs. The online interface allows users to query and explore cell types, genetic pathways and regulatory networks. In addition, we have established a community-curated cell-type marker compendium, containing more than 6000 gene-cell-type associations, as a resource for automatic annotation of cell types.
TL;DR: From studies of copy number variants, it is learned that the rare insertions or deletions account for part of ADHD’s heritability, which has implicated new biological pathways that may eventually have implications for treatment development.
Abstract: Decades of research show that genes play an vital role in the etiology of attention deficit hyperactivity disorder (ADHD) and its comorbidity with other disorders. Family, twin, and adoption studies show that ADHD runs in families. ADHD’s high heritability of 74% motivated the search for ADHD susceptibility genes. Genetic linkage studies show that the effects of DNA risk variants on ADHD must, individually, be very small. Genome-wide association studies (GWAS) have implicated several genetic loci at the genome-wide level of statistical significance. These studies also show that about a third of ADHD’s heritability is due to a polygenic component comprising many common variants each having small effects. From studies of copy number variants we have also learned that the rare insertions or deletions account for part of ADHD’s heritability. These findings have implicated new biological pathways that may eventually have implications for treatment development.
university of lille1, University of Southern Denmark2, University of Calgary3, University of Wolverhampton4, Karolinska Institutet5, University of Melbourne6, Heidelberg University7, National University of Ireland, Galway8, University of Alberta9, Harvard University10, Centre Hospitalier Universitaire de Toulouse11, University of Caen Lower Normandy12, University of Paris13, Genmab14, Janssen Pharmaceutica15
TL;DR: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among thosewho received lenalidmide and Dexameth asone alone.
Abstract: Background Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought...
TL;DR: High-definition spatial transcriptomics is developed, which captures RNA from histological tissue sections on a dense, spatially barcoded bead array, which opens the way to high-resolution spatial analysis of cells and tissues.
Abstract: Spatial and molecular characteristics determine tissue function, yet high-resolution methods to capture both concurrently are lacking. Here, we developed high-definition spatial transcriptomics, which captures RNA from histological tissue sections on a dense, spatially barcoded bead array. Each experiment recovers several hundred thousand transcript-coupled spatial barcodes at 2-μm resolution, as demonstrated in mouse brain and primary breast cancer. This opens the way to high-resolution spatial analysis of cells and tissues.
University of Oxford1, Boston Children's Hospital2, Harvard University3, University of Washington4, University of London5, Université libre de Bruxelles6, University of Nottingham7, RTI International8, University of Notre Dame9, University of Southampton10, Fudan University11, National University of Defense Technology12, Southwestern University of Finance and Economics13, Central South University14, Pan American Health Organization15, Institute of Tropical Medicine Antwerp16, European Centre for Disease Prevention and Control17, Colorado State University18, ETH Zurich19, Karolinska Institutet20, Stockholm School of Economics21, Pasteur Institute22, Université de Namur23, University of California, Davis24, University of Melbourne25
TL;DR: It is shown that human movement patterns explain the spread of both Aedes aegypti and Aedes albopictus in Europe and the United States following their introduction and predicted the future distributions of both species in response to accelerating urbanization, connectivity and climate change.
Abstract: The global population at risk from mosquito-borne diseases-including dengue, yellow fever, chikungunya and Zika-is expanding in concert with changes in the distribution of two key vectors: Aedes aegypti and Aedes albopictus. The distribution of these species is largely driven by both human movement and the presence of suitable climate. Using statistical mapping techniques, we show that human movement patterns explain the spread of both species in Europe and the United States following their introduction. We find that the spread of Ae. aegypti is characterized by long distance importations, while Ae. albopictus has expanded more along the fringes of its distribution. We describe these processes and predict the future distributions of both species in response to accelerating urbanization, connectivity and climate change. Global surveillance and control efforts that aim to mitigate the spread of chikungunya, dengue, yellow fever and Zika viruses must consider the so far unabated spread of these mosquitos. Our maps and predictions offer an opportunity to strategically target surveillance and control programmes and thereby augment efforts to reduce arbovirus burden in human populations globally.
International Agency for Research on Cancer1, University of Leicester2, Karolinska Institutet3, Cancer Institute of New South Wales4, Cancer Council Victoria5, Alberta Health Services6, St. John's University7, Nova Scotia Health Authority8, Cancer Care Ontario9, McGill University10, Public Health England11, Queen's University Belfast12, Cardiff University13, Canadian Partnership Against Cancer14, The Royal Marsden NHS Foundation Trust15, University of Oxford16, King's College London17
TL;DR: Progress in cancer control over the study period was evident for stomach, colon, lung (in males), and ovarian cancer, and the impact of comorbidity are likely the main determinants of patient outcomes.
Abstract: Summary Background Population-based cancer survival estimates provide valuable insights into the effectiveness of cancer services and can reflect the prospects of cure. As part of the second phase of the International Cancer Benchmarking Partnership (ICBP), the Cancer Survival in High-Income Countries (SURVMARK-2) project aims to provide a comprehensive overview of cancer survival across seven high-income countries and a comparative assessment of corresponding incidence and mortality trends. Methods In this longitudinal, population-based study, we collected patient-level data on 3·9 million patients with cancer from population-based cancer registries in 21 jurisdictions in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the UK) for seven sites of cancer (oesophagus, stomach, colon, rectum, pancreas, lung, and ovary) diagnosed between 1995 and 2014, and followed up until Dec 31, 2015. We calculated age-standardised net survival at 1 year and 5 years after diagnosis by site, age group, and period of diagnosis. We mapped changes in incidence and mortality to changes in survival to assess progress in cancer control. Findings In 19 eligible jurisdictions, 3 764 543 cases of cancer were eligible for inclusion in the study. In the 19 included jurisdictions, over 1995–2014, 1-year and 5-year net survival increased in each country across almost all cancer types, with, for example, 5-year rectal cancer survival increasing more than 13 percentage points in Denmark, Ireland, and the UK. For 2010–14, survival was generally higher in Australia, Canada, and Norway than in New Zealand, Denmark, Ireland, and the UK. Over the study period, larger survival improvements were observed for patients younger than 75 years at diagnosis than those aged 75 years and older, and notably for cancers with a poor prognosis (ie, oesophagus, stomach, pancreas, and lung). Progress in cancer control (ie, increased survival, decreased mortality and incidence) over the study period was evident for stomach, colon, lung (in males), and ovarian cancer. Interpretation The joint evaluation of trends in incidence, mortality, and survival indicated progress in four of the seven studied cancers. Cancer survival continues to increase across high-income countries; however, international disparities persist. While truly valid comparisons require differences in registration practice, classification, and coding to be minimal, stage of disease at diagnosis, timely access to effective treatment, and the extent of comorbidity are likely the main determinants of patient outcomes. Future studies are needed to assess the impact of these factors to further our understanding of international disparities in cancer survival. Funding Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; The Scottish Government; Western Australia Department of Health; and Wales Cancer Network.
University of Sydney1, Maastricht University2, Katholieke Universiteit Leuven3, University of Marburg4, Queen Mary University of London5, Rutgers University6, University of New South Wales7, University of Münster8, University of Chieti-Pescara9, University of Paris10, Aarhus University11, Karolinska Institutet12, Heidelberg University13
TL;DR: The goal here is to create a classification that is useful in both primary care and specialized pain management settings for the development of individualized management plans, and to assist both clinicians and researchers by providing a more accurate description of each diagnostic category.
Abstract: This article describes a proposal for the new diagnosis of chronic primary pain (CPP) in ICD-11. Chronic primary pain is chosen when pain has persisted for more than 3 months and is associated with significant emotional distress and/or functional disability, and the pain is not better accounted for by another condition. As with all pain, the article assumes a biopsychosocial framework for understanding CPP, which means all subtypes of the diagnosis are considered to be multifactorial in nature, with biological, psychological, and social factors contributing to each. Unlike the perspectives found in DSM-5 and ICD-10, the diagnosis of CPP is considered to be appropriate independently of identified biological or psychological contributors, unless another diagnosis would better account for the presenting symptoms. Such other diagnoses are called "chronic secondary pain" where pain may at least initially be conceived as a symptom secondary to an underlying disease. The goal here is to create a classification that is useful in both primary care and specialized pain management settings for the development of individualized management plans, and to assist both clinicians and researchers by providing a more accurate description of each diagnostic category.
TL;DR: The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index.
Abstract: Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
TL;DR: A perspective and primer on deep learning applications for genome analysis and successful applications in the fields of regulatory genomics, variant calling and pathogenicity scores are provided.
Abstract: Deep learning methods are a class of machine learning techniques capable of identifying highly complex patterns in large datasets. Here, we provide a perspective and primer on deep learning applications for genome analysis. We discuss successful applications in the fields of regulatory genomics, variant calling and pathogenicity scores. We include general guidance for how to effectively use deep learning methods as well as a practical guide to tools and resources. This primer is accompanied by an interactive online tutorial.
TL;DR: Recent approaches and advances of EV-based therapies are covered, showing how EVs can potentiate tissue regeneration, participate in immune modulation, and function as potential alternatives to stem cell therapy and bioengineered EVs can act as delivery vehicles for therapeutic agents.
Abstract: Extracellular vesicles (EVs) are nanometer-sized, lipid membrane-enclosed vesicles secreted by most, if not all, cells and contain lipids, proteins, and various nucleic acid species of the source cell. EVs act as important mediators of intercellular communication that influence both physiological and pathological conditions. Given their ability to transfer bioactive components and surmount biological barriers, EVs are increasingly being explored as potential therapeutic agents. EVs can potentiate tissue regeneration, participate in immune modulation, and function as potential alternatives to stem cell therapy, and bioengineered EVs can act as delivery vehicles for therapeutic agents. Here, we cover recent approaches and advances of EV-based therapies.
National Institutes of Health1, European Society of Cardiology2, Ghent University3, Karolinska Institutet4, University Medical Center Utrecht5, University of Lausanne6, Vilnius University7, Charles University in Prague8, Hospital Universitario La Paz9, National University of Ireland, Galway10, Kazakh National Medical University11, Erasmus University Rotterdam12, University of Sarajevo13, Shupyk National Medical Academy of Postgraduate Education14, University of Latvia15, Ljubljana University Medical Centre16, University of Ljubljana17, University of Würzburg18, Assiut University19, Jagiellonian University Medical College20, University Hospital Centre Zagreb21, Kyrgyz State Medical Academy22, University of Zagreb23, Hacettepe University24, National and Kapodistrian University of Athens25, University of Banja Luka26
TL;DR: A large majority of coronary patients have unhealthy lifestyles in terms of smoking, diet and sedentary behaviour, which adversely impacts major cardiovascular risk factors, and a majority did not achieve their blood pressure, low-density lipoprotein cholesterol and glucose targets.
Abstract: AimsThe aim of this study was to determine whether the Joint European Societies guidelines on secondary cardiovascular prevention are followed in everyday practice.DesignA cross-sectional ESC-EORP ...
TL;DR: The LISA database allows researchers to identify individuals who do not work because of injury, disease, or rehabilitation and contains data on sick leave and disability pension based on calendar year.
Abstract: Education, income, and occupation are factors known to affect health and disease. In this review we describe the Swedish Longitudinal Integrated Database for Health Insurance and Labour Market Studies (LISA, Longitudinell Integrationsdatabas for Sjukforsakrings- och Arbetsmarknadsstudier). LISA covers the adult Swedish population aged ≥ 16 years registered on December 31 each year since 1990 (since 2010 individuals aged ≥ 15 years). The database was launched in response to rising levels of sick leave in the country. Participation in Swedish government-administered registers such as LISA is compulsory, and hence selection bias is minimized. The LISA database allows researchers to identify individuals who do not work because of injury, disease, or rehabilitation. It contains data on sick leave and disability pension based on calendar year. LISA also includes information on unemployment benefits, disposable income, social welfare payments, civil status, and migration. During 2000–2017, an average of 97,000 individuals immigrated to Sweden each year. This corresponds to about 1% of the Swedish population (10 million people in 2017). Data on occupation have a completeness of 95%. Income data consist primarily of income from employment, capital, and allowances, including parental allowance. In Sweden, work force participation is around 80% (2017: overall: 79.1%; men 80.3% and women 77.9%). Education data are available in > 98% of all individuals aged 25–64 years, with an estimated accuracy for highest attained level of education of 85%. Some information on civil status, income, education, and employment before 1990 can be obtained through the Population and Housing Census data (FoB, Folk- och bostadsrakningen).
TL;DR: Findings from the meta-analysis suggest that physical activity interventions can improve adolescents’ mental health, but additional studies are needed to confirm the effects of physical activity on children’s mental health.
Abstract: Evidence suggests that participation in physical activity may support young people’s current and future mental health. Although previous reviews have examined the relationship between physical activity and a range of mental health outcomes in children and adolescents, due to the large increase in published studies there is a need for an update and quantitative synthesis of effects. The objectives of this study were to determine the effect of physical activity interventions on mental health outcomes by conducting a systematic review and meta-analysis, and to systematically synthesize the observational evidence (both longitudinal and cross-sectional studies) regarding the associations between physical activity and sedentary behavior and mental health in preschoolers (2–5 years of age), children (6–11 years of age) and adolescents (12–18 years of age). A systematic search of the PubMed and Web of Science electronic databases was performed from January 2013 to April 2018, by two independent researchers. Meta-analyses were performed to examine the effect of physical activity on mental health outcomes in randomized controlled trials (RCTs) and non-RCTs (i.e. quasi-experimental studies). A narrative synthesis of observational studies was conducted. Studies were included if they included physical activity or sedentary behavior data and at least one psychological ill-being (i.e. depression, anxiety, stress or negative affect) or psychological well-being (i.e. self-esteem, self-concept, self-efficacy, self-image, positive affect, optimism, happiness and satisfaction with life) outcome in preschoolers, children or adolescents. A total of 114 original articles met all the eligibility criteria and were included in the review (4 RCTs, 14 non-RCTs, 28 prospective longitudinal studies and 68 cross-sectional studies). Of the 18 intervention studies, 12 (3 RCTs and 9 non-RCTs) were included in the meta-analysis. There was a small but significant overall effect of physical activity on mental health in children and adolescents aged 6–18 years (effect size 0.173, 95% confidence interval 0.106–0.239, p < 0.001, percentage of total variability attributed to between-study heterogeneity [I2] = 11.3%). When the analyses were performed separately for children and adolescents, the results were significant for adolescents but not for children. Longitudinal and cross-sectional studies demonstrated significant associations between physical activity and lower levels of psychological ill-being (i.e. depression, stress, negative affect, and total psychological distress) and greater psychological well-being (i.e. self-image, satisfaction with life and happiness, and psychological well-being). Furthermore, significant associations were found between greater amounts of sedentary behavior and both increased psychological ill-being (i.e. depression) and lower psychological well-being (i.e. satisfaction with life and happiness) in children and adolescents. Evidence on preschoolers was nearly non-existent. Findings from the meta-analysis suggest that physical activity interventions can improve adolescents’ mental health, but additional studies are needed to confirm the effects of physical activity on children’s mental health. Findings from observational studies suggest that promoting physical activity and decreasing sedentary behavior might protect mental health in children and adolescents. PROSPERO Registration Number: CRD42017060373.
TL;DR: A large genetic association sample is used to detect novel loci and gain insight into the pathways, tissue and cell types involved in insomnia complaints, identifying 202 loci implicating 956 genes through positional, expression quantitative trait loci, and chromatin mapping.
Abstract: Insomnia is the second most prevalent mental disorder, with no sufficient treatment available. Despite substantial heritability, insight into the associated genes and neurobiological pathways remains limited. Here, we use a large genetic association sample (n = 1,331,010) to detect novel loci and gain insight into the pathways, tissue and cell types involved in insomnia complaints. We identify 202 loci implicating 956 genes through positional, expression quantitative trait loci, and chromatin mapping. The meta-analysis explained 2.6% of the variance. We show gene set enrichments for the axonal part of neurons, cortical and subcortical tissues, and specific cell types, including striatal, hypothalamic, and claustrum neurons. We found considerable genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization identified the causal effects of insomnia on depression, diabetes, and cardiovascular disease, and the protective effects of educational attainment and intracranial volume. Our findings highlight key brain areas and cell types implicated in insomnia, and provide new treatment targets.
TL;DR: Age standardised mortality rates for suicide have greatly reduced since 1990, but suicide remains an important contributor to mortality worldwide and can be targeted towards vulnerable populations if they are informed by variations in mortality rates.
Abstract: Objectives To use the estimates from the Global Burden of Disease Study 2016 to describe patterns of suicide mortality globally, regionally, and for 195 countries and territories by age, sex, and Socio-demographic index, and to describe temporal trends between 1990 and 2016. Design Systematic analysis. Main outcome measures Crude and age standardised rates from suicide mortality and years of life lost were compared across regions and countries, and by age, sex, and Socio-demographic index (a composite measure of fertility, income, and education). Results The total number of deaths from suicide increased by 6.7% (95% uncertainty interval 0.4% to 15.6%) globally over the 27 year study period to 817 000 (762 000 to 884 000) deaths in 2016. However, the age standardised mortality rate for suicide decreased by 32.7% (27.2% to 36.6%) worldwide between 1990 and 2016, similar to the decline in the global age standardised mortality rate of 30.6%. Suicide was the leading cause of age standardised years of life lost in the Global Burden of Disease region of high income Asia Pacific and was among the top 10 leading causes in eastern Europe, central Europe, western Europe, central Asia, Australasia, southern Latin America, and high income North America. Rates for men were higher than for women across regions, countries, and age groups, except for the 15 to 19 age group. There was variation in the female to male ratio, with higher ratios at lower levels of Socio-demographic index. Women experienced greater decreases in mortality rates (49.0%, 95% uncertainty interval 42.6% to 54.6%) than men (23.8%, 15.6% to 32.7%). Conclusions Age standardised mortality rates for suicide have greatly reduced since 1990, but suicide remains an important contributor to mortality worldwide. Suicide mortality was variable across locations, between sexes, and between age groups. Suicide prevention strategies can be targeted towards vulnerable populations if they are informed by variations in mortality rates.
TL;DR: Single-nucleus RNA sequencing analysis identifies different subclusters of oligodendroglia in white matter from individuals with multiple sclerosis compared with controls, and these differences may be important for understanding disease progression and developing therapeutic approaches.
Abstract: Oligodendrocyte pathology is increasingly implicated in neurodegenerative diseases as oligodendrocytes both myelinate and provide metabolic support to axons. In multiple sclerosis (MS), demyelination in the central nervous system thus leads to neurodegeneration, but the severity of MS between patients is very variable. Disability does not correlate well with the extent of demyelination1, which suggests that other factors contribute to this variability. One such factor may be oligodendrocyte heterogeneity. Not all oligodendrocytes are the same—those from the mouse spinal cord inherently produce longer myelin sheaths than those from the cortex2, and single-cell analysis of the mouse central nervous system identified further differences3,4. However, the extent of human oligodendrocyte heterogeneity and its possible contribution to MS pathology remain unknown. Here we performed single-nucleus RNA sequencing from white matter areas of post-mortem human brain from patients with MS and from unaffected controls. We identified subclusters of oligodendroglia in control human white matter, some with similarities to mouse, and defined new markers for these cell states. Notably, some subclusters were underrepresented in MS tissue, whereas others were more prevalent. These differences in mature oligodendrocyte subclusters may indicate different functional states of oligodendrocytes in MS lesions. We found similar changes in normal-appearing white matter, showing that MS is a more diffuse disease than its focal demyelination suggests. Our findings of an altered oligodendroglial heterogeneity in MS may be important for understanding disease progression and developing therapeutic approaches. Single-nucleus RNA sequencing analysis identifies different subclusters of oligodendroglia in white matter from individuals with multiple sclerosis compared with controls, and these differences may be important for understanding disease progression.
F. Kyle Satterstrom1, Jack A. Kosmicki1, Jiebiao Wang2, Michael S. Breen3 +150 more•Institutions (45)
TL;DR: Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, 102 risk genes are identified at a false discovery rate of ≤ 0.1, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.
Abstract: We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.