Showing papers by "University of Glasgow published in 2018"
Gregory A. Roth1, Gregory A. Roth2, Degu Abate3, Kalkidan Hassen Abate4 +1025 more•Institutions (333)
TL;DR: Non-communicable diseases comprised the greatest fraction of deaths, contributing to 73·4% (95% uncertainty interval [UI] 72·5–74·1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional causes accounted for 18·6% (17·9–19·6), and injuries 8·0% (7·7–8·2).
5,211 citations
Lorenzo Galluzzi1, Lorenzo Galluzzi2, Ilio Vitale3, Stuart A. Aaronson4 +183 more•Institutions (111)
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
3,301 citations
Jeffrey D. Stanaway1, Ashkan Afshin1, Emmanuela Gakidou1, Stephen S Lim1 +1050 more•Institutions (346)
TL;DR: This study estimated levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs) by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017 and explored the relationship between development and risk exposure.
2,910 citations
TL;DR: A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent and significant loci and finds important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia.
Abstract: Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.
1,898 citations
TL;DR: This analysis expands upon previous analyses by working under the hypothesis that both bodies were neutron stars that are described by the same equation of state and have spins within the range observed in Galactic binary neutron stars.
Abstract: On 17 August 2017, the LIGO and Virgo observatories made the first direct detection of gravitational waves from the coalescence of a neutron star binary system. The detection of this gravitational-wave signal, GW170817, offers a novel opportunity to directly probe the properties of matter at the extreme conditions found in the interior of these stars. The initial, minimal-assumption analysis of the LIGO and Virgo data placed constraints on the tidal effects of the coalescing bodies, which were then translated to constraints on neutron star radii. Here, we expand upon previous analyses by working under the hypothesis that both bodies were neutron stars that are described by the same equation of state and have spins within the range observed in Galactic binary neutron stars. Our analysis employs two methods: the use of equation-of-state-insensitive relations between various macroscopic properties of the neutron stars and the use of an efficient parametrization of the defining function pðρÞ of the equation of state itself. From the LIGO and Virgo data alone and the first method, we measure the two neutron star radii as R1 ¼ 10.8 þ2.0 −1.7 km for the heavier star and R2 ¼ 10.7 þ2.1 −1.5 km for the lighter star at the 90% credible level. If we additionally require that the equation of state supports neutron stars with masses larger than 1.97 M⊙ as required from electromagnetic observations and employ the equation-of-state parametrization, we further constrain R1 ¼ 11.9 þ1.4 −1.4 km and R2 ¼ 11.9 þ1.4 −1.4 km at the 90% credible level. Finally, we obtain constraints on pðρÞ at supranuclear densities, with pressure at twice nuclear saturation density measured at 3.5 þ2.7 −1.7 × 1034 dyn cm−2 at the 90% level.
1,595 citations
TL;DR: In insights into the role of alcohol consumption in the genetic architecture of hypertension, a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions is conducted.
Abstract: Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
1,218 citations
University of Oxford1, University of Michigan2, Wellcome Trust Sanger Institute3, Amgen4, University of Cambridge5, University of Copenhagen6, University of Liverpool7, University of Freiburg8, Boston University9, University of Tartu10, Erasmus University Medical Center11, Leiden University Medical Center12, Pasteur Institute13, Icahn School of Medicine at Mount Sinai14, UCLA Medical Center15, Vanderbilt University Medical Center16, Wake Forest University17, National University of Singapore18, Imperial College London19, London North West Healthcare NHS Trust20, Charité21, Innsbruck Medical University22, Washington University in St. Louis23, Queen Mary University of London24, University of Southern Denmark25, National and Kapodistrian University of Athens26, Robertson Centre for Biostatistics27, University of Exeter28, Uppsala University29, University of Düsseldorf30, Steno Diabetes Center31, Aalborg University32, University of Eastern Finland33, Broad Institute34, Frederiksberg Hospital35, University of Bergen36, Lund University37, Technische Universität München38, University of North Carolina at Chapel Hill39, Ninewells Hospital40, University of Edinburgh41, University of Minnesota42, University of Glasgow43, Ludwig Maximilian University of Munich44, University of Iceland45, Aarhus University46, Stanford University47, Science for Life Laboratory48, University of Helsinki49, National Institutes of Health50, University of Dundee51, Harvard University52
TL;DR: Combining 32 genome-wide association studies with high-density imputation provides a comprehensive view of the genetic contribution to type 2 diabetes in individuals of European ancestry with respect to locus discovery, causal-variant resolution, and mechanistic insight.
Abstract: We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
1,136 citations
TL;DR: It is shown that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 by lipopolysaccharide in mouse and human macrophages and that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconates production.
Abstract: WebTreatment of lipopolysaccharide-activated macrophages with the cell-permeable itaconate derivative 4-octyl itaconate activates the anti-inflammatory transcription factor Nrf2 by alkylating key cysteine residues on the KEAP1 protein.
948 citations
University of Melbourne1, University of British Columbia2, New York University3, Federal University of São Paulo4, French Institute of Health and Medical Research5, University of California, Los Angeles6, Albert Einstein College of Medicine7, Children's Hospital Los Angeles8, University of Pavia9, Karolinska Institutet10, University of Calgary11, Peking University12, University of Glasgow13, Royal Hospital for Sick Children14
TL;DR: The International League Against Epilepsy Classification of the Epilepsies has been updated to reflect the gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989.
Abstract: The International League Against Epilepsy (ILAE) classification of the epilepsies has been updated to reflect the gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for the clinical diagnosis of patients but it is also critical for epilepsy research, development of antiepileptic treatment and communication around the world. The new classification is based on a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It consists of three levels starting with seizure type, where it is assumed that the epileptic seizures of the patient are defined by the new 2017 ILAE seizure classification. After diagnosis of the seizure type, the next step is the diagnosis of the epilepsy type, which includes focal epilepsy, generalized epilepsy, combined generalized and focal epilepsy and also an unclassified epilepsy group. At the third level the disease is assigned to a specific epilepsy syndrome. The new classification incorporates etiology at each stage, emphasizing the need to consider etiology at each step of the diagnosis, as it often carries significant treatment implications. The various etiologies can be assigned to six subgroups, defined with respect to the potential therapeutic consequences. New terminology is introduced, such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limiting and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the twenty-first century.
903 citations
TL;DR: Patients with type 2 diabetes who had five risk‐factor variables within the target ranges appeared to have little or no excess risk of death, myocardial infarction, or stroke, as compared with the general population.
Abstract: Background Patients with diabetes are at higher risk for death and cardiovascular outcomes than the general population. We investigated whether the excess risk of death and cardiovascular ...
806 citations
TL;DR: In this article, the authors present possible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves.
Abstract: We present possible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves. We estimate the sensitivity of the network to transient gravitational-wave signals, and study the capability of the network to determine the sky location of the source. We report our findings for gravitational-wave transients, with particular focus on gravitational-wave signals from the inspiral of binary neutron star systems, which are the most promising targets for multi-messenger astronomy. The ability to localize the sources of the detected signals depends on the geographical distribution of the detectors and their relative sensitivity, and 90% credible regions can be as large as thousands of square degrees when only two sensitive detectors are operational. Determining the sky position of a significant fraction of detected signals to areas of 5– 20 deg2 requires at least three detectors of sensitivity within a factor of ∼2 of each other and with a broad frequency bandwidth. When all detectors, including KAGRA and the third LIGO detector in India, reach design sensitivity, a significant fraction of gravitational-wave signals will be localized to a few square degrees by gravitational-wave observations alone.
The Royal Marsden NHS Foundation Trust1, University of Birmingham2, University College London3, University of Salford4, University of Manchester5, Guy's and St Thomas' NHS Foundation Trust6, St James's University Hospital7, Kantonsspital St. Gallen8, Beatson West of Scotland Cancer Centre9, Clatterbridge Cancer Centre NHS Foundation Trust10, Cardiff University11, University of Wolverhampton12, University of Glasgow13, University Hospitals Birmingham NHS Foundation Trust14, Queen Alexandra Hospital15, University of London16, Gloucestershire Hospitals NHS Foundation Trust17, Royal Surrey County Hospital18, Queen's University Belfast19, East Lancashire Hospitals NHS Trust20, Freeman Hospital21, Singleton Hospital22, Royal Devon and Exeter Hospital23, Telford24
TL;DR: Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer, and the benefit would be greatest in patients with a low metastatic burden.
Nagoya University1, University of Grenoble2, University of Padua3, University of Liverpool4, Hong Kong University of Science and Technology5, Massachusetts Institute of Technology6, HRL Laboratories7, University of Sheffield8, Katholieke Universiteit Leuven9, Fraunhofer Society10, Nagoya Institute of Technology11, University of Notre Dame12, Virginia Tech13, Infineon Technologies14, University of Glasgow15, University of Texas at Austin16, University of Bristol17, National Institute of Advanced Industrial Science and Technology18, University of Cambridge19, Cardiff University20, Zhejiang University21
TL;DR: This collection of GaN technology developments is not itself a road map but a valuable collection of global state-of-the-art GaN research that will inform the next phase of the technology as market driven requirements evolve.
Abstract: Gallium nitride (GaN) is a compound semiconductor that has tremendous potential to facilitate economic growth in a semiconductor industry that is silicon-based and currently faced with diminishing returns of performance versus cost of investment. At a material level, its high electric field strength and electron mobility have already shown tremendous potential for high frequency communications and photonic applications. Advances in growth on commercially viable large area substrates are now at the point where power conversion applications of GaN are at the cusp of commercialisation. The future for building on the work described here in ways driven by specific challenges emerging from entirely new markets and applications is very exciting. This collection of GaN technology developments is therefore not itself a road map but a valuable collection of global state-of-the-art GaN research that will inform the next phase of the technology as market driven requirements evolve. First generation production devices are igniting large new markets and applications that can only be achieved using the advantages of higher speed, low specific resistivity and low saturation switching transistors. Major investments are being made by industrial companies in a wide variety of markets exploring the use of the technology in new circuit topologies, packaging solutions and system architectures that are required to achieve and optimise the system advantages offered by GaN transistors. It is this momentum that will drive priorities for the next stages of device research gathered here.
Evangelos Evangelou1, Evangelos Evangelou2, Helen R. Warren3, Helen R. Warren4 +338 more•Institutions (93)
TL;DR: In this article, the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry was conducted.
Abstract: High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future
Goethe University Frankfurt1, University of Maryland, College Park2, University of Guelph3, Duke University4, Swedish University of Agricultural Sciences5, Radboud University Nijmegen6, Federal University of Mato Grosso do Sul7, University of Alberta8, Royal Veterinary College9, Wildlife Conservation Society10, Mississippi State University11, Sao Paulo State University12, Michigan Department of Natural Resources13, University of California, Davis14, Aarhus University15, Max Planck Society16, University of Potsdam17, Middle Tennessee State University18, Mammal Research Institute19, Edmund Mach Foundation20, Harvard University21, Smithsonian Conservation Biology Institute22, University of Évora23, University of Montpellier24, Monash University25, Parks Victoria26, Ohio State University27, Fiji National University28, University of Massachusetts Amherst29, United States Geological Survey30, University of Oxford31, Save the Elephants32, German Primate Center33, Technische Universität München34, Institute of Ecosystem Studies35, University of British Columbia36, University of Zurich37, University of Wyoming38, University of Washington39, University of Montana40, University of Freiburg41, Bavarian Forest National Park42, University of Toulouse43, University of Veterinary Medicine Vienna44, University College Cork45, North Carolina Museum of Natural Sciences46, North Carolina State University47, Karatina University48, University of Lethbridge49, Lamont–Doherty Earth Observatory50, University of Valencia51, Stony Brook University52, International Union for Conservation of Nature and Natural Resources53, University of Alicante54, Empresa Brasileira de Pesquisa Agropecuária55, University of Glasgow56, New York University57, University of Oslo58, Hebrew University of Jerusalem59, Norwegian University of Science and Technology60, Field Museum of Natural History61, University of Bayreuth62, University of Grenoble63, University of New South Wales64, Pennsylvania Game Commission65, Princeton University66, University of Konstanz67, University of Haifa68, Polish Academy of Sciences69, Instituto Superior de Agronomia70, University of Lisbon71, University of Porto72, University of California, Santa Cruz73, University of Pretoria74, Colorado State University75
TL;DR: Using a unique GPS-tracking database of 803 individuals across 57 species, it is found that movements of mammals in areas with a comparatively high human footprint were on average one-half to one-third the extent of their movements in area with a low human footprint.
Abstract: Animal movement is fundamental for ecosystem functioning and species survival, yet the effects of the anthropogenic footprint on animal movements have not been estimated across species. Using a unique GPS-tracking database of 803 individuals across 57 species, we found that movements of mammals in areas with a comparatively high human footprint were on average one-half to one-third the extent of their movements in areas with a low human footprint. We attribute this reduction to behavioral changes of individual animals and to the exclusion of species with long-range movements from areas with higher human impact. Global loss of vagility alters a key ecological trait of animals that affects not only population persistence but also ecosystem processes such as predator-prey interactions, nutrient cycling, and disease transmission.
University of Cambridge1, Australian National University2, Norwegian Institute of Public Health3, Utrecht University4, University of Tromsø5, The George Institute for Global Health6, Johns Hopkins University7, University of Oxford8, National Institutes of Health9, University of Copenhagen10, Copenhagen University Hospital11, University of Western Australia12, Fiona Stanley Hospital13, Harry Perkins Institute of Medical Research14, University of London15, Lund University16, University of Pittsburgh17, French Institute of Health and Medical Research18, University College London19, University of Ulm20, Technische Universität München21, University of Padua22, University of Southampton23, German Cancer Research Center24, Erasmus University Medical Center25, Umeå University26, Cardiff University27, Greifswald University Hospital28, Aarhus University29, Portland State University30, University of New South Wales31, National and Kapodistrian University of Athens32, Harvard University33, University of Hawaii34, Columbia University35, University of Iowa36, Duke University37, Yamagata University38, Tuskegee University39, University of Helsinki40, University of Oulu41, Medical University of South Carolina42, Kaiser Permanente43, University of Washington44, University of Groningen45, University of Granada46, Yale University47, Prevention Institute48, University of Edinburgh49, Uppsala University50, Basque Government51, Royal Prince Alfred Hospital52, Kyushu University53, Harokopio University54, University of California, San Diego55, VU University Medical Center56, Aalborg University57, University of Eastern Finland58, Laval University59, University of Vermont60, Wake Forest University61, Wake Forest Baptist Medical Center62, Kanazawa Medical University63, Baker IDI Heart and Diabetes Institute64, Heidelberg University65, Istituto Superiore di Sanità66, Pasteur Institute67, City College of New York68, Howard University69, University of Glasgow70, International Agency for Research on Cancer71, University of Bristol72, University of Auckland73
TL;DR: Current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week, and data support limits for alcohol consumption that are lower than those recommended in most current guidelines.
TL;DR: This Report provides a comprehensive description of all virus taxa covering virus structure, genome structure, biology and phylogenetics, and is replacing the previous hard-copy edition with a completely open access, continuously updated publication.
Abstract: The International Committee on Taxonomy of Viruses (ICTV) is charged with the task of developing, refining, and maintaining a universal virus taxonomy. This task encompasses the classification of virus species and higher-level taxa according to the genetic and biological properties of their members; naming virus taxa; maintaining a database detailing the currently approved taxonomy; and providing the database, supporting proposals, and other virus-related information from an open-access, public web site. The ICTV web site (http://ictv.global) provides access to the current taxonomy database in online and downloadable formats, and maintains a complete history of virus taxa back to the first release in 1971. The ICTV has also published the ICTV Report on Virus Taxonomy starting in 1971. This Report provides a comprehensive description of all virus taxa covering virus structure, genome structure, biology and phylogenetics. The ninth ICTV report, published in 2012, is available as an open-access online publication from the ICTV web site. The current, 10th report (http://ictv.global/report/), is being published online, and is replacing the previous hard-copy edition with a completely open access, continuously updated publication. No other database or resource exists that provides such a comprehensive, fully annotated compendium of information on virus taxa and taxonomy.
TL;DR: Pneumococcal deaths declined by 51% and Hib deaths by 90% from 2000 to 2015 and progress towards further reducing the global burden of Hib and pneumococcal disease burden will depend on the efforts of a few large countries in Africa and Asia.
Mayo Clinic1, Wayne State University2, University of Glasgow3, University of Oxford4, Harvard University5, Yokohama City University6, Mario Negri Institute for Pharmacological Research7, Duke University8, University of Tokyo9, Pierre-and-Marie-Curie University10, University Hospital Southampton NHS Foundation Trust11
TL;DR: Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population.
Abstract: Background Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. Methods We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. Results After 3263 events of disease recurrence or death had been reported in 12,834 patients, the n...
TL;DR: This guide gives a broad overview of the chemokines and chemokine receptor families; summarizes the complex physical interactions that occur in theChemokine network; and, using specific examples, discusses general principles of Chemokine function, focusing particularly on their ability to direct leukocyte migration.
Abstract: The chemokines (or chemotactic cytokines) are a large family of small, secreted proteins that signal through cell surface G protein-coupled heptahelical chemokine receptors. They are best known for their ability to stimulate the migration of cells, most notably white blood cells (leukocytes). Consequently, chemokines play a central role in the development and homeostasis of the immune system, and are involved in all protective or destructive immune and inflammatory responses. Classically viewed as inducers of directed chemotactic migration, it is now clear that chemokines can stimulate a variety of other types of directed and undirected migratory behavior, such as haptotaxis, chemokinesis, and haptokinesis, in addition to inducing cell arrest or adhesion. However, chemokine receptors on leukocytes can do more than just direct migration, and these molecules can also be expressed on, and regulate the biology of, many nonleukocytic cell types. Chemokines are profoundly affected by post-translational modification, by interaction with the extracellular matrix (ECM), and by binding to heptahelical 'atypical' chemokine receptors that regulate chemokine localization and abundance. This guide gives a broad overview of the chemokine and chemokine receptor families; summarizes the complex physical interactions that occur in the chemokine network; and, using specific examples, discusses general principles of chemokine function, focusing particularly on their ability to direct leukocyte migration.
TL;DR: It is proposed that defeat and entrapment drive the emergence of suicidal ideation and that a group of factors, entitled volitional moderators (VMs), govern the transition from suicidal Ideation to suicidal behaviour.
Abstract: Suicide is a major public health concern accounting for 800 000 deaths globally each year. Although there have been many advances in understanding suicide risk in recent decades, our ability to pre...
TL;DR: Efforts to identify, manage, and prevent frailty should include middle-aged individuals with multimorbidity, in whom frailty is significantly associated with mortality, even after adjustment for number of long-term conditions, sociodemographics, and lifestyle.
Abstract: Summary Background Frailty is associated with older age and multimorbidity (two or more long-term conditions); however, little is known about its prevalence or effects on mortality in younger populations. This paper aims to examine the association between frailty, multimorbidity, specific long-term conditions, and mortality in a middle-aged and older aged population. Methods Data were sourced from the UK Biobank. Frailty phenotype was based on five criteria (weight loss, exhaustion, grip strength, low physical activity, slow walking pace). Participants were deemed frail if they met at least three criteria, pre-frail if they fulfilled one or two criteria, and not frail if no criteria were met. Sociodemographic characteristics and long-term conditions were examined. The outcome was all-cause mortality, which was measured at a median of 7 years follow-up. Multinomial logistic regression compared sociodemographic characteristics and long-term conditions of frail or pre-frail participants with non-frail participants. Cox proportional hazards models examined associations between frailty or pre-frailty and mortality. Results were stratified by age group (37–45, 45–55, 55–65, 65–73 years) and sex, and were adjusted for multimorbidity count, socioeconomic status, body-mass index, smoking status, and alcohol use. Findings 493 737 participants aged 37–73 years were included in the study, of whom 16 538 (3%) were considered frail, 185 360 (38%) pre-frail, and 291 839 (59%) not frail. Frailty was significantly associated with multimorbidity (prevalence 18% [4435/25 338] in those with four or more long-term conditions; odds ratio [OR] 27·1, 95% CI 25·3–29·1) socioeconomic deprivation, smoking, obesity, and infrequent alcohol consumption. The top five long-term conditions associated with frailty were multiple sclerosis (OR 15·3; 99·75% CI 12·8–18·2); chronic fatigue syndrome (12·9; 11·1–15·0); chronic obstructive pulmonary disease (5·6; 5·2–6·1); connective tissue disease (5·4; 5·0–5·8); and diabetes (5·0; 4·7–5·2). Pre-frailty and frailty were significantly associated with mortality for all age strata in men and women (except in women aged 37–45 years) after adjustment for confounders. Interpretation Efforts to identify, manage, and prevent frailty should include middle-aged individuals with multimorbidity, in whom frailty is significantly associated with mortality, even after adjustment for number of long-term conditions, sociodemographics, and lifestyle. Research, clinical guidelines, and health-care services must shift focus from single conditions to the requirements of increasingly complex patient populations. Funding CSO Catalyst Grant and National Health Service Research for Scotland Career Research Fellowship.
TL;DR: In this article, the authors determine the association between non-communicable illnesses and HIV-related deaths in people with HIV and cardiovascular diseases, and show that most deaths in persons with HIV are now attributable to noncommunicable diseases, especially cardiovascular diseases.
Abstract: Background: With advances in antiretroviral therapy, most deaths in people with HIV are now attributable to noncommunicable illnesses, especially cardiovascular disease. We determine the associatio...
TL;DR: This large, multi-ethnic genome-wide association study identifies 97 loci significantly associated with atrial fibrillation that are enriched for genes involved in cardiac development, electrophysiology, structure and contractile function.
Abstract: Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
TL;DR: The epidemiology of Helicobacter pylori infection is poorly understood and new treatments are needed to better understand this poorly understood disease.
Abstract: Background:
The epidemiology of Helicobacter pylori infection is poorly understood.
Aim:
To establish the reported regional and national prevalence of H. pylori infection, stratified by age and gender.
Methods:
All relevant English publications from 2000 to 2017 cited by PubMed and Scopus were retrieved using comprehensive combinations of keywords. The overall prevalence of H. pylori was estimated using both random effect and fixed effect meta-analyses, and presented as prevalence rate (% and 95% CI). The analyses were extended by separation into gender and age groups.
Results:
A total of 14 056 records were obtained initially. After applying exclusion criteria in several steps, 183 studies were selected. Analysis of 410 879 participants from 73 countries in six continents revealed an overall prevalence of 44.3% (95% CI: 40.9-47.7) worldwide. This rate ranged from 50.8% (95% CI: 46.8-54.7) in developing countries compared with 34.7% (95% CI: 30.2-39.3) in developed countries. The global H. pylori infection rate was 42.7% (95% CI: 39-46.5) in females compared to 46.3% (95% CI: 42.1-50.5) in males. The prevalence in adults (≥18 years) was significantly higher than in children (48.6% [95% CI: 43.8-53.5] vs 32.6% [95% CI: 28.4-36.8], respectively). There was a statistically nonsignificant decrease in the prevalence in 2009-2016 compared with the 2000-2009 period.
Conclusions:
The observed differences between countries appear to be due to economic and social conditions. H. pylori infection can be a benchmark for the socioeconomic and health status of a country. Further studies are suggested to investigate the natural history of the acquisition of H. pylori infection from childhood into adult life.
Ruhr University Bochum1, Paris Descartes University2, University of Toronto3, University of California, San Diego4, University of Washington5, Charité6, Medical University of Vienna7, VU University Amsterdam8, Ghent University Hospital9, University of Oxford10, University of California, San Francisco11, University of Leeds12, University Health Network13, University of Glasgow14, University College London15, University of Pennsylvania16, University of Rochester Medical Center17, Erasmus University Rotterdam18, Katholieke Universiteit Leuven19, Leiden University Medical Center20
TL;DR: There was broad agreement, now better supported by data than in 2012, that remission/inactive disease and, alternatively, low/minimal disease activity are the principal targets for the treatment of PsA.
Abstract: Therapeutic targets have been defined for axial and peripheral spondyloarthritis (SpA) in 2012, but the evidence for these recommendations was only of indirect nature. These recommendations were re-evaluated in light of new insights. Based on the results of a systematic literature review and expert opinion, a task force of rheumatologists, dermatologists, patients and a health professional developed an update of the 2012 recommendations. These underwent intensive discussions, on site voting and subsequent anonymous electronic voting on levels of agreement with each item. A set of 5 overarching principles and 11 recommendations were developed and voted on. Some items were present in the previous recommendations, while others were significantly changed or newly formulated. The 2017 task force arrived at a single set of recommendations for axial and peripheral SpA, including psoriatic arthritis (PsA). The most exhaustive discussions related to whether PsA should be assessed using unidimensional composite scores for its different domains or multidimensional scores that comprise multiple domains. This question was not resolved and constitutes an important research agenda. There was broad agreement, now better supported by data than in 2012, that remission/inactive disease and, alternatively, low/minimal disease activity are the principal targets for the treatment of PsA. As instruments to assess the patients on the path to the target, the Ankylosing Spondylitis Disease Activity Score (ASDAS) for axial SpA and the Disease Activity index for PSoriatic Arthritis (DAPSA) and Minimal Disease Activity (MDA) for PsA were recommended, although not supported by all. Shared decision-making between the clinician and the patient was seen as pivotal to the process. The task force defined the treatment target for SpA as remission or low disease activity and developed a large research agenda to further advance the field.
TL;DR: The opportunities and challenges faced for the further development of mitochondrial pharmacology for common pathologies are discussed, and a small number of agents have entered clinical trials.
Abstract: Although the development of mitochondrial therapies has largely focused on diseases caused by mutations in mitochondrial DNA or in nuclear genes encoding mitochondrial proteins, it has been found that mitochondrial dysfunction also contributes to the pathology of many common disorders, including neurodegeneration, metabolic disease, heart failure, ischaemia-reperfusion injury and protozoal infections. Mitochondria therefore represent an important drug target for these highly prevalent diseases. Several strategies aimed at therapeutically restoring mitochondrial function are emerging, and a small number of agents have entered clinical trials. This Review discusses the opportunities and challenges faced for the further development of mitochondrial pharmacology for common pathologies.
TL;DR: The current evidence for aberrant predictive coding is reviewed and challenges for this canonical predictive coding account of psychosis are discussed, portending a framework for psychosis more equipped to deal with its many manifestations.
TL;DR: An organic synthesis robot is presented that can perform chemical reactions and analysis faster than they can be performed manually, as well as predict the reactivity of possible reagent combinations after conducting a small number of experiments, thus effectively navigating chemical reaction space.
Abstract: The discovery of chemical reactions is an inherently unpredictable and time-consuming process1. An attractive alternative is to predict reactivity, although relevant approaches, such as computer-aided reaction design, are still in their infancy2. Reaction prediction based on high-level quantum chemical methods is complex3, even for simple molecules. Although machine learning is powerful for data analysis4,5, its applications in chemistry are still being developed6. Inspired by strategies based on chemists’ intuition7, we propose that a reaction system controlled by a machine learning algorithm may be able to explore the space of chemical reactions quickly, especially if trained by an expert8. Here we present an organic synthesis robot that can perform chemical reactions and analysis faster than they can be performed manually, as well as predict the reactivity of possible reagent combinations after conducting a small number of experiments, thus effectively navigating chemical reaction space. By using machine learning for decision making, enabled by binary encoding of the chemical inputs, the reactions can be assessed in real time using nuclear magnetic resonance and infrared spectroscopy. The machine learning system was able to predict the reactivity of about 1,000 reaction combinations with accuracy greater than 80 per cent after considering the outcomes of slightly over 10 per cent of the dataset. This approach was also used to calculate the reactivity of published datasets. Further, by using real-time data from our robot, these predictions were followed up manually by a chemist, leading to the discovery of four reactions.
TL;DR: In this paper, the authors combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci associated with general cognitive function.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.