Showing papers by "Medical Research Council published in 2016"
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.
For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.
Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.
5,187 citations
University of Pennsylvania1, Medical Research Council2, Wellcome Trust Sanger Institute3, European Bioinformatics Institute4, Medical University of Vienna5, Hospital for Sick Children6, University of California, Davis7, National Research Council8, Harvard University9, Baylor College of Medicine10, Nanjing University11, Broad Institute12, University of Strasbourg13, Children's Hospital Oakland Research Institute14, Technische Universität München15, Francis Crick Institute16
TL;DR: It is shown that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts and reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background.
Abstract: Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.
928 citations
Technical University of Madrid1, Carlos III Health Institute2, Ghent University3, University of Zaragoza4, University of Copenhagen5, University of Tromsø6, Harokopio University7, Robert Koch Institute8, Medical Research Council9, Medical University of Graz10, VU University Amsterdam11, University of Iceland12, National Institutes of Health13, University of Helsinki14, Loyola University Chicago15, University College Cork16
TL;DR: Vitamin D deficiency is evident throughout the European population at prevalence rates that are concerning and that require action from a public health perspective, and what direction these strategies take will depend on European policy.
830 citations
University of New Mexico1, Los Alamos National Laboratory2, KAIST3, Francis Crick Institute4, Katholieke Universiteit Leuven5, Wellcome Trust Sanger Institute6, National Health Service7, Kyoto University8, University of Tokyo9, University of Cambridge10, Medical Research Council11, King's College London12
TL;DR: The results are consistent with the proposition that smoking increases cancer risk by increasing the somatic mutation load, although direct evidence for this mechanism is lacking in some smoking-related cancer types.
Abstract: Tobacco smoking increases the risk of at least 17 classes of human cancer. We analyzed somatic mutations and DNA methylation in 5243 cancers of types for which tobacco smoking confers an elevated risk. Smoking is associated with increased mutation burdens of multiple distinct mutational signatures, which contribute to different extents in different cancers. One of these signatures, mainly found in cancers derived from tissues directly exposed to tobacco smoke, is attributable to misreplication of DNA damage caused by tobacco carcinogens. Others likely reflect indirect activation of DNA editing by APOBEC cytidine deaminases and of an endogenous clocklike mutational process. Smoking is associated with limited differences in methylation. The results are consistent with the proposition that smoking increases cancer risk by increasing the somatic mutation load, although direct evidence for this mechanism is lacking in some smoking-related cancer types.
762 citations
University of Manchester1, University of New South Wales2, University College London3, Cardiff University4, University College Hospital5, James Cook University Hospital6, Belfast City Hospital7, Qatar Airways8, Medical Research Council9, Bangor University10, Hamad Medical Corporation11, Royal Derby Hospital12, Derriford Hospital13, Royal Free Hospital14, St. Michael's GAA, Sligo15, St Bartholomew's Hospital16, Harvard University17, St Mary's Hospital18, University Hospital of Wales19, National Health Service20, Public Health England21, Nottingham City Hospital22, Queen Alexandra Hospital23, Brighton and Sussex Medical School24, London School of Economics and Political Science25
TL;DR: Although the mortality reduction was not significant in the primary analysis, it was noted a significant mortality reduction with MMS when prevalent cases were excluded, and encouraging evidence of a mortality reduction in years 7–14 was noted.
756 citations
TL;DR: The whole blood tuberculosis risk signature prospectively identified people at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease.
609 citations
TL;DR: A quantitative molecular diagnostic approach improved population-level and case-level characterisation of the causes of diarrhoea and indicated a high burden of disease associated with six pathogens, for which targeted treatment should be prioritised.
579 citations
Children's Medical Research Institute1, University of Birmingham2, University College Cork3, South Dakota State University4, Mayo Clinic5, Osaka University6, Rambam Health Care Campus7, University of Manchester8, University of the Philippines Manila9, University of Zurich10, University of the Witwatersrand11, Boston Children's Hospital12, Ahmadu Bello University13, Sanjay Gandhi Post Graduate Institute of Medical Sciences14, Zhejiang University15, Medical Research Council16, Karolinska Institutet17, All India Institute of Medical Sciences18, University College London19, University of Lagos20
TL;DR: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents and implementation of international rickets prevention programs, including supplementation and food fortification is urgently required.
Abstract: Background: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, an
486 citations
Harvard University1, Broad Institute2, University of Oslo3, Oslo University Hospital4, University of Helsinki5, Boston Children's Hospital6, University of Tartu7, Illumina8, Brigham and Women's Hospital9, Charité10, deCODE genetics11, Medical Research Council12, VU University Amsterdam13, Leiden University14, Helsinki University Central Hospital15, Ludwig Maximilian University of Munich16, University of Tübingen17, Karolinska Institutet18, QIMR Berghofer Medical Research Institute19, University of Ulm20, University of Oulu21, King's College London22, Erasmus University Medical Center23, University of Tampere24, University of Duisburg-Essen25, Washington University in St. Louis26, University Medical Center Groningen27, Wellcome Trust Sanger Institute28, University of Oxford29, John Radcliffe Hospital30, Max Planck Society31, University of Kiel32, Technische Universität München33, National Institutes of Health34, Norwegian Institute of Public Health35, University of Copenhagen36, Lundbeck37, Mental Health Services38, University of Turku39, Turku University Hospital40, University of Hamburg41, St George's, University of London42, University of Iceland43, Queensland University of Technology44
TL;DR: For example, the authors identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to date is the first to be identified on chromosome X.
Abstract: Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.
471 citations
TL;DR: A meta-analysis of genome-wide association studies for estimated glomerular filtration rate suggests that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
409 citations
French Institute of Health and Medical Research1, University of California, Los Angeles2, University of California, San Diego3, King's College London4, Charité5, University of Illinois at Chicago6, University of Freiburg7, Utrecht University8, University of Pittsburgh9, Medical Research Council10, Centre national de la recherche scientifique11, Heidelberg University12, University of Glasgow13, Johns Hopkins University14, Yale University15, University of Miami16
TL;DR: A broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia is provided, including 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder.
Abstract: Despite a lack of recent progress in the treatment of schizophrenia, our understanding of its genetic and environmental causes has considerably improved, and their relationship to aberrant patterns of neurodevelopment has become clearer. This raises the possibility that 'disease-modifying' strategies could alter the course to — and of — this debilitating disorder, rather than simply alleviating symptoms. A promising window for course-altering intervention is around the time of the first episode of psychosis, especially in young people at risk of transition to schizophrenia. Indeed, studies performed in both individuals at risk of developing schizophrenia and rodent models for schizophrenia suggest that pre-diagnostic pharmacotherapy and psychosocial or cognitive-behavioural interventions can delay or moderate the emergence of psychosis. Of particular interest are 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder. This Review aims to provide a broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia.
TL;DR: Evidence suggests that attention to optimum health early in life might benefit cognitive health late in life, and upstream primary prevention has the largest effect on reduction of later dementia occurrence and disability.
Abstract: Summary Dementia is receiving increasing attention from governments and politicians. Epidemiological research based on western European populations done 20 years ago provided key initial evidence for dementia policy making, but these estimates are now out of date because of changes in life expectancy, living conditions, and health profiles. To assess whether dementia occurrence has changed during the past 20–30 years, investigators of five different studies done in western Europe (Sweden [Stockholm and Gothenburg], the Netherlands [Rotterdam], the UK [England], and Spain [Zaragoza]) have compared dementia occurrence using consistent research methods between two timepoints in well-defined geographical areas. Findings from four of the five studies showed non-significant changes in overall dementia occurrence. The only significant reduction in overall prevalence was found in the study done in the UK, powered and designed explicitly from its outset to detect change across generations (decrease in prevalence of 22%; p=0·003). Findings from the study done in Zaragoza (Spain) showed a significant reduction in dementia prevalence in men (43%; p=0·0002). The studies estimating incidence done in Stockholm and Rotterdam reported non-significant reductions. Such reductions could be the outcomes from earlier population-level investments such as improved education and living conditions, and better prevention and treatment of vascular and chronic conditions. This evidence suggests that attention to optimum health early in life might benefit cognitive health late in life. Policy planning and future research should be balanced across primary (policies reducing risk and increasing cognitive reserve), secondary (early detection and screening), and tertiary (once dementia is present) prevention. Each has their place, but upstream primary prevention has the largest effect on reduction of later dementia occurrence and disability.
TL;DR: Although impossible to prove causality with any single approach, MR is a highly cost-effective strategy for prioritizing intervention targets for disease prevention and for strengthening the evidence base for public health policy.
TL;DR: The study provides new insights into the reproductive risks of PID and the role of CT, and establishes a set of interpretations of the major studies and study designs, under which a coherent set of estimates can be generated.
Abstract: Background and objectives The evidence base supporting the National Chlamydia Screening Programme, initiated in 2003, has been questioned repeatedly, with little consensus on modelling assumptions, parameter values or evidence sources to be used in cost-effectiveness analyses. The purpose of this project was to assemble all available evidence on the prevalence and incidence of Chlamydia trachomatis (CT) in the UK and its sequelae, pelvic inflammatory disease (PID), ectopic pregnancy (EP) and tubal factor infertility (TFI) to review the evidence base in its entirety, assess its consistency and, if possible, arrive at a coherent set of estimates consistent with all the evidence. Methods Evidence was identified using 'high-yield' strategies. Bayesian Multi-Parameter Evidence Synthesis models were constructed for separate subparts of the clinical and population epidemiology of CT. Where possible, different types of data sources were statistically combined to derive coherent estimates. Where evidence was inconsistent, evidence sources were re-interpreted and new estimates derived on a post-hoc basis. Results An internally coherent set of estimates was generated, consistent with a multifaceted evidence base, fertility surveys and routine UK statistics on PID and EP. Among the key findings were that the risk of PID (symptomatic or asymptomatic) following an untreated CT infection is 17.1% [95% credible interval (CrI) 6% to 29%] and the risk of salpingitis is 7.3% (95% CrI 2.2% to 14.0%). In women aged 16-24 years, screened at annual intervals, at best, 61% (95% CrI 55% to 67%) of CT-related PID and 22% (95% CrI 7% to 43%) of all PID could be directly prevented. For women aged 16-44 years, the proportions of PID, EP and TFI that are attributable to CT are estimated to be 20% (95% CrI 6% to 38%), 4.9% (95% CrI 1.2% to 12%) and 29% (95% CrI 9% to 56%), respectively. The prevalence of TFI in the UK in women at the end of their reproductive lives is 1.1%: this is consistent with all PID carrying a relatively high risk of reproductive damage, whether diagnosed or not. Every 1000 CT infections in women aged 16-44 years, on average, gives rise to approximately 171 episodes of PID and 73 of salpingitis, 2.0 EPs and 5.1 women with TFI at age 44 years. Conclusions and research recommendations The study establishes a set of interpretations of the major studies and study designs, under which a coherent set of estimates can be generated. CT is a significant cause of PID and TFI. CT screening is of benefit to the individual, but detection and treatment of incident infection may be more beneficial. Women with lower abdominal pain need better advice on when to seek early medical attention to avoid risk of reproductive damage. The study provides new insights into the reproductive risks of PID and the role of CT. Further research is required on the proportions of PID, EP and TFI attributable to CT to confirm predictions made in this report, and to improve the precision of key estimates. The cost-effectiveness of screening should be re-evaluated using the findings of this report. Funding The Medical Research Council grant G0801947.
Wellcome Trust Sanger Institute1, University of Nottingham2, Katholieke Universiteit Leuven3, King Abdulaziz Medical City4, Harvard University5, Saarland University6, University of Manchester7, Central Manchester University Hospitals NHS Foundation Trust8, Charité9, University of Oxford10, Glenfield Hospital11, London North West Healthcare NHS Trust12, Leipzig University13, University of Cambridge14, Leeds Teaching Hospitals NHS Trust15, University of London16, Dresden University of Technology17, Salisbury NHS Foundation Trust18, Princess Anne Hospital19, University of Southampton20, Western General Hospital21, Hospital for Sick Children22, National Institutes of Health23, St. Michael's GAA, Sligo24, National Guard Health Affairs25, Cambridge University Hospitals NHS Foundation Trust26, Boston Children's Hospital27, Guy's and St Thomas' NHS Foundation Trust28, John Radcliffe Hospital29, NHS Blood and Transplant30, University of Freiburg31, University of Erlangen-Nuremberg32, Newcastle upon Tyne Hospitals NHS Foundation Trust33, Imperial College London34, Newcastle University35, King Saud bin Abdulaziz University for Health Sciences36, Medical Research Council37
TL;DR: Exome sequenced 1,891 probands and identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1, finding evidence for distinct genetic architectures underlying the low sibling recurrence risk in S- CHD and NS-CHd.
Abstract: Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.
TL;DR: It is shown that mtDNA haplotype profoundly influences mitochondrial proteostasis and reactive oxygen species generation, insulin signalling, obesity, and ageing parameters including telomere shortening and mitochondrial dysfunction, resulting in profound differences in health longevity between conplastic strains.
Abstract: Human mitochondrial DNA (mtDNA) shows extensive within-population sequence variability. Many studies suggest that mtDNA variants may be associated with ageing or diseases, although mechanistic evidence at the molecular level is lacking. Mitochondrial replacement has the potential to prevent transmission of disease-causing oocyte mtDNA. However, extension of this technology requires a comprehensive understanding of the physiological relevance of mtDNA sequence variability and its match with the nuclear-encoded mitochondrial genes. Studies in conplastic animals allow comparison of individuals with the same nuclear genome but different mtDNA variants, and have provided both supporting and refuting evidence that mtDNA variation influences organismal physiology. However, most of these studies did not confirm the conplastic status, focused on younger animals, and did not investigate the full range of physiological and phenotypic variability likely to be influenced by mitochondria. Here we systematically characterized conplastic mice throughout their lifespan using transcriptomic, proteomic, metabolomic, biochemical, physiological and phenotyping studies. We show that mtDNA haplotype profoundly influences mitochondrial proteostasis and reactive oxygen species generation, insulin signalling, obesity, and ageing parameters including telomere shortening and mitochondrial dysfunction, resulting in profound differences in health longevity between conplastic strains.
University of Exeter1, University of Tartu2, Medical Research Council3, Ludwig Maximilian University of Munich4, University of Edinburgh5, University of Lübeck6, Korea University7, Seoul National University Bundang Hospital8, University of Queensland9, University of Pennsylvania10, Erasmus University Rotterdam11
TL;DR: The total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans, are brought to light.
Abstract: Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.
University of Basel1, Swiss Tropical and Public Health Institute2, Tunis University3, Fudan University4, University of Bern5, Sichuan University6, University of California, San Francisco7, Ifakara Health Institute8, University of Ghana9, Makerere University10, University of Amsterdam11, Case Western Reserve University12, Auckland City Hospital13, RMIT University14, University of Cape Town15, Francis Crick Institute16, Imperial College London17, Papua New Guinea Institute of Medical Research18, Institute of Tropical Medicine Antwerp19, Tartu University Hospital20, University of Tübingen21, University of Yaoundé I22, University of Arkansas for Medical Sciences23, Jomo Kenyatta University of Agriculture and Technology24, Aga Khan University Hospital25, Medical Research Council26, University of the Witwatersrand27, National Institute for Medical Research28, Ludwig Maximilian University of Munich29, Public Health Agency of Sweden30, Vilnius University31, Instituto de Medicina Tropical Alexander von Humboldt32, Brown University33, Moi University34, Pasteur Institute35, Spanish National Research Council36
TL;DR: It is shown that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists, and further support a European origin for the most common generalist sublineage.
Abstract: Generalist and specialist species differ in the breadth of their ecological niches Little is known about the niche width of obligate human pathogens Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists Our data further support a European origin for the most common generalist sublineage Hence, the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration
University of Oxford1, Wellcome Trust Sanger Institute2, Mahidol University3, Medical Research Council4, National Institutes of Health5, University for Development Studies6, Pasteur Institute7, University of Buea8, University of Ghana9, University of Antwerp10, National Institute for Medical Research11, Walter and Eliza Hall Institute of Medical Research12, University of Melbourne13, Kenya Medical Research Institute14, University of Tübingen15, University of London16, New York University17, Liverpool School of Tropical Medicine18, University of Bamako19, Purdue University20
TL;DR: It is shown that African kelch13 mutations have originated locally, and that kelCh13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes.
Abstract: Malaria is an infectious disease caused by a microscopic parasite called Plasmodium, which is transferred between humans by mosquitos. One species of malaria parasite called Plasmodium falciparum can cause particularly severe and life-threatening forms of the disease. Currently, the most widely used treatment for P. falciparum infections is artemisinin combination therapy, a treatment that combines the drug artemisinin (or a closely related molecule) with another antimalarial drug. However, resistance to artemisinin has started to spread throughout Southeast Asia. Artemisinin resistance is caused by mutations in a parasite gene called kelch13, and researchers have identified over 20 different mutations in P. falciparum that confer artemisinin resistance. The diversity of mutations involved, and the fact that the same mutation can arise independently in different locations, make it difficult to track the spread of resistance using conventional molecular marker approaches. Here, Amato, Miotto et al. sequenced the entire genomes of more than 3,000 clinical samples of P. falciparum from Southeast Asia and Africa, collected as part of a global network of research groups called the MalariaGEN Plasmodium falciparum Community Project. Amato, Miotto et al. found that African parasites had independently acquired many of the same kelch13 mutations that are known to cause resistance to artemisinin in Southeast Asia. However the kelch13 mutations seen in Africa remained at low levels in the parasite population, and appeared to be under much less pressure for evolutionary selection than those found in Southeast Asia. These findings demonstrate that the emergence and spread of resistance to antimalarial drugs does not depend solely on the mutational process, but also on other factors that influence whether the mutations will spread in the population. Understanding how this is affected by different patterns of drug treatments and other environmental conditions will be important in developing more effective strategies for combating malaria.
Centers for Disease Control and Prevention1, RMIT University2, University of Edinburgh3, Public Health Foundation of India4, Children's Hospital at Westmead5, Chinese Center for Disease Control and Prevention6, Addis Ababa University7, University of Auckland8, Medical Research Council9, University of Otago10, University of Ghana11, National Institute of Virology12, Pasteur Institute13, Universidad Autónoma de San Luis Potosí14, Federal Ministry of Health15, Research Institute for Tropical Medicine16, University of Pretoria17, Thailand Ministry of Public Health18
TL;DR: Influenza-associated hospitalization rates were more than three times higher in developing countries than in industrialized countries (150/ 100,000 children/year versus 48/100,000); however, differences in hospitalization practices between settings are an important limitation in interpreting these findings.
Abstract: BACKGROUND: The global burden of pediatric severe respiratory illness is substantial, and influenza viruses contribute to this burden. Systematic surveillance and testing for influenza among hospitalized children has expanded globally over the past decade. However, only a fraction of the data has been used to estimate influenza burden. In this analysis, we use surveillance data to provide an estimate of influenza-associated hospitalizations among children worldwide. METHODS AND FINDINGS: We aggregated data from a systematic review (n = 108) and surveillance platforms (n = 37) to calculate a pooled estimate of the proportion of samples collected from children hospitalized with respiratory illnesses and positive for influenza by age group (<6 mo, <1 y, <2 y, <5 y, 5-17 y, and <18 y). We applied this proportion to global estimates of acute lower respiratory infection hospitalizations among children aged <1 y and <5 y, to obtain the number and per capita rate of influenza-associated hospitalizations by geographic region and socio-economic status. Influenza was associated with 10% (95% CI 8%-11%) of respiratory hospitalizations in children <18 y worldwide, ranging from 5% (95% CI 3%-7%) among children <6 mo to 16% (95% CI 14%-20%) among children 5-17 y. On average, we estimated that influenza results in approximately 374,000 (95% CI 264,000 to 539,000) hospitalizations in children <1 y-of which 228,000 (95% CI 150,000 to 344,000) occur in children <6 mo-and 870,000 (95% CI 610,000 to 1,237,000) hospitalizations in children <5 y annually. Influenza-associated hospitalization rates were more than three times higher in developing countries than in industrialized countries (150/100,000 children/year versus 48/100,000). However, differences in hospitalization practices between settings are an important limitation in interpreting these findings. CONCLUSIONS: Influenza is an important contributor to respiratory hospitalizations among young children worldwide. Increasing influenza vaccination coverage among young children and pregnant women could reduce this burden and protect infants <6 mo.
TL;DR: It is suggested that the RMET measures emotion recognition rather than ToM ability and support the alexithymia hypothesis of emotion-related deficits in ASD.
Abstract: The ability to represent mental states (theory of mind [ToM]) is crucial in understanding individual differences in social ability and social impairments evident in conditions such as autism spectrum disorder (ASD). The Reading the Mind in the Eyes Test (RMET) is a popular measure of ToM ability, validated in part by the poor performance of those with ASD. However, the RMET requires recognition of facial emotion, which is impaired in those with alexithymia, which frequently co-occurs with ASD. Thus, it is unclear whether the RMET indexes emotion recognition, associated with alexithymia, or ToM, associated with ASD. We therefore investigated the independent contributions of ASD and alexithymia to performance on the RMET. ASD and alexithymia-matched control participants did not differ on RMET performance, whereas ASD participants demonstrated impaired performance on an alternative test of ToM, the Movie for Assessment of Social Cognition (MASC). Furthermore, alexithymia, but not ASD diagnosis, significantly influenced RMET performance but did not affect MASC performance. These results suggest that the RMET measures emotion recognition rather than ToM ability and support the alexithymia hypothesis of emotion-related deficits in ASD. (PsycINFO Database Record
TL;DR: The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases and health economic analysis suggests that the intervention would be cost effective.
Abstract: Background: Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial. Methods: The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction. Results: 247 354 individuals aged 50–75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm3 or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm3 at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569). Conclusions: The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective—this needs to be confirmed using data on observed lung cancer mortality reduction.
TL;DR: The GPR is a more accurate routine laboratory marker than APRI and Fib-4 to stage liver fibrosis in patients with CHB in West Africa and represents a simple and inexpensive alternative to liver biopsy and Fibroscan in sub-Saharan Africa.
Abstract: Background Simple and inexpensive non-invasive fibrosis tests are highly needed but have been poorly studied in sub-Saharan Africa. Methods Using liver histology as a gold standard, we developed a novel index using routine laboratory tests to predict significant fibrosis in patients with chronic HBV infection in The Gambia, West Africa. We prospectively assessed the diagnostic accuracy of the novel index, Fibroscan, aspartate transaminase-to-platelet ratio index (APRI), and Fib-4 in Gambian patients with CHB (training set) and also in French and Senegalese CHB cohorts (validation sets). Results Of 135 consecutive treatment-naive patients with CHB who had liver biopsy, 39% had significant fibrosis (Metavir fibrosis stage ≥F2) and 15% had cirrhosis (F4). In multivariable analysis, gamma-glutamyl transpeptidase (GGT) and platelet count were independent predictors of significant fibrosis. Consequently, GGT-to-platelet ratio (GPR) was developed. In The Gambia, the area under the receiver operating characteristic curve (AUROC) of the GPR was significantly higher than that of APRI and Fib-4 to predict ≥F2, ≥F3 and F4. In Senegal, the AUROC of GPR was significantly better than Fib-4 and APRI for ≥F2 (0.73, 95% CI 0.59 to 0.86) and better than Fib-4 and Fibroscan for ≥F3 (0.93, 0.87 to 0.99). In France, the AUROC of GPR to diagnose ≥F2 (0.72, 95% CI 0.59 to 0.85) and F4 (0.87, 0.76 to 0.98) was equivalent to that of APRI and Fib-4. Conclusions The GPR is a more accurate routine laboratory marker than APRI and Fib-4 to stage liver fibrosis in patients with CHB in West Africa. The GPR represents a simple and inexpensive alternative to liver biopsy and Fibroscan in sub-Saharan Africa.
TL;DR: Expanding this approach to other physiological domains requires collecting and interpreting data from life course epidemiological studies, establishing normative measures of mobility, physical function, and physical activity, and connecting them with life course trajectories of the mobility-relevant physiological domains.
Abstract: Mobility is the most studied and most relevant physical ability affecting quality of life with strong prognostic value for disability and survival. Natural selection has built the "engine" of mobility with great robustness, redundancy, and functional reserve. Efficient patterns of mobility can be acquired during development even by children affected by severe impairments. Analogously, age-associated impairments in mobility-related physiological systems are compensated and overt limitations of mobility only occur when the severity can no longer be compensated. Mobility loss in older persons usually results from multiple impairments in the central nervous system, muscles, joints, and energetic and sensory physiological systems. Early preclinical changes in these physiological systems that precede mobility loss have been poorly studied. Peak performance, rate of decline, compensatory behaviors, or subclinical deterioration of physiological resources may cumulatively influence both timing of mobility loss and chances of recovery, but their role as risk factors has not been adequately characterized. Understanding the natural history of these early changes and intervening on them would likely be the most effective strategy to reduce the burden of disability in the population. For example, young women with low bone peak mass could be counseled to start strength resistance exercise to reduce their high risk of developing osteoporosis and fracture later in life. Expanding this approach to other physiological domains requires collecting and interpreting data from life course epidemiological studies, establishing normative measures of mobility, physical function, and physical activity, and connecting them with life course trajectories of the mobility-relevant physiological domains.
Erasmus University Rotterdam1, University of Pennsylvania2, University of Bristol3, Statens Serum Institut4, Ludwig Maximilian University of Munich5, University of Copenhagen6, University of Oxford7, University of Eastern Finland8, University of Turku9, University College London10, Queen Mary University of London11, University of Oulu12, Imperial College London13, VU University Amsterdam14, University of Helsinki15, University of Western Australia16, University Hospital of South Manchester NHS Foundation Trust17, Novo Nordisk18, Norwegian Institute of Public Health19, Pompeu Fabra University20, University of Leicester21, Harokopio University22, National Institute for Health and Welfare23, University of Groningen24, Leipzig University25, University of Warwick26, Broad Institute27, Harvard University28, Shanghai Jiao Tong University29, Dalian Maritime University30, University of Manchester31, University of Gothenburg32, Wellcome Trust Sanger Institute33, Hammersmith Hospital34, Medical Research Council35, University of South Australia36, Churchill Hospital37, Stanford University38, Cincinnati Children's Hospital Medical Center39, Creighton University40, University of Southern California41, Columbia University42
TL;DR: A meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores, identifies three novel loci that likely represent age-related differences in strength of the associations with bodymass index.
Abstract: A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.
TL;DR: Addition of bedaquiline to a background regimen was well tolerated and led to good outcomes in this clinically relevant patient cohort with MDR-TB.
Abstract: Bedaquiline, a diarylquinoline, improved cure rates when added to a multidrug-resistant tuberculosis (MDR-TB) treatment regimen in a previous placebo-controlled, phase 2 trial (TMC207-C208; NCT00449644). The current phase 2, multicenter, open-label, single-arm trial (TMC207-C209; NCT00910871) reported here was conducted to confirm the safety and efficacy of bedaquiline.Newly diagnosed or previously treated patients with MDR-TB (including pre-extensively drug-resistant (pre-XDR)-TB or extensively drug-resistant (XDR)-TB) received bedaquiline for 24 weeks with a background regimen of anti-TB drugs continued according to National TB Programme treatment guidelines. Patients were assessed during and up to 120 weeks after starting bedaquiline.Of 233 enrolled patients, 63.5% had MDR-TB, 18.9% had pre-XDR-TB and 16.3% had XDR-TB, with 87.1% having taken second-line drugs prior to enrolment. 16 patients (6.9%) died. 20 patients (8.6%) discontinued before week 24, most commonly due to adverse events or MDR-TB-related events. Adverse events were generally those commonly associated with MDR-TB treatment. In the efficacy population (n=205), culture conversion (missing outcome classified as failure) was 72.2% at 120 weeks, and 73.1%, 70.5% and 62.2% in MDR-TB, pre-XDR-TB and XDR-TB patients, respectively.Addition of bedaquiline to a background regimen was well tolerated and led to good outcomes in this clinically relevant patient cohort with MDR-TB.
TL;DR: The findings support the use of the authors' British grip strength centiles and their associated cut points in consensus definitions for sarcopenia and frailty across developed regions, but highlight the need for different cutpoints in developing regions.
Abstract: Background: weak grip strength is a key component of sarcopenia and is associated with subsequent disability and mortality. We have recently established life course normative data for grip strength in Great Britain, but it is unclear whether the cut points we derived for weak grip strength are suitable for use in other settings. Our objective was to investigate differences in grip strength by world region using our data as a reference standard.
Methods: we searched MEDLINE and EMBASE for reporting age- and gender-stratified normative data for grip strength. We extracted each item of normative data and converted it on to a Z-score scale relative to our British centiles. We performed meta-regression to pool the Z-scores and compare them by world region.
Findings: our search returned 806 abstracts. Sixty papers met inclusion criteria and reported on 63 different samples. Seven UN regions were represented, although most samples (n = 44) were based in developed regions. We extracted 726 normative data items relating to 96,537 grip strength observations. Normative data from developed regions were broadly similar to our British centiles, with a pooled Z-score 0.12 SDs (95% CI: 0.07, 0.17) above the corresponding British centiles. By comparison, normative data from developing regions were clearly lower, with a pooled Z-score of −0.85 SDs (95% CI: −0.94, −0.76).
Interpretation: our findings support the use of our British grip strength centiles and their associated cut points in consensus definitions for sarcopenia and frailty across developed regions, but highlight the need for different cut points in developing regions.
Wellcome Trust1, Los Alamos National Laboratory2, Wellcome Trust Sanger Institute3, Lund University4, Erasmus University Medical Center5, Radboud University Nijmegen6, Hanyang University7, Université libre de Bruxelles8, University of Texas MD Anderson Cancer Center9, University of Antwerp10, Royal Brisbane and Women's Hospital11, University of Queensland12, University of Iceland13, University of Dundee14, University of Amsterdam15, University of Oslo16, Harvard University17, Medical Research Council18, Cambridge University Hospitals NHS Foundation Trust19
TL;DR: Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, it is shown that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization.
Abstract: Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.
University of London1, Stanford University2, University of Maryland, Baltimore3, Emory University4, Brown University5, Katholieke Universiteit Leuven6, University of Alcalá7, Federal University of Rio de Janeiro8, University of Granada9, University of Zurich10, University of Paris11, Harvard University12, Médecins Sans Frontières13, Israel Ministry of Health14, Erasmus University Rotterdam15, University of Rome Tor Vergata16, Karolinska Institutet17, University of Modena and Reggio Emilia18, Kaiser Permanente19, Centers for Disease Control and Prevention20, Public Health England21, Robert Koch Institute22, University College London23, Medical Research Council24, IBM25, University of the Free State26, University of Cologne27, Chulalongkorn University28
TL;DR: A global assessment of drug resistance after virological failure with first-line tenofovir-containing ART, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase ( RT ) gene.
Abstract: Summary Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase ( RT ) gene. Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27–1·77 for CD4 cell count Interpretation We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. Funding The Wellcome Trust.
TL;DR: This study demonstrates polygenic overlaps between common genetic polymorphisms associated with schizophrenia and negative symptoms and anxiety disorder but not with psychotic experiences or depression.
Abstract: Importance Schizophrenia is a highly heritable, polygenic condition characterized by a relatively diverse phenotype and frequent comorbid conditions, such as anxiety and depression. At present, limited evidence explains how genetic risk for schizophrenia is manifest in the general population.
Objective To investigate the extent to which genetic risk for schizophrenia is associated with different phenotypes during adolescence in a population-based birth cohort.
Design, Setting, and Participants This cohort study used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Of 14 062 children in the birth cohort, genetic data were available for 9912 adolescents. Data were collected periodically from September 6, 1990, and collection is ongoing. Data were analyzed from March 4 to August 13, 2015.
Exposures Polygenic risk scores (PRSs) for schizophrenia generated for individuals in the ALSPAC cohort using results of the second Psychiatric Genomics Consortium Schizophrenia genome-wide association study as a training set.
Main Outcomes and Measures Logistic regression was used to assess associations between the schizophrenia PRS and (1) psychotic experiences (Psychosis-Like Symptom Interview at 12 and 18 years of age), (2) negative symptoms (Community Assessment of Psychic Experiences at 16.5 years of age), (3) depressive disorder (Development and Well-Being Assessment at 15.5 years of age), and (4) anxiety disorder (Development and Well-Being Assessment at 15.5 years of age) in adolescence.
Results Of the 8230 ALSPAC participants whose genetic data passed quality control checks (51.2% male, 48.8% female), 3676 to 5444 participated in assessments from 12 to 18 years of age. The PRSs created using single-nucleotide polymorphisms with a training-set P ≤ .05 threshold were associated with negative symptoms (odds ratio [OR] per SD increase in PRS, 1.21; 95% CI, 1.08-1.36; R2 = 0.007) and anxiety disorder (OR per SD increase in PRS, 1.17; 95% CI, 1.06- 1.29; R2 = 0.005). No evidence was found of an association between schizophrenia PRS and psychotic experiences (OR per SD increase in PRS, 1.08; 95% CI, 0.98-1.19; R2 = 0.001) or depressive disorder (OR per SD increase in PRS, 1.02; 95% CI, 0.91-1.13; R2 = 0.00005). Results were mostly consistent across different training-set P value thresholds and using different cutoffs and measures of the psychopathological outcomes.
Conclusions and Relevance This study demonstrates polygenic overlaps between common genetic polymorphisms associated with schizophrenia and negative symptoms and anxiety disorder but not with psychotic experiences or depression. Because the genetic risk for schizophrenia appears to be manifest as anxiety and negative symptoms during adolescence, a greater focus on these phenotypes rather than on psychotic experiences might be required for prediction of transition in at-risk samples.