Showing papers by "Medical Research Council published in 2017"
University of Edinburgh1, University of Glasgow2, Johns Hopkins University3, University of Colorado Boulder4, University of the Witwatersrand5, International Military Sports Council6, Aga Khan University7, Medical Research Council8, King George's Medical University9, Kenya Medical Research Institute10, Centers for Disease Control and Prevention11, International Centre for Diarrhoeal Disease Research, Bangladesh12, University of Bergen13, Tribhuvan University14, University of Barcelona15, Utrecht University16, Emory University17, All India Institute of Medical Sciences18, University of Liverpool19, Boston Children's Hospital20, National Institute of Virology21, University of Zambia22, University of Health Sciences Antigua23, National Health Laboratory Service24, Chinese Center for Disease Control and Prevention25, Austral University26, University of Michigan27, Vanderbilt University28, University of New South Wales29, University of Otago30, University of Auckland31, Universidad del Valle de Guatemala32, University of Jordan33, University of Maryland, Baltimore34, National Scientific and Technical Research Council35, Research Institute for Tropical Medicine36, Pwani University College37, University of Cape Town38, University of Warwick39, Academy of Medical Sciences, United Kingdom40, Tohoku University41, École normale supérieure de Lyon42, John E. Fogarty International Center43, Charité44, Universidad Nacional de Asunción45, Tehran University of Medical Sciences46, Robert Koch Institute47, University of London48, University of New Mexico49, Capital Medical University50, Alaska Native Tribal Health Consortium51, Innlandet Hospital Trust52, Columbia University53, Mahidol University54, University of Pretoria55, Thailand Ministry of Public Health56, Peking Union Medical College57, Nagasaki University58, Public Health Foundation of India59
TL;DR: In this paper, the authors estimated the incidence and hospital admission rate of RSV-associated acute lower respiratory infection (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions.
1,470 citations
University of Oxford1, Hungarian Academy of Sciences2, University of South Florida3, National Institutes of Health4, Queen's University5, Medical Research Council6, Systems Research Institute7, University of California, San Francisco8, Moscow State University9, Leiden University Medical Center10, John Innes Centre11, Institute for Animal Health12, Pasteur Institute13, University of Alabama at Birmingham14, Harvard University15, Pennsylvania State University16, Mississippi State University17, Ohio State University18, University of British Columbia19, Canadian Institute for Advanced Research20, University of Texas Medical Branch21, Wageningen University and Research Centre22, Arizona State University23, Universidade Federal de Viçosa24
TL;DR: The rationale for why metagenomic sequence data should, and how it can, be incorporated into the ICTV taxonomy is considered, and present proposals that have been endorsed by the Executive Committee of the ITV.
Abstract: The number and diversity of viral sequences that are identified in metagenomic data far exceeds that of experimentally characterized virus isolates. In a recent workshop, a panel of experts discussed the proposal that, with appropriate quality control, viruses that are known only from metagenomic data can, and should be, incorporated into the official classification scheme of the International Committee on Taxonomy of Viruses (ICTV). Although a taxonomy that is based on metagenomic sequence data alone represents a substantial departure from the traditional reliance on phenotypic properties, the development of a robust framework for sequence-based virus taxonomy is indispensable for the comprehensive characterization of the global virome. In this Consensus Statement article, we consider the rationale for why metagenomic sequence data should, and how it can, be incorporated into the ICTV taxonomy, and present proposals that have been endorsed by the Executive Committee of the ICTV.
525 citations
TL;DR: The findings underscore the relevance of adaptive and also maladaptive emotion regulation strategies in depressive and anxiety symptoms in youth, and highlight the need to further investigate the patterns of emotion regulation as a potential transdiagnostic factor.
Abstract: The role of emotion regulation in subclinical symptoms of mental disorders in adolescence is not yet well understood. This meta-analytic review examines the relationship between the habitual use of prominent adaptive emotion regulation strategies (cognitive reappraisal, problem solving, and acceptance) and maladaptive emotion regulation strategies (avoidance, suppression, and rumination) with depressive and anxiety symptoms in adolescence. Analyzing 68 effect sizes from 35 studies, we calculated overall outcomes across depressive and anxiety symptoms as well as psychopathology-specific outcomes. Age was examined as a continuous moderator via meta-regression models. The results from random effects analyses revealed that the habitual use of all emotion regulation strategies was significantly related to depressive and anxiety symptoms overall, with the adaptive emotion regulation strategies showing negative associations (i.e., less symptoms) with depressive and anxiety symptoms whereas the maladaptive emotion regulation strategies showed positive associations (i.e., more symptoms). A less frequent use of adaptive and a more frequent use of maladaptive emotion regulation strategies were associated with depressive and anxiety symptoms comparably in the respective directions. Regarding the psychopathology-specific outcomes, depressive and anxiety symptoms displayed similar patterns across emotion regulation strategies showing the strongest negative associations with acceptance, and strongest positive associations with avoidance and rumination. The findings underscore the relevance of adaptive and also maladaptive emotion regulation strategies in depressive and anxiety symptoms in youth, and highlight the need to further investigate the patterns of emotion regulation as a potential transdiagnostic factor.
422 citations
VU University Amsterdam1, Erasmus University Rotterdam2, South London and Maudsley NHS Foundation Trust3, Medical Research Council4, King's College London5, VU University Medical Center6, Erasmus University Medical Center7, New York University8, Union College9, University of Minnesota10, Stockholm School of Economics11, Harvard University12, Karolinska Institutet13, University of Manchester14, Manchester Academic Health Science Centre15, Leiden University16
TL;DR: A meta-analysis for intelligence of 78,308 individuals identifies 336 associated SNPs in 18 genomic loci, implicating 22 genes and indicates the involvement of genes regulating cell development in brain tissue and pathway analysis provides new insight into the genetic architecture of intelligence.
Abstract: Intelligence is associated with important economic and health-related life outcomes Despite intelligence having substantial heritability (054) and a confirmed polygenic nature, initial genetic studies were mostly underpowered Here we report a meta-analysis for intelligence of 78,308 individuals We identify 336 associated SNPs (METAL P < 5 × 10-8) in 18 genomic loci, of which 15 are new Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings Gene-based analyses identified an additional 30 genes (MAGMA P < 273 × 10-6), of which all but one had not been implicated previously We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 35 × 10-6) Despite the well-known difference in twin-based heritability for intelligence in childhood (045) and adulthood (080), we show substantial genetic correlation (rg = 089, LD score regression P = 54 × 10-29) These findings provide new insight into the genetic architecture of intelligence
411 citations
TL;DR: The hypothesis that normal HMO concentrations and profiles vary geographically, even in healthy women is supported and targeted genomic analyses are required to determine whether these differences are due at least in part to genetic variation.
263 citations
French Institute of Health and Medical Research1, Pasteur Institute2, Medical Research Council3, University of Edinburgh4, Manchester Academic Health Science Centre5, Necker-Enfants Malades Hospital6, Paris Descartes University7, Central Manchester University Hospitals NHS Foundation Trust8, Leiden University Medical Center9, Katholieke Universiteit Leuven10, Guy's Hospital11, Francis Crick Institute12
TL;DR: Measurement of IFN&agr; attomolar concentrations by digital ELISA will enhance the understanding ofIFN biology and potentially improve the diagnosis and stratification of pathologies associated with IFN dysregulation.
Abstract: Type I interferons (IFNs) are essential mediators of antiviral responses. These cytokines have been implicated in the pathogenesis of autoimmunity, most notably systemic lupus erythematosus (SLE), diabetes mellitus, and dermatomyositis, as well as monogenic type I interferonopathies. Despite a fundamental role in health and disease, the direct quantification of type I IFNs has been challenging. Using single-molecule array (Simoa) digital ELISA technology, we recorded attomolar concentrations of IFNα in healthy donors, viral infection, and complex and monogenic interferonopathies. IFNα protein correlated well with functional activity and IFN-stimulated gene expression. High circulating IFNα levels were associated with increased clinical severity in SLE patients, and a study of the cellular source of IFNα protein indicated disease-specific mechanisms. Measurement of IFNα attomolar concentrations by digital ELISA will enhance our understanding of IFN biology and potentially improve the diagnosis and stratification of pathologies associated with IFN dysregulation.
263 citations
TL;DR: Data suggest that both presynaptic and postsynaptic aspects of the dopamine system in the striatum are down-regulated in stimulant users, and this has implications for future drug development.
Abstract: Importance Stimulant use disorder is common, affecting between 0.3% and 1.1% of the population, and costs more than $85 billion per year globally. There are no licensed treatments to date. Several lines of evidence implicate the dopamine system in the pathogenesis of substance use disorder. Therefore, understanding the nature of dopamine dysfunction seen in stimulant users has the potential to aid the development of new therapeutics. Objective To comprehensively review the in vivo imaging evidence for dopaminergic alterations in stimulant (cocaine, amphetamine, or methamphetamine) abuse or dependence. Data Sources The entire PubMed, EMBASE, and PsycINFO databases were searched for studies from inception date to May 14, 2016. Study Selection Case-control studies were identified that compared dopaminergic measures between stimulant users and healthy controls using positron emission tomography or single-photon emission computed tomography to measure striatal dopamine synthesis or release or to assess dopamine transporter availability or dopamine receptor availability. Data Extraction and Synthesis Demographic, clinical, and imaging measures were extracted from each study, and meta-analyses and sensitivity analyses were conducted for stimulants combined, as well as for cocaine and for amphetamine and methamphetamine separately if there were sufficient studies. Main Outcomes and Measures Differences were measured in dopamine release (assessed using change in the D2/D3 receptor availability after administration of amphetamine or methylphenidate), dopamine transporter availability, and dopamine receptor availability in cocaine users, amphetamine and methamphetamine users, and healthy controls. Results A total of 31 studies that compared dopaminergic measures between 519 stimulant users and 512 healthy controls were included in the final analysis. In most of the studies, the duration of abstinence varied from 5 days to 3 weeks. There was a significant decrease in striatal dopamine release in stimulant users compared with healthy controls: the effect size was −0.84 (95% CI, −1.08 to −0.60; P P P P P P P Conclusions and Relevance Data suggest that both presynaptic and postsynaptic aspects of the dopamine system in the striatum are down-regulated in stimulant users. The commonality and differences between these findings and the discrepancies with the preclinical literature and models of drug addiction are discussed, as well as their implications for future drug development.
216 citations
TL;DR: To investigate whether patients with first-episode schizophrenia exhibit greater variability of regional brain volumes in addition to mean volume differences, and whether these findings were robust to choice of outcome measure, a large number of case-control studies were examined.
Abstract: Importance Schizophrenia is associated with alterations in mean regional brain volumes However, it is not known whether the clinical heterogeneity seen in the disorder is reflected at the neurobiological level, for example, in differences in the interindividual variability of these brain volumes relative to control individuals Objective To investigate whether patients with first-episode schizophrenia exhibit greater variability of regional brain volumes in addition to mean volume differences Data Sources Studies that reported regional brain volumetric measures in patients and controls by using magnetic resonance imaging in the MEDLINE, EMBASE, and PsycINFO databases from inception to October 1, 2016, were examined Study Selection Case-control studies that reported regional brain volumes in patients with first-episode schizophrenia and healthy controls by using magnetic resonance imaging were selected Data Extraction and Synthesis Means and variances (SDs) were extracted for each measure to calculate effect sizes, which were combined using multivariate meta-analysis Main Outcomes and Measures Relative variability of regional brain volumetric measurements in patients compared with control groups as indexed by the variability ratio (VR) and coefficient of variation ratio (CVR) Hedges g was used to quantify mean differences Results A total of 108 studies that reported measurements from 3901 patients (1272 [326%] female) with first-episode schizophrenia and 4040 controls (1613 [399%] female) were included in the analyses Variability of putamen (VR, 113; 95% CI, 103-124; P = 01), temporal lobe (VR, 112; 95% CI, 104-121; P = 004), thalamus (VR, 116; 95% CI, 107-126; P P −5 ) volume was significantly greater in patients, whereas variability of anterior cingulate cortex volume was lower (VR, 089; 95% CI, 081-098; P = 02) These findings were robust to choice of outcome measure There was no evidence of altered variability of caudate nucleus or frontal lobe volumes Mean volumes of the lateral ( g = 040; 95% CI, 029-051; P g = 043; 95% CI, 026-059; P g = −046; −065 to −026; P g = −026; 95% CI, −043 to −010; P = 005), frontal lobe ( g = −031; 95% CI, −044 to −019; P = 001), hippocampus ( g = −066; 95% CI, −084 to −047; P g = −022; 95% CI, −036 to −009; P = 001), and thalamus ( g = −036; 95% CI, −057 to −015; P = 001) were lower in patients There was no evidence of altered mean volume of caudate nucleus or putamen Conclusions and Relevance In addition to altered mean volume of many brain structures, schizophrenia is associated with significantly greater variability of temporal cortex, thalamus, putamen, and third ventricle volumes, consistent with biological heterogeneity in these regions, but lower variability of anterior cingulate cortex volume This finding indicates greater homogeneity of anterior cingulate volume and, considered with the significantly lower mean volume of this region, suggests that this is a core region affected by the disorder
216 citations
TL;DR: Overall results may be promising but are inconclusive, and further prospective cohorts assessing dietary polyphenol exposure and studies using other methods to evaluate exposure are needed to confirm and determine consumption levels required to achieve health benefits.
Abstract: cope
To summarize available evidence on the association between dietary flavonoid as well as lignan intake and cancer risk in observational studies.
Methods and results
A systematic search on electronic databases of all English language case–control and prospective studies published up to June 2016 was performed. Risk ratios (RRs) and 95% confidence intervals were calculated by random-effects model separately by study design. Heterogeneity and publication bias were tested. Out of the 143 studies included, meta-analyses of prospective studies showed isoflavones significantly associated with decreased risk of lung and stomach cancers and nearly significant breast and colorectal cancers; total flavonoids showed nonsignificant decreased risk of breast cancer. Meta-analyses of case–control studies showed: total and/or individual classes of flavonoids associated with upper aero-digestive tract, colorectal, breast, and lung cancers; isoflavones with ovarian, breast, and colorectal cancers, endometrial and lung cancers.
Conclusions
Most evidence reported in previous meta-analyses was driven by case–control studies. Overall results may be promising but are inconclusive. Further prospective cohorts assessing dietary polyphenol exposure and studies using other methods to evaluate exposure (i.e. markers of consumption, metabolism, excretion) are needed to confirm and determine consumption levels required to achieve health benefits.
208 citations
TL;DR: Disadvantaged social groups have greater alcohol-attributable harms compared with individuals from advantaged areas for given levels of alcohol consumption, even after accounting for different drinking patterns, obesity, and smoking status at the individual level.
Abstract: Summary Background Alcohol-related mortality and morbidity are high in socioeconomically disadvantaged populations compared with individuals from advantaged areas. It is unclear if this increased harm reflects differences in alcohol consumption between these socioeconomic groups, reverse causation (ie, downward social selection for high-risk drinkers), or a greater risk of harm in individuals of low socioeconomic status compared with those of higher status after similar consumption. We aimed to investigate whether the harmful effects of alcohol differ by socioeconomic status, accounting for alcohol consumption and other health-related factors. Methods The Scottish Health Surveys are record-linked cross-sectional surveys representative of the adult population of Scotland. We obtained baseline demographics and data for alcohol consumption (units per week and binge drinking) from Scottish Health Surveys done in 1995, 1998, 2003, 2008, 2009, 2010, 2011, and 2012. We matched these data to records for deaths, admissions, and prescriptions. The primary outcome was alcohol-attributable admission or death. The relation between alcohol-attributable harm and socioeconomic status was investigated for four measures (education level, social class, household income, and area-based deprivation) using Cox proportional hazards models. The potential for alcohol consumption and other risk factors (including smoking and body-mass index [BMI]) mediating social patterning was explored in separate regression models. Reverse causation was tested by comparing change in area deprivation over time. Findings 50 236 participants (21 777 men and 28 459 women) were included in the analytical sample, with 429 986 person-years of follow-up. Low socioeconomic status was associated consistently with strikingly raised alcohol-attributable harms, including after adjustment for weekly consumption, binge drinking, BMI, and smoking. Evidence was noted of effect modification; for example, relative to light drinkers living in advantaged areas, the risk of alcohol-attributable admission or death for excessive drinkers was increased (hazard ratio 6·12, 95% CI 4·45–8·41 in advantaged areas; and 10·22, 7·73–13·53 in deprived areas). We found little support for reverse causation. Interpretation Disadvantaged social groups have greater alcohol-attributable harms compared with individuals from advantaged areas for given levels of alcohol consumption, even after accounting for different drinking patterns, obesity, and smoking status at the individual level. Funding Medical Research Council, NHS Research Scotland, Scottish Government Chief Scientist Office.
202 citations
European Bioinformatics Institute1, Children's Hospital Oakland Research Institute2, Queen Mary University of London3, Wellcome Trust Sanger Institute4, Medical Research Council5, University of Portland6, Lawrence Berkeley National Laboratory7, Baylor College of Medicine8, University of California, Davis9, Charles River Laboratories10, Nanjing University11, National Research Council12, Seoul National University13
TL;DR: Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to the knowledge, for type C Bernard–Soulier, Bardet–Biedl-5 and Gordon Holmes syndromes, and 90% of phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases.
Abstract: Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.
Medical Research Council1, University of Bristol2, Pompeu Fabra University3, Dartmouth College4, Erasmus University Medical Center5, Erasmus University Rotterdam6, Université de Sherbrooke7, University of California, Berkeley8, Emory University9, Norwegian Institute of Public Health10, National Institutes of Health11, University of Western Australia12, University Medical Center Groningen13, University of Paris14, North Carolina State University15, Columbia University16, University of Washington17, University of California, San Francisco18, University of Southampton19, International Agency for Research on Cancer20, Karolinska Institutet21, University of Michigan22, University of Memphis23, University of Southern Denmark24, North Carolina Central University25, Harvard University26, Kaiser Permanente27, United States Department of Health and Human Services28, Utrecht University29, University of South Carolina30, Stockholm County Council31, University of California, Davis32, Drexel University33, Duke University34, Johns Hopkins University35, Boston Children's Hospital36, Oslo University Hospital37, Southampton General Hospital38, Frederiksberg Hospital39, University of Copenhagen40
TL;DR: In this article, the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs).
Abstract: Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.
Washington University in St. Louis1, Brandeis University2, Northwestern University3, University of Pennsylvania4, Swiss Institute of Bioinformatics5, University of Lausanne6, Weizmann Institute of Science7, University of California, Irvine8, University of Central Florida9, Texas A&M University10, New York University11, University of Zurich12, Fundación Instituto Leloir13, University of Texas Health Science Center at Houston14, University of California, Davis15, Max Planck Society16, Dartmouth College17, Morehouse School of Medicine18, University of Surrey19, University of Kansas20, Harvard University21, University of Notre Dame22, University of Florida23, University of Michigan24, Cincinnati Children's Hospital Medical Center25, University of California, San Francisco26, Nestlé27, University of Amsterdam28, University of California, San Diego29, University of Texas Southwestern Medical Center30, Duke University31, Medical Research Council32, Charité33, Vanderbilt University34, Rensselaer Polytechnic Institute35, University of Washington36, Kyoto Prefectural University of Medicine37, Ohio State University38, Scripps Research Institute39, Amherst College40, University of Missouri41, Wuhan University42, University of Memphis43, University of Guelph44, Ludwig Maximilian University of Munich45, University of Edinburgh46, Donald Danforth Plant Science Center47, École Polytechnique Fédérale de Lausanne48, University of Geneva49, Yale University50, University of Seville51, University of Warwick52, University College London53, Francis Crick Institute54, University of North Carolina at Chapel Hill55, McGill University56, Soochow University (Suzhou)57, Leibniz Association58, University of Southampton59, Rockefeller University60
TL;DR: CircaInSilico is introduced, a web-based application for generating synthetic genome biology data to benchmark statistical methods for studying biological rhythms, and several unmet analytical needs, including applications to clinical medicine, are discussed and productive avenues to address them are suggested.
Abstract: Genome biology approaches have made enormous contributions to our understanding of biological rhythms, particularly in identifying outputs of the clock, including RNAs, proteins, and metabolites, whose abundance oscillates throughout the day. These methods hold significant promise for future discovery, particularly when combined with computational modeling. However, genome-scale experiments are costly and laborious, yielding "big data" that are conceptually and statistically difficult to analyze. There is no obvious consensus regarding design or analysis. Here we discuss the relevant technical considerations to generate reproducible, statistically sound, and broadly useful genome-scale data. Rather than suggest a set of rigid rules, we aim to codify principles by which investigators, reviewers, and readers of the primary literature can evaluate the suitability of different experimental designs for measuring different aspects of biological rhythms. We introduce CircaInSilico, a web-based application for generating synthetic genome biology data to benchmark statistical methods for studying biological rhythms. Finally, we discuss several unmet analytical needs, including applications to clinical medicine, and suggest productive avenues to address them.
TL;DR: Urinary metabolite models developed in a highly controlled environment can classify groups of free-living people into consumers of diets associated with lower or higher non-communicable disease risk on the basis of multivariate metabolite patterns.
TL;DR: Hormonal therapy with vigabatrin is significantly more effective at stopping infantile spasms than hormonal therapy alone and the 4 week period of spasm cessation required to achieve a primary clinical response to treatment suggests that the effect seen might be sustained, but this needs to be confirmed at the 18 month follow-up.
Abstract: Summary Background Infantile spasms constitutes a severe infantile epilepsy syndrome that is difficult to treat and has a high morbidity. Hormonal therapies or vigabatrin are the most commonly used treatments. We aimed to assess whether combining the treatments would be more effective than hormonal therapy alone. Methods In this multicentre, open-label randomised trial, 102 hospitals (Australia [three], Germany [11], New Zealand [two], Switzerland [three], and the UK [83]) enrolled infants who had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) EEG no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing electro-clinical outcome were masked to treatment allocation. Minimum doses were prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without vigabatrin 100 mg/kg per day. The primary outcome was cessation of spasms, which was defined as no witnessed spasms on and between day 14 and day 42 from trial entry, as recorded by parents and carers in a seizure diary. Analysis was by intention to treat. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 54363174, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2006-000788-27. Findings Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (186) or hormonal therapy alone (191). All 377 infants were assessed for the primary outcome. Between days 14 and 42 inclusive no spasms were witnessed in 133 (72%) of 186 patients on hormonal therapy with vigabatrin compared with 108 (57%) of 191 patients on hormonal therapy alone (difference 15·0%, 95% CI 5·1–24·9, p=0·002). Serious adverse reactions necessitating hospitalisation occurred in 33 infants (16 on hormonal therapy alone and 17 on hormonal therapy with vigabatrin). The most common serious adverse reaction was infection occurring in five infants on hormonal therapy alone and four on hormonal therapy with vigabatrin. There were no deaths attributable to treatment. Interpretation Hormonal therapy with vigabatrin is significantly more effective at stopping infantile spasms than hormonal therapy alone. The 4 week period of spasm cessation required to achieve a primary clinical response to treatment suggests that the effect seen might be sustained, but this needs to be confirmed at the 18 month follow-up. Funding The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, the BRONNER-BENDUNG Stifung/Gernsbach, and University Children's Hospital Zurich.
Queen Elizabeth Hospital Birmingham1, The Royal Marsden NHS Foundation Trust2, Medical Research Council3, University Hospitals Bristol NHS Foundation Trust4, Royal Victoria Infirmary5, University of Leeds6, Maastricht University7, University of Bern8, Royal United Hospital9, St George's, University of London10
TL;DR: The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen, and cannot be considered standard of care.
Abstract: Summary Background Neoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer. The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen. Methods OE05 was an open-label, phase 3, randomised clinical trial. Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 were recruited from 72 UK hospitals. Eligibility criteria included WHO performance status 0 or 1, adequate respiratory, cardiac, and liver function, white blood cell count at least 3 × 10 9 cells per L, platelet count at least 100 × 10 9 platelets per L, and a glomerular filtration rate at least 60 mL/min. Participants were randomly allocated (1:1) using a computerised minimisation program with a random element and stratified by centre and tumour stage, to receive two cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin [80 mg/m 2 intravenously on day 1] and fluorouracil [1 g/m 2 per day intravenously on days 1–4]) or four cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin [50 mg/m 2 ] and cisplatin [60 mg/m 2 ] intravenously on day 1, and capecitabine [1250 mg/m 2 ] daily throughout the four cycles) before surgery, stratified according to centre and clinical disease stage. Neither patients nor study staff were masked to treatment allocation. Two-phase oesophagectomy with two-field (abdomen and thorax) lymphadenectomy was done within 4–6 weeks of completion of chemotherapy. The primary outcome measure was overall survival, and primary and safety analyses were done in the intention-to-treat population. This trial is registered with the ISRCTN registry (number 01852072) and ClinicalTrials.gov (NCT00041262), and is completed. Findings Between Jan 13, 2005, and Oct 31, 2011, 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group. By Nov 14, 2016, 327 (73%) of 451 patients in the CF group and 302 (68%) of 446 in the ECX group had died. Median survival was 23·4 months (95% CI 20·6–26·3) with CF and 26·1 months (22·5–29·7) with ECX (hazard ratio 0·90 (95% CI 0·77–1·05, p=0·19). No unexpected chemotherapy toxicity was seen, and neutropenia was the most commonly reported event (grade 3 or 4 neutropenia: 74 [17%] of 446 patients in the CF group vs 101 [23%] of 441 people in the ECX group). The proportions of patients with postoperative complications (224 [56%] of 398 people for whom data were available in the CF group and 233 [62%] of 374 in the ECX group; p=0·089) were similar between the two groups. One patient in the ECX group died of suspected treatment-related neutropenic sepsis. Interpretation Four cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival, and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma. Funding Cancer Research UK and Medical Research Council Clinical Trials Unit at University College London.
TL;DR: In this review, existing aDBS studies are evaluated as proof‐of‐principle, their limitations are discussed, most of which stem from their acute nature, and what is needed to take a DBS into a chronic setting is proposed.
Abstract: Continuous high-frequency DBS is an established treatment for essential tremor and Parkinson's disease. Current developments focus on trying to widen the therapeutic window of DBS. Adaptive DBS (aDBS), where stimulation is dynamically controlled by feedback from biomarkers of pathological brain circuit activity, is one such development. Relevant biomarkers may be central, such as local field potential activity, or peripheral, such as inertial tremor data. Moreover, stimulation may be directed by the amplitude or the phase (timing) of the biomarker signal. In this review, we evaluate existing aDBS studies as proof-of-principle, discuss their limitations, most of which stem from their acute nature, and propose what is needed to take aDBS into a chronic setting. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
University of Pennsylvania1, Medical Research Council2, University of Bristol3, University of California, San Diego4, Punjab Institute of Cardiology5, Karachi Institute of Heart Diseases6, Civil Hospital Karachi7, Liaquat National Hospital8, University of Washington9, Wellcome Trust Sanger Institute10
TL;DR: Human genetic data suggest that both smaller apolipoprotein(a) isoform size and increased lipoprotein( a) concentration are independent and causal risk factors for coronary heart disease.
TL;DR: It is shown that the warm ambient temperature transcriptome is dependent upon the HSFA1 clade of Arabidopsis HSFs, which cause a rapid and dynamic eviction of H2A.Z nucleosomes at target genes, and it is proposed that the antagonistic effects of H1.Z and HSF1 provide a mechanism to activate gene expression rapidly and precisely in response to temperature, while preventing leaky transcription in the absence of an activation signal.
Wellcome Trust Sanger Institute1, Wellcome Trust Centre for Human Genetics2, Medical Research Council3, University of London4, Royal Victoria Teaching Hospital5, Sapienza University of Rome6, University of Buea7, Wellcome Trust8, Imperial College London9, National Institute for Medical Research10, Malawi-Liverpool-Wellcome Trust Clinical Research Programme11, Liverpool School of Tropical Medicine12, College of Osteopathic Medicine of the Pacific13, NHS Blood and Transplant14
TL;DR: A complex CNV called DUP4 is associated with resistance to severe malaria and fully explains the previously reported signal of association, and a systematic catalog of CNVs is provided, describing structural diversity that may have functional importance at this locus.
Abstract: INTRODUCTION Malaria parasites cause human disease by invading and replicating inside red blood cells In the case of Plasmodium falciparum , this can lead to severe forms of malaria that are a major cause of childhood mortality in Africa This species of parasite enters the red blood cell through interactions with surface proteins including the glycophorins GYPA and GYPB, which determine the polymorphic MNS blood group system In a recent genome-wide association study, we identified alleles associated with protection against severe malaria near the cluster of genes encoding these invasion receptors RATIONALE Investigation of genetic variants at this locus and their relation to severe malaria is challenging because of the high sequence similarity between the neighboring glycophorin genes and the relative lack of available sequence data capturing the genetic diversity of sub-Saharan Africa To better assess whether variation in the glycophorin genes could explain the signal of association, we generated additional sequence data from sub-Saharan African populations and developed an analytical approach to characterize structural variation at this complex locus RESULTS Using 765 newly sequenced human genomes from 10 African ethnic groups along with data from the 1000 Genomes Project, we generated a reference panel of haplotypes across the glycophorin region In addition to single-nucleotide polymorphisms and short indels, we assayed large copy number variants (CNVs) using sequencing read depth and uncovered extensive structural diversity By imputing from this reference panel into 4579 severe malaria cases and 5310 controls from three African populations, we found that a complex CNV, here called DUP4, is associated with resistance to severe malaria and fully explains the previously reported signal of association In our sample, DUP4 is present only in east Africa, and this localization, as well as the extent of similarity between DUP4 haplotypes, suggests that it has recently increased in frequency, presumably under natural selection due to malaria To evaluate the potential functional consequences of this structural variant, we analyzed high-coverage sequence-read data from multiple individuals to generate a model of the DUP4 chromosome structure The DUP4 haplotype contains five glycophorin genes, including two hybrid genes that juxtapose the extracellular domain of GYPB with the transmembrane and intracellular domains of GYPA Noting that these predicted hybrids are characteristic of the Dantu antigen in the MNS blood group system, we sequenced a Dantu positive individual and confirmed that DUP4 is the molecular basis of the Dantu NE blood group variant CONCLUSION Although a role for GYPA and GYPB in parasite invasion is well known, a direct link between glycophorin polymorphisms and clinical susceptibility to malaria has been elusive Here we have provided a systematic catalog of CNVs, describing structural diversity that may have functional importance at this locus Our results identify a specific variant that encodes hybrid glycophorin proteins and is associated with protection against severe malaria This discovery calls for further work to determine how this particular molecular rearrangement affects parasite invasion and the red blood cell response and may lead us toward new parasite vulnerabilities that can be utilized in future interventions against this deadly disease
TL;DR: The data suggest that gene expression variability in infected host cells shapes different cellular environments, some of which may favour a growth arrest of Salmonella facilitating immune evasion and the establishment of a long-term niche, while others allowSalmonella to escape intracellular antimicrobial activity and proliferate.
Abstract: Intracellular bacterial pathogens can exhibit large heterogeneity in growth rate inside host cells, with major consequences for the infection outcome. If and how the host responds to this heterogeneity remains poorly understood. Here, we combined a fluorescent reporter of bacterial cell division with single-cell RNA-sequencing analysis to study the macrophage response to different intracellular states of the model pathogen Salmonella enterica serovar Typhimurium. The transcriptomes of individual infected macrophages revealed a spectrum of functional host response states to growing and non-growing bacteria. Intriguingly, macrophages harbouring non-growing Salmonella display hallmarks of the proinflammatory M1 polarization state and differ little from bystander cells, suggesting that non-growing bacteria evade recognition by intracellular immune receptors. By contrast, macrophages containing growing bacteria have turned into an anti-inflammatory, M2-like state, as if fast-growing intracellular Salmonella overcome host defence by reprogramming macrophage polarization. Additionally, our clustering approach reveals intermediate host functional states between these extremes. Altogether, our data suggest that gene expression variability in infected host cells shapes different cellular environments, some of which may favour a growth arrest of Salmonella facilitating immune evasion and the establishment of a long-term niche, while others allow Salmonella to escape intracellular antimicrobial activity and proliferate.
QIMR Berghofer Medical Research Institute1, VU University Amsterdam2, VU University Medical Center3, Åbo Akademi University4, University of Turku5, University of Gothenburg6, National Institutes of Health7, University of Eastern Finland8, University of Helsinki9, Erasmus University Rotterdam10, Medical Research Council11, Michigan State University12, University College London13, Washington University in St. Louis14, King Abdulaziz University15, Florida State University16, Emory University17, Veterans Health Administration18, Yale University19, University of Pennsylvania20, Boston University21, University of Cambridge22, Karolinska Institutet23, Virginia Commonwealth University24, Karabük University25, State University of New York Upstate Medical University26
TL;DR: The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.
Abstract: Importance Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. Objectives To estimate the single-nucleotide polymorphism–based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. Design, Setting, and Participants Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). Main Outcome and Measures This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. Results The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1:rs2764450, chromosome 11:rs11215217; 7772 male individuals, chromosome X,rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model,P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = –0.52,P = .005) was detected. Conclusions and Relevance The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.
TL;DR: Comparison of the structures reveals insights into the timing of rRNA folding and protein incorporation during the final steps of ribosomal maturation and the evolutionary adaptations that are required to preserve biogenesis after the structural diversification of mitoribosomes.
Abstract: Mammalian mitochondrial ribosomes (mitoribosomes) have less rRNA content and 36 additional proteins compared with the evolutionarily related bacterial ribosome. These differences make the assembly of mitoribosomes more complex than the assembly of bacterial ribosomes, but the molecular details of mitoribosomal biogenesis remain elusive. Here, we report the structures of two late-stage assembly intermediates of the human mitoribosomal large subunit (mt-LSU) isolated from a native pool within a human cell line and solved by cryo-EM to ∼3-A resolution. Comparison of the structures reveals insights into the timing of rRNA folding and protein incorporation during the final steps of ribosomal maturation and the evolutionary adaptations that are required to preserve biogenesis after the structural diversification of mitoribosomes. Furthermore, the structures redefine the ribosome silencing factor (RsfS) family as multifunctional biogenesis factors and identify two new assembly factors (L0R8F8 and mt-ACP) not previously implicated in mitoribosomal biogenesis.
TL;DR: Mother’s HMO composition and infant gut microbiota from 33 Gambian mother/infant pairs at 4, 16, and 20 weeks postpartum were analyzed and suggest that specific types and structures of HMOs are sensitive to environmental conditions, protective of morbidity, predictive of growth, and correlated with specific microbiota.
Abstract: Human milk oligosaccharides (HMOs) play an important role in the health of an infant as substrate for beneficial gut bacteria. Little is known about the effects of HMO composition and its changes on the morbidity and growth outcomes of infants living in areas with high infection rates. Mother's HMO composition and infant gut microbiota from 33 Gambian mother/infant pairs at 4, 16, and 20 weeks postpartum were analyzed for relationships between HMOs, microbiota, and infant morbidity and growth. The data indicate that lacto-N-fucopentaose I was associated with decreased infant morbidity, and 3'-sialyllactose was found to be a good indicator of infant weight-for-age. Because HMOs, gut microbiota, and infant health are interrelated, the relationship between infant health and their microbiome were analyzed. While bifidobacteria were the dominant genus in the infant gut overall, Dialister and Prevotella were negatively correlated with morbidity, and Bacteroides was increased in infants with abnormal calprotectin. Mothers nursing in the wet season (July to October) produced significantly less oligosaccharides compared to those nursing in the dry season (November to June). These results suggest that specific types and structures of HMOs are sensitive to environmental conditions, protective of morbidity, predictive of growth, and correlated with specific microbiota.
TL;DR: This Review describes and compares the different available 3C-based approaches, with a focus on the analysis of mammalian genomes, and discusses the strengths and weaknesses of each technique.
Abstract: In this Review, the authors compare commonly used chromosome conformation capture techniques, describing their respective strengths and weaknesses, and provide advice for the end user on which approach and analysis method to use.
University of London1, University of Bristol2, King's College London3, Haramaya University4, National Research Foundation of South Africa5, University of the Witwatersrand6, Medical Research Council7, University College London Hospitals NHS Foundation Trust8, Baylor College of Medicine9, Johns Hopkins University10, University of Washington11, St George’s University Hospitals NHS Foundation Trust12, The Chinese University of Hong Kong13, Imperial College London14, National Center for Immunization and Respiratory Diseases15, Bill & Melinda Gates Foundation16, World Health Organization17, Public Health England18, University of Cambridge19
TL;DR: The percentage of survivors of infant GBS disease with NDI is estimated, with aconservative estimate that the number of survivors is between 1 and 2% of the population.
Abstract: Background: Survivors of infant group B streptococcal (GBS) disease are at risk of neurodevelopmental impairment (NDI), a burden not previously systematically quantified. This is the 10th of 11 articles estimating the burden of GBS disease. Here we aimed to estimate NDI in survivors of infant GBS disease. Methods: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data on the risk of NDI after invasive GBS disease in infants <90 days of age. We did meta-analyses to derive pooled estimates of the percentage of infants with NDI following GBS meningitis. Results: We identified 6127 studies, of which 18 met eligibility criteria, all from middle- or high-income contexts. All 18 studies followed up survivors of GBS meningitis; only 5 of these studies also followed up survivors of GBS sepsis and were too few to pool in a meta-analysis. Of meningitis survivors, 32% (95% CI, 25%-38%) had NDI at 18 months of follow-up, including 18% (95% CI, 13%-22%) with moderate to severe NDI. Conclusions: GBS meningitis is an important risk factor for moderate to severe NDI, affecting around 1 in 5 survivors. However, data are limited, and we were unable to estimate NDI after GBS sepsis. Comparability of studies is difficult due to methodological differences including variability in timing of clinical reviews and assessment tools. Follow-up of clinical cases and standardization of methods are essential to fully quantify the total burden of NDI associated with GBS disease, and inform program priorities.
Tulio Guadalupe1, Samuel R. Mathias2, Theo G.M. vanErp3, Christopher D. Whelan4 +186 more•Institutions (73)
TL;DR: The largest ever analysis of subcortical brain asymmetries is presented, in a harmonized multi-site study using meta-analysis methods, which revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus.
Abstract: The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.
TL;DR: The understanding of the molecular mechanisms underlying the clonal dominance of MPN stem cells advances will help facilitate the development of therapies that preferentially target MPNstem cells over normal HSC.
TL;DR: The current knowledge of the structure and regulatory features directing lineage-specific expression of Runx genes, the models of embryonic and adult hematopoietic development that provide information on their function, and some of the mechanisms by which they affect hematopolietic function are presented.
Imperial College London1, University of Southern California2, University of Warwick3, University of London4, Haramaya University5, St George’s University Hospitals NHS Foundation Trust6, Baylor College of Medicine7, Johns Hopkins University8, University of the Witwatersrand9, The Chinese University of Hong Kong10, National Health Laboratory Service11, University of Washington12, National Center for Immunization and Respiratory Diseases13, Bill & Melinda Gates Foundation14, World Health Organization15, Medical Research Council16
TL;DR: There is heterogeneity in intrapartum antibiotic use and implementation of policy varies widely, and global strategies to enhance the prevention of group B streptococcal disease that may include maternal vaccination are needed.
Abstract: Background: Intrapartum antibiotic chemoprophylaxis (IAP) prevents most early-onset group B streptococcal (GBS) disease. However, there is no description of how IAP is used around the world. This article is the sixth in a series estimating the burden of GBS disease. Here we aimed to review GBS screening policies and IAP implementation worldwide. Methods: We identified data through (1) systematic literature reviews (PubMed/Medline, Embase, Literature in the Health Sciences in Latin America and the Caribbean [LILACS], World Health Organization library database [WHOLIS], and Scopus) and unpublished data from professional societies and (2) an online survey and searches of policies from medical societies and professionals. We included data on whether an IAP policy was in use, and if so whether it was based on microbiological or clinical risk factors and how these were applied, as well as the estimated coverage (percentage of women receiving IAP where indicated). Results: We received policy information from 95 of 195 (49%) countries. Of these, 60 of 95 (63%) had an IAP policy; 35 of 60 (58%) used microbiological screening, 25 of 60 (42%) used clinical risk factors. Two of 15 (13%) low-income, 4 of 16 (25%) lower-middle-income, 14 of 20 (70%) upper-middle-income, and 40 of 44 (91%) high-income countries had any IAP policy. The remaining 35 of 95 (37%) had no national policy (25/33 from low-income and lower-middle-income countries). Coverage varied considerably; for microbiological screening, median coverage was 80% (range, 20%-95%); for clinical risk factor-based screening, coverage was 29% (range, 10%-50%). Although there were differences in the microbiological screening methods employed, the individual clinical risk factors used were similar. Conclusions: There is considerable heterogeneity in IAP screening policies and coverage worldwide. Alternative global strategies, such as maternal vaccination, are needed to enhance the scope of global prevention of GBS disease.