Showing papers by "Medical Research Council published in 2009"
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27 Apr 200910,518 citations
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University of Ottawa1, University of Modena and Reggio Emilia2, Mario Negri Institute for Pharmacological Research3, Ottawa Hospital Research Institute4, University of Oxford5, University of Freiburg6, Veterans Health Administration7, Johnson & Johnson8, Johnson & Johnson Pharmaceutical Research and Development9, University of Birmingham10, McMaster University11, Johns Hopkins University12, University of Bern13, University of Copenhagen14, Medical Research Council15, GlaxoSmithKline16, University of California, San Francisco17, FHI 36018, Cochrane Collaboration19
TL;DR: Provide a structured summary including, as applicable, background, objectives, data sources, study eligibility criteria, participants, interventions, study appraisal and synthesis methods, results, limitations, conclusions and implications of key findings, systematic review registration number 2.
Abstract: Provide a structured summary including, as applicable, background, objectives, data sources, study eligibility criteria, participants, interventions, study appraisal and synthesis methods, results, limitations, conclusions and implications of key findings, systematic review registration number 2 Structured summary
3,655 citations
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Cardiff University1, Medical Research Council2, University of Bristol3, National Institute for Health Research4, King's College5, Trinity College, Dublin6, University of Cambridge7, University of Nottingham8, Queen's University Belfast9, University of Southampton10, University of Manchester11, John Radcliffe Hospital12, UCL Institute of Neurology13, University of Bonn14, University of Hamburg15, Charité16, University of Erlangen-Nuremberg17, University of Duisburg-Essen18, Ludwig Maximilian University of Munich19, Heidelberg University20, University College Dublin21, University of Freiburg22, Washington University in St. Louis23, Brigham Young University24, University of Antwerp25, University College London26, Wellcome Trust Sanger Institute27, King's College London28, Aristotle University of Thessaloniki29, National Institutes of Health30, Mayo Clinic31
TL;DR: A two-stage genome-wide association study of Alzheimer's disease involving over 16,000 individuals, the most powerful AD GWAS to date, produced compelling evidence for association with Alzheimer's Disease in the combined dataset.
Abstract: We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 10-157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 10-9) and 5' to the PICALM gene (rs3851179, P = 1.9 10-8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 10-10, odds ratio = 0.86; rs3851179, P = 1.3 10-9, odds ratio = 0.86).
2,956 citations
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TL;DR: A missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6, is identified, which suggests that a common mechanism may underlie motor neuron degeneration.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.
2,373 citations
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TL;DR: The dopamine hypothesis of schizophrenia-version III is synthesized into a comprehensive framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function.
Abstract: The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia-version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.
2,311 citations
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TL;DR: A balanced critical appraisal of the BUGS software is provided, highlighting how various ideas have led to unprecedented flexibility while at the same time producing negative side effects.
Abstract: BUGS is a software package for Bayesian inference using Gibbs sampling. The software has been instrumental in raising awareness of Bayesian modelling among both academic and commercial communities internationally, and has enjoyed considerable success over its 20-year life span. Despite this, the software has a number of shortcomings and a principal aim of this paper is to provide a balanced critical appraisal, in particular highlighting how various ideas have led to unprecedented flexibility while at the same time producing negative side effects. We also present a historical overview of the BUGS project and some future perspectives. Copyright © 2009 John Wiley & Sons, Ltd.
1,865 citations
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TL;DR: It is suggested that random-effects meta-analyses as currently conducted often fail to provide the key results, and the extent to which distribution-free, classical and Bayesian approaches can provide satisfactory methods is investigated.
Abstract: Meta-analysis in the presence of unexplained heterogeneity is frequently undertaken by using a random-effects model, in which the effects underlying different studies are assumed to be drawn from a normal distribution. Here we discuss the justification and interpretation of such models, by addressing in turn the aims of estimation, prediction and hypothesis testing. A particular issue that we consider is the distinction between inference on the mean of the random-effects distribution and inference on the whole distribution. We suggest that random-effects meta-analyses as currently conducted often fail to provide the key results, and we investigate the extent to which distribution-free, classical and Bayesian approaches can provide satisfactory methods. We conclude that the Bayesian approach has the advantage of naturally allowing for full uncertainty, especially for prediction. However, it is not without problems, including computational intensity and sensitivity to a priori judgements. We propose a simple prediction interval for classical meta-analysis and offer extensions to standard practice of Bayesian meta-analysis, making use of an example of studies of 'set shifting' ability in people with eating disorders.
1,792 citations
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TL;DR: In this article, the present invention discloses cell penetrating peptides and conjugates of a cell-penetrating peptide and a cargo molecule, as well as their conjugations.
1,590 citations
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TL;DR: This review defines the DMN concept with regard to its neuro-anatomy, its functional organisation through low frequency neuronal oscillations, its relation to other recently discovered low frequency resting state networks, and the cognitive functions it is thought to serve, and introduces methodological and analytical issues and challenges.
1,515 citations
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TL;DR: Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.
Abstract: CONTEXT: Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes. STUDY SELECTION: Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators. DATA EXTRACTION: Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline. DATA SYNTHESIS: Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer. CONCLUSION: Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.
1,335 citations
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TL;DR: Results from this randomised trial provide convincing and consistent evidence that short-course preoperative radiotherapy is an effective treatment for patients with operable rectal cancer.
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Christopher Newton-Cheh1, Christopher Newton-Cheh2, Toby Johnson3, Toby Johnson4 +359 more•Institutions (64)
TL;DR: In this paper, the association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2(P = 1 × 10-23), FGF5 (P=1 × 10 -21), SH2B3(P= 3 × 10−18), MTHFR(MTHFR), c10orf107(P), ZNF652(ZNF652), PLCD3 (P,P = 5 × 10 −9),
Abstract: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
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Stanford University1, NorthShore University HealthSystem2, Columbia University3, Medical Research Council4, Cardiff University5, Centre for Mental Health6, University of Colorado Denver7, Emory University8, Washington University in St. Louis9, Icahn School of Medicine at Mount Sinai10, LSU Health Sciences Center New Orleans11, University of California, San Francisco12, Roy J. and Lucille A. Carver College of Medicine13, Massachusetts Institute of Technology14, Virginia Commonwealth University15
TL;DR: It is demonstrated that common schizophrenia susceptibility alleles can be detected and the characterization of these signals will suggest important directions for research on susceptibility mechanisms.
Abstract: Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5-1%, with high heritability (80-85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 x 10(-9)). This region includes a histone gene cluster and several immunity-related genes--possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.
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TL;DR: The launching of a national initiative to establish sites of service excellence in urban and rural settings throughout South Africa to trial, assess, and implement integrated care interventions for chronic infectious and non-communicable diseases is urged.
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TL;DR: In rectal cancer, the plane of surgery achieved is an important prognostic factor for local recurrence, and both a negative circumferential resection margin and a superior plane of Surgery achieved were associated with lowLocal recurrence rates.
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TL;DR: Long-term follow-up confirms that preoperative chemotherapy improves survival in operable esophageal cancer and should be considered as a standard of care.
Abstract: Purpose OEO2 is a randomized, controlled trial of preoperative chemotherapy in patients undergoing radical surgery for esophageal cancer. Random assignment was to surgery alone (S) or to two cycles of combination cisplatin and fluorouracil before surgery (CS). Initial results reported in 2002 demonstrated an advantage for both disease-free and overall survival in the CS group. The analysis has now been updated after a median follow-up of 6 years. Patients and Methods OEO2 recruited 802 patients, 400 on CS and 402 on S. The nature of the first recurrence event and cause of death are detailed. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test. Survival by extent of resection is presented. Results There were 655 deaths, 335 for S and 320 for CS. The survival benefit has been maintained with a hazard ratio (HR) of 0.84 (95% CI, 0.72 to 0.98; P .03) which in absolute terms is a 5-year survival of 23.0% for CS compared with 17.1% for S. The treatment effect is consistent in both adenocarcinoma and squamous cell carcinoma. The first disease-free survival event was macroscopic residual disease from incomplete resection (R2) or no resection in 26.4% of the S group versus 14.3% of the CS P .001. Three-year survival by type of resection was R0 42.4%, R1 was 18.0%, and R2 was 8.6%. Conclusion Long-term follow-up confirms that preoperative chemotherapy improves survival in operable esophageal cancer and should be considered as a standard of care.
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TL;DR: The results show that maintenance of the ovarian phenotype is an active process throughout life and might have important medical implications for the understanding and treatment of some disorders of sexual development in children and premature menopause in women.
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01 May 2009
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University College London1, St Bartholomew's Hospital2, Nottingham City Hospital3, St Mary's Hospital4, Royal Free Hospital5, St. Michael's GAA, Sligo6, Belfast City Hospital7, Cardiff University8, James Cook University Hospital9, London School of Economics and Political Science10, Brighton and Sussex Medical School11, Queen Mary University of London12, Harvard University13, Medical Research Council14
TL;DR: The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) as mentioned in this paper was a randomized controlled trial designed to assess the effect of screening on mortality, and the outcome of the initial screening was summarised in the report.
Abstract: Background: Ovarian cancer has a high case–fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS.
Methods: Between 2001 and 2005, a total of 202 638 post-menopausal women aged 50–74 years were randomly assigned to no treatment (control; n=101 359); annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50 640); or annual screening with transvaginal ultrasound (USS; n=50 639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032.
Findings: In the prevalence screen, 50 078 (98·9%) women underwent MMS, and 48 230 (95·2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1490 USS). Overall, 4355 of 50 078 (8.7%) women in the MMS group and 5779 of 48 230 (12·0%) women in the USS group required a repeat test, and 167 (0·3%) women in the MMS group and 1894 (3·9%) women in the USS group required clinical evaluation. 97 of 50 078 (0·2%) women from the MMS group and 845 of 48 230 (1·8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48·3%; 95% CI 35·0–61·8) of the invasive cancers were stage I/II, with no difference (p=0·396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89·4%, 99·8%, and 43·3% for MMS, and 84·9%, 98·2%, and 5·3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89·5%, 99·8%, and 35·1% for MMS, and 75·0%, 98·2%, and 2·8% for USS, respectively. There was a significant difference in specificity (p<0·0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers.
Interpretation: The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined.
Funding: Medical Research Council, Cancer Research UK and the Department of Health, UK; with additional support from the Eve Appeal, Special Trustees of Bart's and the London, and Special Trustees of University College London Hospital.
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Wellcome Trust Centre for Human Genetics1, Medical Research Council2, Broad Institute3, Harvard University4, King's College London5, Wellcome Trust Sanger Institute6, deCODE genetics7, Boston University8, University of Michigan9, Erasmus University Rotterdam10, National Institutes of Health11, VU University Amsterdam12, University of Oulu13, Lund University14, University of Virginia15, University of Lausanne16, University Hospital of Lausanne17, University of Southern California18, Imperial College London19, Ninewells Hospital20, University of California, Los Angeles21, University of Düsseldorf22, Novartis23, Swiss Institute of Bioinformatics24, European Bioinformatics Institute25, University of Eastern Finland26, GlaxoSmithKline27, University of North Carolina at Chapel Hill28, Oulu University Hospital29, University Medical Center Groningen30, University of Helsinki31, Ludwig Maximilian University of Munich32, University of Cambridge33, VU University Medical Center34, Leiden University Medical Center35, Brigham and Women's Hospital36, Massachusetts Institute of Technology37, University of Iceland38, University of Oxford39
TL;DR: Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten genome-wide association scans, and previous associations of fasting glucose with variants at the G6PC2 and GCK loci are confirmed.
Abstract: To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
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TL;DR: The magnitude, contexts of occurrence, and patterns of violence, and refer to traffic-related and other unintentional injuries are reviewed, with a focus on homicide, and violence against women and children.
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Cold Spring Harbor Laboratory1, Medical Research Council2, National Institutes of Health3, University of Washington4, University of North Carolina at Chapel Hill5, State University of New York System6, Harvard University7, University of Chicago8, University of Pennsylvania9, Ontario Institute for Cancer Research10, Rockefeller University11, Warneford Hospital12, Columbia University13, Johns Hopkins University14, Heidelberg University15, University of Bonn16, Vanderbilt University17, University College London18, Trinity College, Dublin19, Stony Brook University20, Veterans Health Administration21, University of Massachusetts Medical School22
TL;DR: A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia, bipolar disorder, and autism, while the reciprocal microdeletion was associated only with autism and developmental disorders.
Abstract: Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders1, 2, 3. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 10-5, OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 10-7), bipolar disorder (P = 0.017) and autism (P = 1.9 10-7). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 10-13). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).
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TL;DR: Bariatric surgery was associated with reduced cancer incidence in obese women but not in obese men, and after exclusion of all cancer cases during the first 3 years of the intervention.
Abstract: Summary Background Obesity is a risk factor for cancer. Intentional weight loss in the obese might protect against malignancy, but evidence is limited. To our knowledge, the Swedish Obese Subjects (SOS) study is the first intervention trial in the obese population to provide prospective, controlled cancer-incidence data. Methods The SOS study started in 1987 and involved 2010 obese patients (body-mass index [BMI] ≥34 kg/m 2 in men, and ≥38 kg/m 2 in women) who underwent bariatric surgery and 2037 contemporaneously matched obese controls, who received conventional treatment. While the main endpoint of SOS was overall mortality, the main outcome of this exploratory report was cancer incidence until Dec 31, 2005. Cancer follow-up rate was 99·9% and the median follow-up time was 10·9 years (range 0–18·1 years). Findings Bariatric surgery resulted in a sustained mean weight reduction of 19·9 kg (SD 15·6 kg) over 10 years, whereas the mean weight change in controls was a gain of 1·3 kg (SD 13·7 kg). The number of first-time cancers after inclusion was lower in the surgery group (n=117) than in the control group (n=169; HR 0·67, 95% CI 0·53–0·85, p=0·0009). The sex–treatment interaction p value was 0·054. In women, the number of first-time cancers after inclusion was lower in the surgery group (n=79) than in the control group (n=130; HR 0·58, 0·44–0·77; p=0·0001), whereas there was no effect of surgery in men (38 in the surgery group vs 39 in the control group; HR 0·97, 0·62–1·52; p=0·90). Similar results were obtained after exclusion of all cancer cases during the first 3 years of the intervention. Interpretation Bariatric surgery was associated with reduced cancer incidence in obese women but not in obese men. Funding Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Federal Government under the LUA/ALF agreement, Hoffmann La Roche, Cederoths, AstraZeneca, Sanofi-Aventis, Ethicon Endosurgery.
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TL;DR: A new command is introduced, stpm2, that extends the methodology of Royston and Parmar's flexible parametric survival models and enables simple quantification of differences between any two covariate patterns through calculation of time-dependent hazard ratios, hazard differences, and survival differences.
Abstract: Royston and Parmar (2002, Statistics in Medicine 21: 2175–2197) developed a class of flexible parametric survival models that were programmed in Stata with the stpm command (Royston, 2001, Stata Jo...
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TL;DR: A phage strategy for the selection of ligands based on bicyclic or linear peptides attached covalently to an organic core for generating and selecting bicyclic macrocycles as ligands poised at the interface of small-molecule drugs and biologics is described.
Abstract: Here we describe a phage strategy for the selection of ligands based on bicyclic or linear peptides attached covalently to an organic core. We designed peptide repertoires with three reactive cysteine residues, each spaced apart by several random amino acid residues, and we fused the repertoires to the phage gene-3-protein. Conjugation with tris-(bromomethyl)benzene via the reactive cysteines generated repertoires of peptide conjugates with two peptide loops anchored to a mesitylene core. Iterative affinity selections yielded several enzyme inhibitors; after further mutagenesis and selection, we were able to chemically synthesize a lead inhibitor (PK15; Ki = 1.5 nM) specific to human plasma kallikrein that efficiently interrupted the intrinsic coagulation pathway in human plasma tested ex vivo. This approach offers a powerful means of generating and selecting bicyclic macrocycles (or if cleaved, linear derivatives thereof) as ligands poised at the interface of small-molecule drugs and biologics.
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TL;DR: It is shown that PRIMA-1 is converted to compounds that form adducts with thiols in mutant p53, which is sufficient to induce apoptosis in tumor cells and facilitate the design of more potent and specific mutant p 53-targeting anticancer drugs.
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University of Lübeck1, University of Leicester2, University of Regensburg3, University of Leeds4, Harvard University5, French Institute of Health and Medical Research6, University of Washington7, Lund University8, National Institutes of Health9, Wellcome Trust Sanger Institute10, University of Milan11, University of Pavia12, Medical Research Council13, University of Mainz14, University of Kiel15, Synlab Group16, Heidelberg University17, Medical University of Graz18, Technische Universität München19, University of Cambridge20
TL;DR: A three-stage analysis of genome-wide SNP data in 1,222 German individuals with myocardial infarction and 1,298 controls is presented and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43 is identified.
Abstract: We present a three-stage analysis of genome-wide SNP data in 1,222 German individuals with myocardial infarction and 1,298 controls, in silico replication in three additional genome-wide datasets of coronary artery disease (CAD) and subsequent replication in similar to 25,000 subjects. We identified one new CAD risk locus on 3q22.3 in MRAS (P = 7.44 x 10(-13); OR = 1.15, 95% CI = 1.11-1.19), and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43 (P = 4.81 x 10(-7); OR = 1.08, 95% CI = 1.05-1.11).
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Harukazu Suzuki, Alistair R. R. Forrest1, Erik van Nimwegen2, Carsten O. Daub +159 more•Institutions (33)
TL;DR: The results indicate that cellular states are constrained by complex networks involving both positive and negative regulatory interactions among substantial numbers of transcription factors and that no single transcription factor is both necessary and sufficient to drive the differentiation process.
Abstract: Using deep sequencing (deepCAGE), the FANTOM4 study measured the genome-wide dynamics of transcription-start-site usage in the human monocytic cell line THP-1 throughout a time course of growth arrest and differentiation. Modeling the expression dynamics in terms of predicted cis-regulatory sites, we identified the key transcription regulators, their time-dependent activities and target genes. Systematic siRNA knockdown of 52 transcription factors confirmed the roles of individual factors in the regulatory network. Our results indicate that cellular states are constrained by complex networks involving both positive and negative regulatory interactions among substantial numbers of transcription factors and that no single transcription factor is both necessary and sufficient to drive the differentiation process.
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TL;DR: Mask use is associated with low adherence, but adherent mask users are significantly protected against seasonal disease.
Abstract: Many countries are stockpiling face masks for use as a nonpharmaceutical intervention to control virus transmission during an influenza pandemic. We conducted a prospective cluster-randomized trial comparing surgical masks, non–fit-tested P2 masks, and no masks in prevention of influenza-like illness (ILI) in households. Mask use adherence was self-reported. During the 2006 and 2007 winter seasons, 286 exposed adults from 143 households who had been exposed to a child with clinical respiratory illness were recruited. We found that adherence to mask use significantly reduced the risk for ILI-associated infection, but <50% of participants wore masks most of the time. We concluded that household use of face masks is associated with low adherence and is ineffective for controlling seasonal respiratory disease. However, during a severe pandemic when use of face masks might be greater, pandemic transmission in households could be reduced.
Many countries are stockpiling face masks for use as nonpharmaceutical interventions to reduce viral transmission during an influenza pandemic. We conducted a prospective cluster-randomized trial comparing surgical masks, non–fit-tested P2 masks, and no masks in prevention of influenza-like illness (ILI) in households. During the 2006 and 2007 winter seasons, 286 exposed adults from 143 households who had been exposed to a child with clinical respiratory illness were recruited. Intent-to-treat analysis showed no significant difference in the relative risk of ILI in the mask use groups compared with the control group; however, <50% of those in the mask use groups reported wearing masks most of the time. Adherence to mask use was associated with a significantly reduced risk of ILI-associated infection. We concluded that household use of masks is associated with low adherence and is ineffective in controlling seasonal ILI. If adherence were greater, mask use might reduce transmission during a severe influenza pandemic.
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Medical Research Council1, Wellcome Trust Sanger Institute2, Wellcome Trust Centre for Human Genetics3, University of Oxford4, Malawi-Liverpool-Wellcome Trust Clinical Research Programme5, University of Buea6, Kwame Nkrumah University of Science and Technology7, Papua New Guinea Institute of Medical Research8, University of Ibadan9, National Institute for Biological Standards and Control10, University of Bamako11, University of London12, University College London13, Bernhard Nocht Institute for Tropical Medicine14, University of Colombo15, University of Khartoum16, Wellcome Trust17, University of Ghana18, National Institute for Medical Research19, Muhimbili University of Health and Allied Sciences20, Sapienza University of Rome21, University of Malawi22, University of Maryland, Baltimore23, Pasteur Institute24, Mahidol University25, Michigan State University26, Stockholm University27
TL;DR: These findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.
Abstract: We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.