Showing papers by "Erasmus University Medical Center published in 2016"
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TL;DR: In this article, the authors used a Bayesian hierarchical model to estimate trends in diabetes prevalence, defined as fasting plasma glucose of 7.0 mmol/L or higher, or history of diagnosis with diabetes, or use of insulin or oral hypoglycaemic drugs in 200 countries and territories in 21 regions, by sex and from 1980 to 2014.
2,782 citations
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Cambridge University Hospitals NHS Foundation Trust1, Wellcome Trust Sanger Institute2, Lund University3, Erasmus University Medical Center4, Radboud University Nijmegen5, European Bioinformatics Institute6, University of Oslo7, Oslo University Hospital8, Gachon University9, Netherlands Cancer Institute10, Université libre de Bruxelles11, University of Antwerp12, Harvard University13, University of Amsterdam14, University of Ulsan15, Hanyang University16, Memorial Sloan Kettering Cancer Center17, University of Texas MD Anderson Cancer Center18, French Institute of Health and Medical Research19, Ninewells Hospital20, ICM Partners21, University of Queensland22, University of Iceland23, Curie Institute24, University of Cambridge25, King's College London26, Institute of Cancer Research27, University of Bergen28, Singapore General Hospital29
TL;DR: This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
Abstract: We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
1,696 citations
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James Bentham1, Mariachiara Di Cesare2, Mariachiara Di Cesare1, Gretchen A Stevens3 +787 more•Institutions (246)
TL;DR: The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
Abstract: Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3–19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8–144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
1,348 citations
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TL;DR: This guideline was produced by a multidisciplinary group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to September 2014 and consensus within the guideline group on all recommendations.
Abstract: study question: What is the optimal management of women with premature ovarian insufficiency (POI) based on the best available
evidence in the literature?
summary answer: The guideline development group (GDG) formulated 99 recommendations answering 31 key questions on the
diagnosis and treatment of women with POI.
what is known already: NA.
study design, size, duration: This guideline was produced by a multidisciplinary group of experts in the field using the methodology
of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included
papers up to September 2014 and consensus within the guideline group on all recommendations. The GDG included a patient representative
to ensure input from women with POI. After finalization of the draft, the European Society for Human Reproduction and Embryology
(ESHRE) members and professional organizations were asked to review the guideline.
participants/materials, setting, methods: NA.
main results and the role of chance: The guideline provides 17 recommendations on diagnosis and assessment of POI and 46
recommendations on the different sequelae of POI and their consequences for monitoring and treatment. Furthermore, 24 recommendations
were formulated on hormone replacement therapy in women with POI, and two on alternative and complementary treatment. A chapter on
puberty induction resulted in five recommendations.
limitations, reasons for caution: The main limitation of the guideline is that, due to the lack of data, many of the recommendations
are based on expert opinion or indirect evidence from studies on post-menopausal women or women with Turner Syndrome.
wider implications of the findings: Despite the limitations, the guideline group is confident that this document will be able to
guide health care professionals in providing the best practice for managing women with POI given current evidence. Furthermore, the guideline
grouphas formulated research recommendations on the gaps in knowledge identified in the literature searches, in an attempt to stimulate research
on the key issues in POI.
801 citations
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University College London1, Karolinska Institutet2, Memorial Sloan Kettering Cancer Center3, University of Colorado Denver4, Dresden University of Technology5, Ohio State University6, Fred Hutchinson Cancer Research Center7, Erasmus University Medical Center8, French Institute of Health and Medical Research9
TL;DR: A plethora of new agents — including those targeted at specific biochemical pathways and immunotherapeutic approaches — are now in trial based on improved understanding of disease pathophysiology, providing good grounds for optimism, although mortality remains high especially in older patients.
Abstract: Acute myeloid leukaemia (AML) is a disorder characterized by a clonal proliferation derived from primitive haematopoietic stem cells or progenitor cells. Abnormal differentiation of myeloid cells results in a high level of immature malignant cells and fewer differentiated red blood cells, platelets and white blood cells. The disease occurs at all ages, but predominantly occurs in older people (>60 years of age). AML typically presents with a rapid onset of symptoms that are attributable to bone marrow failure and may be fatal within weeks or months when left untreated. The genomic landscape of AML has been determined and genetic instability is infrequent with a relatively small number of driver mutations. Mutations in genes involved in epigenetic regulation are common and are early events in leukaemogenesis. The subclassification of AML has been dependent on the morphology and cytogenetics of blood and bone marrow cells, but specific mutational analysis is now being incorporated. Improvements in treatment in younger patients over the past 35 years has largely been due to dose escalation and better supportive care. Allogeneic haematopoietic stem cell transplantation may be used to consolidate remission in those patients who are deemed to be at high risk of relapse. A plethora of new agents - including those targeted at specific biochemical pathways and immunotherapeutic approaches - are now in trial based on improved understanding of disease pathophysiology. These advances provide good grounds for optimism, although mortality remains high especially in older patients.
771 citations
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University of Helsinki1, University of Oulu2, Turku University Hospital3, University of Tampere4, University of Turku5, Hannover Medical School6, University of Cambridge7, Netherlands Cancer Institute8, Institute of Cancer Research9, University of Melbourne10, University of California, Los Angeles11, University of Erlangen-Nuremberg12, University of London13, King's College London14, Wellcome Trust Centre for Human Genetics15, Heidelberg University16, German Cancer Research Center17, French Institute of Health and Medical Research18, Copenhagen University Hospital19, University of Copenhagen20, Beckman Research Institute21, University of California, Irvine22, Technische Universität München23, University of Cologne24, Bosch25, University of Tübingen26, Ruhr University Bochum27, Karolinska Institutet28, University of Eastern Finland29, QIMR Berghofer Medical Research Institute30, Katholieke Universiteit Leuven31, University of Hamburg32, Mayo Clinic33, Cancer Council Victoria34, University of Southern California35, Laval University36, The Breast Cancer Research Foundation37, Oslo University Hospital38, Vanderbilt University39, Oulu University Hospital40, Lunenfeld-Tanenbaum Research Institute41, University of Toronto42, Leiden University Medical Center43, Erasmus University Rotterdam44, Erasmus University Medical Center45, University of Sheffield46, Pontifical Xavierian University47, Pomeranian Medical University48
TL;DR: It is suggested that loss-of-function mutations in RAD 51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
Abstract: Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
715 citations
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TL;DR: A higher risk of CHD, CVD mortality, and overall mortality in women who experience premature or early-onset menopause is indicated by a systematically review and meta-analyze of studies evaluating studies evaluating the effect of age at onset of Menopause and duration since onset ofMenopause on intermediate CVD end points,CVD outcomes, and all-cause mortality.
Abstract: Importance As many as 10% of women experience natural menopause by the age of 45 years. If confirmed, an increased risk of cardiovascular disease (CVD) and all-cause mortality associated with premature and early-onset menopause could be an important factor affecting risk of disease and mortality among middle-aged and older women. Objective To systematically review and meta-analyze studies evaluating the effect of age at onset of menopause and duration since onset of menopause on intermediate CVD end points, CVD outcomes, and all-cause mortality. Data Sources Medical databases (ie, Medline, EMBASE, and Web of Science) until March 2015. Study Selection Studies (ie, observational cohort, case-control, or cross-sectional) that assessed age at onset of menopause and/or time since onset of menopause as exposures as well as risk of cardiovascular outcomes and intermediate CVD end points in perimenopausal, menopausal, or postmenopausal women. Data Extraction and Synthesis Studies were sought if they were observational cohort, case-control, or cross-sectional studies; reported on age at onset of menopause and/or time since onset of menopause as exposures; and assessed associations with risk of CVD-related outcomes, all-cause mortality, or intermediate CVD end points. Data were extracted by 2 independent reviewers using a predesigned data collection form. The inverse-variance weighted method was used to combine relative risks to produce a pooled relative risk using random-effects models to allow for between-study heterogeneity. Main Outcomes and Measures Cardiovascular disease outcomes (ie, composite CVD, fatal and nonfatal coronary heart disease [CHD], and overall stroke and stroke mortality), CVD mortality, all-cause mortality, and intermediate CVD end points. Results Of the initially identified references, 32 studies were selected that included 310 329 nonoverlapping women. Outcomes were compared between women who experienced menopause younger than 45 years and women 45 years or older at onset; the relative risks (95% CIs) were 1.50 (1.28-1.76) for overall CHD, 1.11 (1.03-1.20) for fatal CHD, 1.23 (0.98-1.53) for overall stroke, 0.99 (0.92-1.07) for stroke mortality, 1.19 (1.08-1.31) for CVD mortality, and 1.12 (1.03-1.21) for all-cause mortality. Outcomes were also compared between women between 50 and 54 years at onset of menopause and women younger than 50 years at onset; there was a decreased risk of fatal CHD (relative risk, 0.87; 95% CI, 0.80-0.96) and no effect on stroke. Time since onset of menopause in relation to risk of developing intermediate cardiovascular traits or CVD outcomes was reported in 4 observational studies with inconsistent results. Conclusions and Relevance The findings of this review indicate a higher risk of CHD, CVD mortality, and overall mortality in women who experience premature or early-onset menopause.
484 citations
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University of Sheffield1, University of Southampton2, University of Manitoba3, University of Lausanne4, Lyon College5, Laval University6, VU University Medical Center7, Kindai University8, McGill University Health Centre9, Lund University10, Uppsala University Hospital11, Deakin University12, Nara Medical University13, The Chinese University of Hong Kong14, University of Gothenburg15, Erasmus University Medical Center16, Osaka Medical College17
TL;DR: The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines.
Abstract: Trabecular bone score (TBS) is a grey-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a BMD-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables and outcomes during follow up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% CI: 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR 1.32, 95%CI: 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95%CI: 1.65, 1.87 vs. 1.70, 95%CI: 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. This article is protected by copyright. All rights reserved.
475 citations
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Broad Institute1, Harvard University2, Oslo University Hospital3, University of Oslo4, University of Helsinki5, University of Tartu6, Boston Children's Hospital7, Illumina8, Charité9, Brigham and Women's Hospital10, deCODE genetics11, Medical Research Council12, VU University Amsterdam13, Leiden University14, Helsinki University Central Hospital15, Ludwig Maximilian University of Munich16, University of Tübingen17, Karolinska Institutet18, QIMR Berghofer Medical Research Institute19, University of Ulm20, University of Oulu21, King's College London22, Erasmus University Medical Center23, University of Tampere24, University of Duisburg-Essen25, Washington University in St. Louis26, University Medical Center Groningen27, Wellcome Trust Sanger Institute28, University of Oxford29, John Radcliffe Hospital30, Max Planck Society31, University of Kiel32, Technische Universität München33, National Institutes of Health34, Norwegian Institute of Public Health35, University of Copenhagen36, Lundbeck37, Mental Health Services38, Turku University Hospital39, University of Turku40, University of Hamburg41, St George's, University of London42, University of Iceland43, Queensland University of Technology44
TL;DR: For example, the authors identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to date is the first to be identified on chromosome X.
Abstract: Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.
471 citations
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TL;DR: Precursor origin does not affect the development of functional self-maintaining tissue-resident macrophages and the plasticity of the mononuclear phagocyte system is largest at the precursor stage.
445 citations
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TL;DR: In vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation.
Abstract: Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects. In vitro drug responses in rectal organoids positively correlated with published outcome data from clinical trials with VX-809 and VX-770, allowing us to predict from preclinical data the potential for CF patients carrying rare CFTR mutations to respond to drug therapy. We demonstrated proof of principle by selecting two subjects expressing an uncharacterized rare CFTR genotype (G1249R/F508del) who showed clinical responses to treatment with ivacaftor and one subject (F508del/R347P) who showed a limited response to drug therapy both in vitro and in vivo. These data suggest that in vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation.
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University of Amsterdam1, University of Düsseldorf2, University of Colorado Boulder3, Mayo Clinic4, University of Dammam5, French Institute of Health and Medical Research6, Otto-von-Guericke University Magdeburg7, University of Geneva8, Sun Yat-sen University9, Brown University10, Cornell University11, Erasmus University Medical Center12, University of Bari13, Sapienza University of Rome14, Policlinico Umberto I15, University of Insubria16, Beth Israel Deaconess Medical Center17, Hospital de Sant Pau18, Leipzig University19, University of São Paulo20, Dresden University of Technology21, University of Genoa22
TL;DR: In patients having surgery, intraoperative high driving pressure and changes in the level of PEEP that result in an increase of driving pressure are associated with more postoperative pulmonary complications, and a randomised controlled trial comparing ventilation based on driving pressure with usual care is needed to confirm these findings.
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TL;DR: Optimal management of IBD before and during pregnancy is essential to achieving favorable maternal and neonatal outcomes.
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TL;DR: Von Willebrand's disease is the most common inherited bleeding disorder and is generally transmitted as an autosomal dominant trait.
Abstract: Von Willebrand's disease is the most common inherited bleeding disorder and is generally transmitted as an autosomal dominant trait. It is mainly associated with mucosal bleeding and excessive bleeding after trauma or surgery. A variety of effective treatments are available.
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Virginia Commonwealth University1, University of Tokyo2, Erasmus University Rotterdam3, University of Queensland4, QIMR Berghofer Medical Research Institute5, VU University Amsterdam6, Georgetown University7, Veterans Health Administration8, University of Colorado Boulder9, University of Lausanne10, University Hospital of Lausanne11, Swiss Institute of Bioinformatics12, Greifswald University Hospital13, University of Greifswald14, VU University Medical Center15, Washington University in St. Louis16, Florida Atlantic University17, University Medical Center Groningen18, Johns Hopkins University19, Erasmus University Medical Center20
TL;DR: To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, two phenotypic approaches were applied: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative Phenotypic factor scores derived from a multivariate analysis combining information across the clinical phenotypes.
Abstract: Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat–response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case–control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10−8); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10−9). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.
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TL;DR: It is observed that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression, and genetic and epigenetic heterogeneity can occur with distinct kinetics likely to affect the biological and clinical features of tumors.
Abstract: Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diversity for epigenetic compartments, and almost no data exist for acute myeloid leukemia (AML). We examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epialleles), somatic mutations, and transcriptomes of AML patient samples at serial time points. We observed that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression. Epigenetic and genetic allelic burden and patterning followed different patterns and kinetics during disease progression. We observed a subset of AMLs with high epiallele and low somatic mutation burden at diagnosis, a subset with high somatic mutation and lower epiallele burdens at diagnosis, and a subset with a mixed profile, suggesting distinct modes of tumor heterogeneity. Genes linked to promoter-associated epiallele shifts during tumor progression showed increased single-cell transcriptional variance and differential expression, suggesting functional impact on gene regulation. Thus, genetic and epigenetic heterogeneity can occur with distinct kinetics likely to affect the biological and clinical features of tumors.
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TL;DR: Of the criteria used to recommend a switch to active treatment, more than two positive cores and a PSA DT of 0-3 yr were not predictive of unfavorable pathologic outcome on RP, resulting in a substantial group of men discontinued AS without subsequent unfavorable tumor features on RP.
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TL;DR: A large cohort of patients with antibodies against contactin-associated protein-like 2 (Caspr2) and the clinical spectrum of this disorder is reported, finding that the resulting syndrome may vary among patients but it usually includes a set of well-established symptoms.
Abstract: Objective: To report a large cohort of patients with antibodies against contactin-associated protein-like 2 (Caspr2) and provide the clinical spectrum of this disorder. Methods: Serum and CSF samples were assessed at 2 neuroimmunology centers in Barcelona and Rotterdam. Patients were included if Caspr2 antibodies were confirmed with 2 independent techniques, including brain immunohistochemistry and cell-based assay. Clinical information was obtained by the authors or provided by treating physicians after patients9 informed consent. Results: Median age at symptom onset was 66 years. Of 38 patients, 34 were male. Median time to nadir of disease was 4 months (in 30% >1 year). The most frequent syndromes included limbic encephalitis (42%) and Morvan syndrome (29%). Seventy-seven percent of the patients had ≥3 of the following symptoms: encephalopathy (cognitive deficits/seizures), cerebellar dysfunction, peripheral nervous system hyperexcitability, dysautonomia, insomnia, neuropathic pain, or weight loss. A tumor, mostly thymoma, occurred in 19% of the patients. Immunoglobulin G4 subclass antibodies were present in all patients; 63% also had immunoglobulin G1 antibodies. Treatment response occurred in 93% of the patients and 25% had clinical relapses. Conclusions: Caspr2 antibodies associate with a treatable disorder that predominantly affects elderly men. The resulting syndrome may vary among patients but it usually includes a set of well-established symptoms. Recognition of this spectrum of symptoms and consideration of the protracted clinical course are important for early diagnosis of this disorder. Prompt immunotherapy and tumor therapy (if needed) often result in improvement.
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TL;DR: Recent advances in the study of the transmission, pathogenesis and evolution of human noroviruses are described, and the ongoing risk of norovirus outbreaks is considered, together with the future prospects for therapeutics, in a rapidly changing world.
Abstract: Norovirus infections are a major cause of gastroenteritis, and outbreaks occur frequently. Several factors are currently increasing the challenge posed by norovirus infections to global health, notably the increasing number of infections in immunocompromised individuals, who are more susceptible to disease, and the globalization of the food industry, which enables large norovirus outbreaks to occur on an international scale. Furthermore, the rapid rate of the genetic and antigenic evolution of circulating noroviruses complicates the development of vaccines and therapies that are required to counter these challenges. In this Review, we describe recent advances in the study of the transmission, pathogenesis and evolution of human noroviruses, and consider the ongoing risk of norovirus outbreaks, together with the future prospects for therapeutics, in a rapidly changing world.
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TL;DR: Enhanced neonatal Th2 cell skewing to inhaled allergens results from postnatal hyperactivity of the IL-33 axis during a period of maximal lung remodeling.
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TL;DR: S sarcopenia is an independent predictor for outcome in liver transplantation patients and could be used for risk assessment and less‐consistent evidence suggested a higher complication rate, particularly infections, in sarcopenic patients.
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TL;DR: In this paper, the feasibility, safety, and cost of DPYD*2A genotype-guided dosing were investigated for patients who intended to be treated with fluoropyrimidine-based chemotherapy.
Abstract: PurposeFluoropyrimidines are frequently prescribed anticancer drugs. A polymorphism in the fluoropyrimidine metabolizing enzyme dihydropyrimidine dehydrogenase (DPD; ie, DPYD*2A) is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. This study determined the feasibility, safety, and cost of DPYD*2A genotype–guided dosing.Patients and MethodsPatients intended to be treated with fluoropyrimidine-based chemotherapy were prospectively genotyped for DPYD*2A before start of therapy. Variant allele carriers received an initial dose reduction of ≥ 50% followed by dose titration based on tolerance. Toxicity was the primary end point and was compared with historical controls (ie, DPYD*2A variant allele carriers receiving standard dose described in literature) and with DPYD*2A wild-type patients treated with the standard dose in this study. Secondary end points included a model-based cost analysis, as well as pharmacokinetic and DPD enzyme activity analyses.ResultsA total of 2,03...
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TL;DR: According to moderate quality evidence, corticosteroids given alone do not significantly hasten recovery from GBS or affect the long-term outcome.
Abstract: Background
Guillain-Barre syndrome (GBS) is an acute paralysing disease caused by inflammation of the peripheral nerves, which corticosteroids would be expected to benefit.
Objectives
To examine the ability of corticosteroids to hasten recovery and reduce the long-term morbidity from GBS.
Search methods
On 12 January 2016, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We also searched trials registries.
Selection criteria
We included randomised controlled trials (RCTs) or quasi-RCTs of any form of corticosteroid or adrenocorticotrophic hormone versus placebo or supportive care alone in GBS. Our primary outcome was change in disability grade on a seven-point scale after four weeks. Secondary outcomes included time from randomisation until recovery of unaided walking, time from randomisation until discontinuation of ventilation (for those ventilated), death, death or disability (inability to walk without aid) after 12 months, relapse, and adverse events.
Data collection and analysis
The review authors used standard methods expected by Cochrane.
Main results
The review authors discovered no new trials in the new searches in June 2009, November 2011, or January 2016. Six trials with 587 participants provided data for the primary outcome. According to moderate quality evidence, the disability grade change after four weeks in the corticosteroid groups was not significantly different from that in the control groups, mean difference (MD) 0.36 less improvement (95% confidence intervals (CI) 0.16 more to 0.88 less improvement). In four trials of oral corticosteroids with 120 participants in total, there was very low quality evidence of less improvement after four weeks with corticosteroids than without corticosteroids, MD 0.82 disability grades less improvement (95% CI 0.17 to 1.47 grades less). In two trials with a combined total of 467 participants, there was moderate quality evidence of no significant difference of a disability grade more improvement after four weeks with intravenous corticosteroids (MD 0.17, 95% CI -0.06 to 0.39). According to moderate quality evidence, there was also no significant difference between the corticosteroid treated and control groups for improvement by one or more grades after four weeks (risk ratio (RR) 1.08, 95% CI 0.93 to 1.24) or for death or disability after one year (RR 1.51, 95% CI 0.91 to 2.5). We found high quality evidence that the occurrence of diabetes was more common (RR 2.21, 95% CI 1.19 to 4.12) and hypertension less common (RR 0.15, 95% CI 0.05 to 0.41) in the corticosteroid-treated participants.
Authors' conclusions
According to moderate quality evidence, corticosteroids given alone do not significantly hasten recovery from GBS or affect the long-term outcome. According to very low quality evidence, oral corticosteroids delay recovery. Diabetes requiring insulin was more common and hypertension less common with corticosteroids based on high quality evidence.
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TL;DR: The role of endothelial dysfunction and inflammation is reviewed to explain the link between renal dysfunction and HFpEF, which allows for identification of new early risk markers, prognostic factors, and unique targets for intervention.
Abstract: Renal dysfunction in heart failure with preserved ejection fraction (HFpEF) is common and is associated with increased mortality. Impaired renal function is also a risk factor for developing HFpEF. A new paradigm for HFpEF, proposing a sequence of events leading to myocardial remodelling and dysfunction in HFpEF, was recently introduced, involving inflammatory, microvascular, and cardiac components. The kidney might play a key role in this systemic process. Renal impairment causes metabolic and systemic derangements in circulating factors, causing an activated systemic inflammatory state and endothelial dysfunction, which may lead to cardiomyocyte stiffening, hypertrophy, and interstitial fibrosis via cross-talk between the endothelium and cardiomyocyte compartments. Here, we review the role of endothelial dysfunction and inflammation to explain the link between renal dysfunction and HFpEF, which allows for identification of new early risk markers, prognostic factors, and unique targets for intervention.
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TL;DR: The loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
Abstract: To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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Erasmus University Rotterdam1, University of Alabama at Birmingham2, Boston University3, Harvard University4, National Institutes of Health5, Emory University6, University of Minnesota7, University of Washington8, University of Cambridge9, University of Edinburgh10, University of Queensland11, University of Michigan12, University of Texas Health Science Center at Houston13, Johns Hopkins University14, Stanford University15, University of Turin16, Technische Universität München17, University of Exeter18, VA Palo Alto Healthcare System19, VA Boston Healthcare System20, University of Düsseldorf21, University of California, Los Angeles22, Max Planck Society23, Mayo Clinic24, University of Ulm25, University of Kentucky26, Imperial College London27, Erasmus University Medical Center28
TL;DR: A meta-analysis of epigenome-wide association studies of serum C-reactive protein (CRP) in a large European population and trans-ethnic replication in African Americans identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.
Abstract: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.
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TL;DR: The benefit of IAT was greatest in patients with good collaterals on baseline computed tomographic angiography in the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN).
Abstract: Background and Purpose— Recent randomized trials have proven the benefit of intra-arterial treatment (IAT) with retrievable stents in acute ischemic stroke. Patients with poor or absent collaterals (preexistent anastomoses to maintain blood flow in case of a primary vessel occlusion) may gain less clinical benefit from IAT. In this post hoc analysis, we aimed to assess whether the effect of IAT was modified by collateral status on baseline computed tomographic angiography in the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN).
Methods— MR CLEAN was a multicenter, randomized trial of IAT versus no IAT. Primary outcome was the modified Rankin Scale at 90 days. The primary effect parameter was the adjusted common odds ratio for a shift in direction of a better outcome on the modified Rankin Scale. Collaterals were graded from 0 (absent) to 3 (good). We used multivariable ordinal logistic regression analysis with interaction terms to estimate treatment effect modification by collateral status.
Results— We found a significant modification of treatment effect by collaterals ( P =0.038). The strongest benefit (adjusted common odds ratio 3.2 [95% confidence intervals 1.7–6.2]) was found in patients with good collaterals (grade 3). The adjusted common odds ratio was 1.6 [95% confidence intervals 1.0–2.7] for moderate collaterals (grade 2), 1.2 [95% confidence intervals 0.7–2.3] for poor collaterals (grade 1), and 1.0 [95% confidence intervals 0.1–8.7] for patients with absent collaterals (grade 0).
Conclusions— In MR CLEAN, baseline computed tomographic angiography collateral status modified the treatment effect. The benefit of IAT was greatest in patients with good collaterals on baseline computed tomographic angiography. Treatment benefit appeared less and may be absent in patients with absent or poor collaterals.
Clinical Trial Registration— URL: and . Unique identifier: (NTR)1804 and [ISRCTN10888758][1], respectively.
[1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN10888758
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TL;DR: Current developments in the field of alternative donors, including cord blood and haploidentical donors are highlighted, and reduced-intensity alloHSCT in older AML recipients who represent the predominant category of patients with AML who have a high risk of relapse in first remission are discussed.
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Wellcome Trust1, Los Alamos National Laboratory2, Wellcome Trust Sanger Institute3, Lund University4, Erasmus University Medical Center5, Radboud University Nijmegen6, Hanyang University7, Université libre de Bruxelles8, University of Texas MD Anderson Cancer Center9, University of Antwerp10, Royal Brisbane and Women's Hospital11, University of Queensland12, University of Iceland13, University of Dundee14, University of Amsterdam15, University of Oslo16, Harvard University17, Medical Research Council18, Cambridge University Hospitals NHS Foundation Trust19
TL;DR: Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, it is shown that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization.
Abstract: Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.
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TL;DR: Meuwissen and collaborators define a novel genetic cause of pseudo-TORCH syndrome, which resembles the sequelae of congenital infection and represents a novel type I interferonopathy.
Abstract: Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutieres syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.