Showing papers by "University of Gothenburg published in 2013"
TL;DR: A practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics, which makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries.
Abstract: The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
10,947 citations
John N. Weinstein1, John N. Weinstein2, Eric A. Collisson3, Gordon B. Mills2 +376 more•Institutions (31)
TL;DR: The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA with a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages.
Abstract: The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.
5,294 citations
European Institute of Oncology1, Harvard University2, University of Sydney3, Institut Jules Bordet4, Kantonsspital St. Gallen5, University of St. Gallen6, Loyola University Chicago7, Institut Gustave Roussy8, Karolinska Institutet9, University of Bordeaux10, University of Geneva11, University of Pittsburgh12, University of Copenhagen13, University of Newcastle14, Medical University of Vienna15, University of Toronto16, University of Michigan17, Memorial Sloan Kettering Cancer Center18, Mayo Clinic19, Gdańsk Medical University20, University of Gothenburg21, Baylor College of Medicine22, University of North Carolina at Chapel Hill23, Université libre de Bruxelles24, Netherlands Cancer Institute25, Fudan University26, Kyoto University27, King's College London28, University of Göttingen29, Emory University30
TL;DR: The 13th St Gallen International Breast Cancer Conference (2013) Expert Panel reviewed and endorsed substantial new evidence on aspects of the local and regional therapies for early breast cancer, supporting less extensive surgery to the axilla and shorter durations of radiation therapy.
2,831 citations
University of Tartu1, American Museum of Natural History2, University of Gothenburg3, University of Aberdeen4, James Hutton Institute5, Cooperative Institute for Research in Environmental Sciences6, University of California, Berkeley7, Aberystwyth University8, Estonian University of Life Sciences9, Spanish National Research Council10, Royal Botanic Gardens11, Academy of Sciences of the Czech Republic12, Swedish University of Agricultural Sciences13, University of Tennessee14, University of Helsinki15, Stanford University16, Ludwig Maximilian University of Munich17, University of Toronto18, University of Florida19, University of New Mexico20, University of Tübingen21
TL;DR: All fungal species represented by at least two ITS sequences in the international nucleotide sequence databases are now given a unique, stable name of the accession number type, and the term ‘species hypothesis’ (SH) is introduced for the taxa discovered in clustering on different similarity thresholds.
Abstract: The nuclear ribosomal internal transcribed spacer (ITS) region is the formal fungal barcode and in most cases the marker of choice for the exploration of fungal diversity in environmental samples. Two problems are particularly acute in the pursuit of satisfactory taxonomic assignment of newly generated ITS sequences: (i) the lack of an inclusive, reliable public reference data set and (ii) the lack of means to refer to fungal species, for which no Latin name is available in a standardized stable way. Here, we report on progress in these regards through further development of the UNITE database (http://unite.ut.ee) for molecular identification of fungi. All fungal species represented by at least two ITS sequences in the international nucleotide sequence databases are now given a unique, stable name of the accession number type (e.g. Hymenoscyphus pseudoalbidus|GU586904|SH133781.05FU), and their taxonomic and ecological annotations were corrected as far as possible through a distributed, third-party annotation effort. We introduce the term ‘species hypothesis’ (SH) for the taxa discovered in clustering on different similarity thresholds (97–99%). An automatically or manually designated sequence is chosen to represent each such SH. These reference sequences are released (http://unite.ut.ee/repository.php) for use by the scientific community in, for example, local sequence similarity searches and in the QIIME pipeline. The system and the data will be updated automatically as the number of public fungal ITS sequences grows. We invite everybody in the position to improve the annotation or metadata associated with their particular fungal lineages of expertise to do so through the new Web-based sequence management system in UNITE.
2,605 citations
TL;DR: The gut microbiota has a beneficial role during normal homeostasis, modulating the host's immune system as well as influencing host development and physiology, including organ development and morphogenesis, and host metabolism.
Abstract: Establishing and maintaining beneficial interactions between the host and its associated microbiota are key requirements for host health. Although the gut microbiota has previously been studied in the context of inflammatory diseases, it has recently become clear that this microbial community has a beneficial role during normal homeostasis, modulating the host's immune system as well as influencing host development and physiology, including organ development and morphogenesis, and host metabolism. The underlying molecular mechanisms of host-microorganism interactions remain largely unknown, but recent studies have begun to identify the key signalling pathways of the cross-species homeostatic regulation between the gut microbiota and its host.
2,585 citations
TL;DR: This work uses shotgun sequencing to characterize the faecal metagenome of 145 European women with normal, impaired or diabetic glucose control, and develops a mathematical model based on metagenomic profiles that identified T2D with high accuracy.
Abstract: Recent evidence has suggested that altered gut microbiota are associated with various metabolic diseases including obesity, diabetes and cardiovascular disease. Fredrik Bckhed and colleagues characterized the faecal metagenome of a cohort of European women with normal, impaired or diabetic glucose control and compared these findings to a recently described Chinese cohort. Their analysis reveals differences in the discriminant metagenomic markers for type 2 diabetes between the two cohorts, suggesting that metagenomic predictive tools may have to be specific for age and geographical populations under investigation.
2,248 citations
TL;DR: In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targetedTemperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C.
Abstract: In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P = 0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P = 0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P = 0.87). The results of analyses adjusted for known prognostic factors were similar. Conclusions In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart–Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.)
2,159 citations
TL;DR: Empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Abstract: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
2,058 citations
Copenhagen University Hospital1, French Institute of Health and Medical Research2, University College London3, Columbia University4, University of Gothenburg5, University of Western Ontario6, University of the Witwatersrand7, University of Amsterdam8, University of São Paulo9, University of Western Australia10, Ludwig Maximilian University of Munich11, University of Palermo12, University of Milan13, University of Groningen14, University Medical Center15, University of California, Los Angeles16, University of London17, Radboud University Nijmegen18, University of Helsinki19, University of Copenhagen20
TL;DR: There is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition, familial hypercholesterolaemia.
Abstract: Aims The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD).
Methods and results Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD.
Conclusion Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.
2,039 citations
TL;DR: The need for standardization of specimen handling, appropriate normative controls, and isolation and analysis techniques to facilitate comparison of results is emphasized, and it is recognized that continual development and evaluation of techniques will be necessary as new knowledge is amassed.
Abstract: The emergence of publications on extracellular RNA (exRNA) and extracellular vesicles (EV) has highlighted the potential of these molecules and vehicles as biomarkers of disease and therapeutic targets. These findings have created a paradigm shift, most prominently in the field of oncology, prompting expanded interest in the field and dedication of funds for EV research. At the same time, understanding of EV subtypes, biogenesis, cargo and mechanisms of shuttling remains incomplete. The techniques that can be harnessed to address the many gaps in our current knowledge were the subject of a special workshop of the International Society for Extracellular Vesicles (ISEV) in New York City in October 2012. As part of the “ISEV Research Seminar: Analysis and Function of RNA in Extracellular Vesicles (evRNA)”, 6 round-table discussions were held to provide an evidence-based framework for isolation and analysis of EV, purification and analysis of associated RNA molecules, and molecular engineering of EV for therapeutic intervention. This article arises from the discussion of EV isolation and analysis at that meeting. The conclusions of the round table are supplemented with a review of published materials and our experience. Controversies and outstanding questions are identified that may inform future research and funding priorities. While we emphasize the need for standardization of specimen handling, appropriate normative controls, and isolation and analysis techniques to facilitate comparison of results, we also recognize that continual development and evaluation of techniques will be necessary as new knowledge is amassed. On many points, consensus has not yet been achieved and must be built through the reporting of well-controlled experiments. Keywords: extracellular vesicle; exosome; microvesicle; standardization; isolation (Published: 27 May 2013) Citation: Journal of Extracellular Vesicles 2013, 2 : 20360 - http://dx.doi.org/10.3402/jev.v2i0.20360
1,840 citations
TL;DR: It is suggested that the gut microbiota not only regulates secondary bile acids metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum.
TL;DR: Whereas high insulin and/or high glucose at baseline predicted favourable treatment effects, high baseline BMI did not, indicating that current selection criteria for bariatric surgery need to be revised.
Abstract: Obesity is a risk factor for diabetes, cardiovascular disease events, cancer and overall mortality. Weight loss may protect against these conditions, but robust evidence for this has been lacking. The Swedish Obese Subjects (SOS) study is the first long-term, prospective, controlled trial to provide information on the effects of bariatric surgery on the incidence of these objective endpoints. The SOS study involved 2010 obese subjects who underwent bariatric surgery [gastric bypass (13%), banding (19%) and vertical banded gastroplasty (68%)] and 2037 contemporaneously matched obese control subjects receiving usual care. The age of participants was 37-60 years and body mass index (BMI) was ≥34 kg m(-2) in men and ≥38 kg m(-2) in women. Here, we review the key SOS study results published between 2004 and 2012. Follow-up periods varied from 10 to 20 years in different reports. The mean changes in body weight after 2, 10, 15 and 20 years were -23%, -17%, -16% and -18% in the surgery group and 0%, 1%, -1% and -1% in the control group respectively. Compared with usual care, bariatric surgery was associated with a long-term reduction in overall mortality (primary endpoint) [adjusted hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.54-0.92; P = 0.01] and decreased incidences of diabetes (adjusted HR=0.17; P < 0.001), myocardial infarction (adjusted HR = 0.71; P = 0.02), stroke (adjusted HR=0.66; P = 0.008) and cancer (women: adjusted HR = 0.58; P = 0.0008; men: n.s.]. The diabetes remission rate was increased severalfold at 2 years [adjusted odds ratio (OR) = 8.42; P < 0.001] and 10 years (adjusted OR = 3.45; P < 0.001). Whereas high insulin and/or high glucose at baseline predicted favourable treatment effects, high baseline BMI did not, indicating that current selection criteria for bariatric surgery need to be revised.
TL;DR: A review of fundamental brain development processes that occur in both rodents and humans to delineate a comparable time course of postnatal brain development across species offers guidelines for researchers when considering the most appropriate rodent age for the developmental stage or process of interest to approximate human brain development.
Imperial College London1, Copenhagen Business School2, University of Gothenburg3, Royal Institute of Technology4, Polytechnic University of Valencia5, University of Bologna6, Collegio Carlo Alberto7, University of Turin8, University of Cambridge9, University of Kassel10, University of Strasbourg11, University of Bordeaux12
TL;DR: In this paper, the authors present a systematic review of research on academic scientists' involvement in collaborative research, contract research, consulting and informal relationships for university-industry knowledge transfer, which they refer as academic engagement.
Population Health Research Institute1, The George Institute for Global Health2, University of Isfahan3, College of Health Sciences, Bahrain4, Aga Khan University5, University of La Frontera6, Cardiovascular Institute of the South7, Université de Sherbrooke8, Peking Union Medical College9, University of the Western Cape10, University of Gothenburg11, Wrocław Medical University12, University of Ottawa13, Independent University, Bangladesh14, Dubai Health Authority15, University of London16, St. John's University17
TL;DR: The findings suggest substantial room for improvement in hypertension diagnosis and treatment and suggest low education was associated with lower rates of awareness, treatment, and control in LICs, but not in other countries.
Abstract: Importance Hypertension is the most important preventable cause of morbidity and mortality globally, yet there are relatively few data collected using standardized methods. Objective To examine hypertension prevalence, awareness, treatment, and control in participants at baseline in the Prospective Urban Rural Epidemiology (PURE) study. Design, Setting, and Participants A cross-sectional study of 153 996 adults (complete data for this analysis on 142 042) aged 35 to 70 years, recruited between January 2003 and December 2009. Participants were from 628 communities in 3 high-income countries (HIC), 10 upper–middle-income and low–middle-income countries (UMIC and LMIC), and 4 low-income countries (LIC). Main Outcomes and Measures Hypertension was defined as individuals with self-reported treated hypertension or with an average of 2 blood pressure measurements of at least 140/90 mm Hg using an automated digital device. Awareness was based on self-reports, treatment was based on the regular use of blood pressure–lowering medications, and control was defined as individuals with blood pressure lower than 140/90 mm Hg. Results Among the 142 042 participants, 57 840 (40.8%; 95% CI, 40.5%-41.0%) had hypertension and 26 877 (46.5%; 95% CI, 46.1%-46.9%) were aware of the diagnosis. Of those who were aware of the diagnosis, the majority (23 510 [87.5%; 95% CI, 87.1%-87.9%] of those who were aware) were receiving pharmacological treatments, but only a minority of those receiving treatment were controlled (7634 [32.5%; 95% CI, 31.9%-33.1%]). Overall, 30.8%, 95% CI, 30.2%-31.4% of treated patients were taking 2 or more types of blood pressure–lowering medications. The percentages aware (49.0% [95% CI, 47.8%-50.3%] in HICs, 52.5% [95% CI, 51.8%-53.2%] in UMICs, 43.6% [95% CI, 42.9%-44.2%] in LMICs, and 40.8% [95% CI, 39.9%-41.8%] in LICs) and treated (46.7% [95% CI, 45.5%-47.9%] in HICs, 48.3%, [95% CI, 47.6%-49.1%] in UMICs, 36.9%, [95% CI, 36.3%-37.6%] in LMICs, and 31.7% [95% CI, 30.8%-32.6%] in LICs) were lower in LICs compared with all other countries for awareness (P Conclusions and Relevance Among a multinational study population, 46.5% of participants with hypertension were aware of the diagnosis, with blood pressure control among 32.5% of those being treated. These findings suggest substantial room for improvement in hypertension diagnosis and treatment.
Ashley Beecham1, Nikolaos A. Patsopoulos2, Nikolaos A. Patsopoulos3, Dionysia K. Xifara4 +203 more•Institutions (73)
TL;DR: This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
Abstract: Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 10 × 10(-4)) In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 50 × 10(-8)), 3 of which we found after conditioning on previously identified variants Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals
TL;DR: Strategies to prevent retinopathy of prematurity will depend on optimisation of oxygen saturation, nutrition, and normalisation of concentrations of essential factors such as insulin-like growth factor 1 and ω-3 polyunsaturated fatty acids to promote normal growth and limit suppression of neurovascular development.
TL;DR: The stomach and colon have two layers of mucus; the inner layer is attached and the outer layer is less dense and unattached, and the inner mucus layer can be penetrable to bacteria by several other mechanisms, including aberrations in the immune system.
Abstract: Gastrointestinal mucus is the first line of defence against bac-teria; the organization of this protective system varies markedly along the digestive tract. In this Review, the authors provide an overview of the mucus system and discuss the role of mucus in health and disease.
University of Gothenburg1, Uppsala University2, University of California, Berkeley3, Yale University4, University of Tennessee5, Goethe University Frankfurt6, Kansas State University7, University of Greifswald8, Chalmers University of Technology9, American Museum of Natural History10, University of Oslo11
TL;DR: ITSx is introduced, a Perl‐based software tool to extract ITS1, 5.8S and ITS2 – as well as full‐length ITS sequences – from both Sanger and high‐throughput sequencing data sets, and is rich in features and written to be easily incorporated into automated sequence analysis pipelines.
Abstract: Summary 1. The nuclear ribosomal internal transcribed spacer (ITS) region is the primary choice for molecular identification of fungi. Its two highly variable spacers (ITS1 and ITS2) are usually species specific, whereas the intercalary 5.8S gene is highly conserved. For sequence clustering and BLAST searches, it is often advantageous to rely on either one of the variable spacers but not the conserved 5.8S gene. To identify and extract ITS1 and ITS2 from large taxonomic and environmental data sets is, however, often difficult, and many ITS sequences are incorrectly delimited in the public sequence databases. 2. We introduce ITSx, a Perl-based software tool to extract ITS1, 5.8S and ITS2 – as well as full-length ITS sequences – from both Sanger and high-throughput sequencing data sets. ITSx uses hidden Markov models computed from large alignments of a total of 20 groups of eukaryotes, including fungi, metazoans and plants, and the sequence extraction is based on the predicted positions of the ribosomal genes in the sequences. 3. ITSx has a very high proportion of true-positive extractions and a low proportion of false-positive extractions. Additionally, process parallelization permits expedient analyses of very large data sets, such as a one million sequence amplicon pyrosequencing data set. ITSx is rich in features and written to be easily incorporated into automated sequence analysis pipelines. 4. ITSx paves the way for more sensitive BLAST searches and sequence clustering operations for the ITS region in eukaryotes. The software also permits elimination of non-ITS sequences from any data set. This is particularly useful for amplicon-based next-generation sequencing data sets, where insidious non-target sequences are often found among the target sequences. Such non-target sequences are difficult to find by other means and would contribute noise to diversity estimates if left in the data set.
UCL Institute of Child Health1, University of Helsinki2, National Institutes of Health3, University of Graz4, VU University Amsterdam5, Harvard University6, University of Cambridge7, McGill University8, Wake Forest University9, Peninsula College of Medicine and Dentistry10, University of Gothenburg11, University of Zagreb12, University of Edinburgh13, University of Maryland, Baltimore14, Churchill Hospital15, Wellcome Trust Centre for Human Genetics16, University of Oxford17, University of Oulu18, Heidelberg University19, Uppsala University20, Western General Hospital21, King's College London22, Wellcome Trust Sanger Institute23, NHS Blood and Transplant24, University of Southampton25, GlaxoSmithKline26, University of London27, University College London28
TL;DR: A mendelian randomization study based on data from multiple cohorts conducted by Karani Santhanakrishnan Vimaleswaran and colleagues re-examines the causal nature of the relationship between vitamin D levels and obesity.
Abstract: BACKGROUND: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS AND FINDINGS: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). CONCLUSIONS: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
TL;DR: A systematic review of longitudinal studies to evaluate the direction of association between symptoms of depression and intimate partner violence finds no clear direction in either direction.
Abstract: Karen Devries and colleagues conduct a systematic review of longitudinal studies to evaluate the direction of association between symptoms of depression and intimate partner violence. Please see later in the article for the Editors' Summary
TL;DR: The authors' results demonstrate that centrifugation-based protocols are simple and fast systems to distinguish subpopulations of extracellular vesicles, but they are indistinguishable using CD63-coated beads for flow cytometry analysis.
Abstract: Introduction: In recent years, there has been an exponential increase in the number of studies aiming to understand the biology of exosomes, as well as other extracellular vesicles. However, classification of membrane vesicles and the appropriate protocols for their isolation are still under intense discussion and investigation. When isolating vesicles, it is crucial to use systems that are able to separate them, to avoid cross-contamination. Method: EVs released from three different kinds of cell lines: HMC-1, TF-1 and BV-2 were isolated using two centrifugation-based protocols. In protocol 1, apoptotic bodies were collected at 2,000g, followed by filtering the supernatant through 0.8 mm pores and pelleting of microvesicles at 12,200g. In protocol 2, apoptotic bodies and microvesicles were collected together at 16,500g, followed by filtering of the supernatant through 0.2 mm pores and pelleting of exosomes at 120,000g. Extracellular vesicles were analyzed by transmission electron microscopy, flow cytometry and the RNA profiles were investigated using a Bioanalyzer † . Results: RNA profiles showed that ribosomal RNA was primary detectable in apoptotic bodies and smaller RNAs without prominent ribosomal RNA peaks in exosomes. In contrast, microvesicles contained little or no RNA except for microvesicles collected from TF-1 cell cultures. The different vesicle pellets showed highly different distribution of size, shape and electron density with typical apoptotic body, microvesicle and exosome characteristics when analyzed by transmission electron microscopy. Flow cytometry revealed the presence of CD63 and CD81 in all vesicles investigated, as well as CD9 except in the TF-1-derived vesicles, as these cells do not express CD9. Conclusions: Our results demonstrate that centrifugation-based protocols are simple and fast systems to distinguish subpopulations of extracellular vesicles. Different vesicles show different RNA profiles and morphological characteristics, but they are indistinguishable using CD63-coated beads for flow cytometry analysis.
TL;DR: Administration of 25 or 50 mg OCA for 6 weeks was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease.
TL;DR: In this article, a genome-wide association study of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490 individuals, and three independent SNPs are genome wide significant (rs9320913, rs11584700, rs4851266).
Abstract: A genome-wide association study of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent SNPs are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (R2 ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈ 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.
TL;DR: A critical review of current hypotheses regarding the pathogenetic involvement of microbiota in FGID is provided and the results of microbiota-directed interventions are evaluated and clinical guidance on modulation of gut microbiota in IBS is provided.
Abstract: It is increasingly perceived that gut host–microbial interactions are important elements in the pathogenesis of functional gastrointestinal disorders (FGID) The most convincing evidence to date is the finding that functional dyspepsia and irritable bowel syndrome (IBS) may develop in predisposed individuals following a bout of infectious gastroenteritis There has been a great deal of interest in the potential clinical and therapeutic implications of small intestinal bacterial overgrowth in IBS However, this theory has generated much debate because the evidence is largely based on breath tests which have not been validated The introduction of culture-independent molecular techniques provides a major advancement in our understanding of the microbial community in FGID Results from 16S rRNA-based microbiota profiling approaches demonstrate both quantitative and qualitative changes of mucosal and faecal gut microbiota, particularly in IBS Investigators are also starting to measure host–microbial interactions in IBS The current working hypothesis is that abnormal microbiota activate mucosal innate immune responses which increase epithelial permeability, activate nociceptive sensory pathways and dysregulate the enteric nervous system While we await important insights in this field, the microbiota is already a therapeutic target Existing controlled trials of dietary manipulation, prebiotics, probiotics, synbiotics and non-absorbable antibiotics are promising, although most are limited by suboptimal design and small sample size In this article, the authors provide a critical review of current hypotheses regarding the pathogenetic involvement of microbiota in FGID and evaluate the results of microbiota-directed interventions The authors also provide clinical guidance on modulation of gut microbiota in IBS
TL;DR: Taking advantage of the collective experience of six research groups, the different stages involved in fungal community analysis are reviewed, from field sampling via laboratory procedures to bioinformatics and data interpretation, and potential pitfalls, alternatives, and solutions are discussed.
Abstract: Summary Novel high-throughput sequencing methods outperform earlier approaches in terms of resolution and magnitude. They enable identification and relative quantification of community members and offer new insights into fungal community ecology. These methods are currently taking over as the primary tool to assess fungal communities of plant-associated endophytes, pathogens, and mycorrhizal symbionts, as well as free-living saprotrophs. Taking advantage of the collective experience of six research groups, we here review the different stages involved in fungal community analysis, from field sampling via laboratory procedures to bioinformatics and data interpretation. We discuss potential pitfalls, alternatives, and solutions. Highlighted topics are challenges involved in: obtaining representative DNA/RNA samples and replicates that encompass the targeted variation in community composition, selection of marker regions and primers, options for amplification and multiplexing, handling of sequencing errors, and taxonomic identification. Without awareness of methodological biases, limitations of markers, and bioinformatics challenges, large-scale sequencing projects risk yielding artificial results and misleading conclusions.
TL;DR: In this article, the authors take a critical look at the design thinking discourse, one that has different meanings depending on its context, and find five different discourses of "designerly thinking" or ways to describe what designers do in practice, that have distinctly different epistemological roots.
Abstract: This paper takes a critical look at the design thinking discourse, one that has different meanings depending on its context. Within the managerial realm, design thinking has been described as the best way to be creative and innovate, while within the design realm, design thinking may be partly ignored and taken for granted, despite a long history of academic development and debate. In the design area, we find five different discourses of ‘designerly thinking’, or ways to describe what designers do in practice, that have distinctly different epistemological roots. These different discourses do not stand in competition with each other but could be developed in parallel. We also observe that the management discourse has three distinct origins, but in general has a more superficial and popular character and is less academically anchored than the designerly one. Also, the management design thinking discourse seldom refers to designerly thinking and thereby hinders cumulative knowledge construction. We suggest further research to link the discourses.
TL;DR: It is the intention of this paper to encourage transparency and accuracy in future studies that measure the aerobic metabolism of fishes, and to highlight the fundamental issues with assuming broad relevance of the OCLTT hypothesis.
Abstract: Measurements of aerobic scope [the difference between minimum and maximum oxygen consumption rate (![Graphic][1] and ![Graphic][2] , respectively)] are increasing in prevalence as a tool to address questions relating to fish ecology and the effects of climate change. However, there are underlying issues regarding the array of methods used to measure aerobic scope across studies and species. In an attempt to enhance quality control before the diversity of issues becomes too great to remedy, this paper outlines common techniques and pitfalls associated with measurements of ![Graphic][3] , ![Graphic][4] and aerobic scope across species and under different experimental conditions. Additionally, we provide a brief critique of the oxygen- and capacity-limited thermal tolerance (OCLTT) hypothesis, a concept that is intricately dependent on aerobic scope measurements and is spreading wildly throughout the literature despite little evidence for its general applicability. It is the intention of this paper to encourage transparency and accuracy in future studies that measure the aerobic metabolism of fishes, and to highlight the fundamental issues with assuming broad relevance of the OCLTT hypothesis.
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TL;DR: Bioinspired exosome-mimetic nanovesicles that deliver chemotherapeutics to the tumor tissue after systemic administration and removal of the plasma membrane proteins by trypsinization eliminated the therapeutic effects of the nanovesicle both in vitro and in vivo are suggested.
Abstract: Exosomes, the endogenous nanocarriers that can deliver biological information between cells, were recently introduced as new kind of drug delivery system. However, mammalian cells release relatively low quantities of exosomes, and purification of exosomes is difficult. Here, we developed bioinspired exosome-mimetic nanovesicles that deliver chemotherapeutics to the tumor tissue after systemic administration. The chemotherapeutics-loaded nanovesicles were produced by the breakdown of monocytes or macrophages using a serial extrusion through filters with diminishing pore sizes (10, 5, and 1 μm). These cell-derived nanovesicles have similar characteristics with the exosomes but have 100-fold higher production yield. Furthermore, the nanovesicles have natural targeting ability of cells by maintaining the topology of plasma membrane proteins. In vitro, chemotherapeutic drug-loaded nanovesicles induced TNF-α-stimulated endothelial cell death in a dose-dependent manner. In vivo, experiments in mice showed that t...
Australian Red Cross Blood Service1, Heidelberg University2, Emory University3, University of Manitoba4, Leiden University5, University of California, Los Angeles6, University of Alberta7, Millennium Institute8, Harvard University9, University of Padua10, University of Oxford11, University of British Columbia12, University of Paris13, Charité14, Washington University in St. Louis15, Columbia University16, University of Gothenburg17, Cambridge University Hospitals NHS Foundation Trust18, Stanford University19, University of Pittsburgh20
TL;DR: A group of laboratory and clinical experts in the field of transplantation was convened to prepare a consensus report and make recommendations on the use of this new technology based on both published evidence and expert opinion.
Abstract: BACKGROUND The introduction of solid-phase immunoassay (SPI) technology for the detection and characterization of human leukocyte antigen (HLA) antibodies in transplantation while providing greater sensitivity than was obtainable by complement-dependent lymphocytotoxicity (CDC) assays has resulted in a new paradigm with respect to the interpretation of donor-specific antibodies (DSA). Although the SPI assay performed on the Luminex instrument (hereafter referred to as the Luminex assay), in particular, has permitted the detection of antibodies not detectable by CDC, the clinical significance of these antibodies is incompletely understood. Nevertheless, the detection of these antibodies has led to changes in the clinical management of sensitized patients. In addition, SPI testing raises technical issues that require resolution and careful consideration when interpreting antibody results. METHODS With this background, The Transplantation Society convened a group of laboratory and clinical experts in the field of transplantation to prepare a consensus report and make recommendations on the use of this new technology based on both published evidence and expert opinion. Three working groups were formed to address (a) the technical issues with respect to the use of this technology, (b) the interpretation of pretransplantation antibody testing in the context of various clinical settings and organ transplant types (kidney, heart, lung, liver, pancreas, intestinal, and islet cells), and (c) the application of antibody testing in the posttransplantation setting. The three groups were established in November 2011 and convened for a "Consensus Conference on Antibodies in Transplantation" in Rome, Italy, in May 2012. The deliberations of the three groups meeting independently and then together are the bases for this report. RESULTS A comprehensive list of recommendations was prepared by each group. A summary of the key recommendations follows. Technical Group: (a) SPI must be used for the detection of pretransplantation HLA antibodies in solid organ transplant recipients and, in particular, the use of the single-antigen bead assay to detect antibodies to HLA loci, such as Cw, DQA, DPA, and DPB, which are not readily detected by other methods. (b) The use of SPI for antibody detection should be supplemented with cell-based assays to examine the correlations between the two types of assays and to establish the likelihood of a positive crossmatch (XM). (c) There must be an awareness of the technical factors that can influence the results and their clinical interpretation when using the Luminex bead technology, such as variation in antigen density and the presence of denatured antigen on the beads. Pretransplantation Group: (a) Risk categories should be established based on the antibody and the XM results obtained. (b) DSA detected by CDC and a positive XM should be avoided due to their strong association with antibody-mediated rejection and graft loss. (c) A renal transplantation can be performed in the absence of a prospective XM if single-antigen bead screening for antibodies to all class I and II HLA loci is negative. This decision, however, needs to be taken in agreement with local clinical programs and the relevant regulatory bodies. (d) The presence of DSA HLA antibodies should be avoided in heart and lung transplantation and considered a risk factor for liver, intestinal, and islet cell transplantation. Posttransplantation Group: (a) High-risk patients (i.e., desensitized or DSA positive/XM negative) should be monitored by measurement of DSA and protocol biopsies in the first 3 months after transplantation. (b) Intermediate-risk patients (history of DSA but currently negative) should be monitored for DSA within the first month. If DSA is present, a biopsy should be performed. (c) Low-risk patients (nonsensitized first transplantation) should be screened for DSA at least once 3 to 12 months after transplantation. If DSA is detected, a biopsy should be performed. In all three categories, the recommendations for subsequent treatment are based on the biopsy results. CONCLUSIONS A comprehensive list of recommendations is provided covering the technical and pretransplantation and posttransplantation monitoring of HLA antibodies in solid organ transplantation. The recommendations are intended to provide state-of-the-art guidance in the use and clinical application of recently developed methods for HLA antibody detection when used in conjunction with traditional methods.