Showing papers by "Cardiff University published in 2009"
Harvard University1, Broad Institute2, QIMR Berghofer Medical Research Institute3, Cardiff University4, North Carolina State University5, Trinity College, Dublin6, University of Edinburgh7, Uppsala University8, Karolinska Institutet9, University of Southern California10, University of North Carolina at Chapel Hill11, University College London12, National Health Service13, University of Oxford14, University of Aberdeen15, Strathclyde Institute of Pharmacy and Biomedical Sciences16, State University of New York Upstate Medical University17, University of Coimbra18
TL;DR: The extent to which common genetic variation underlies the risk of schizophrenia is shown, using two analytic approaches, and the major histocompatibility complex is implicate, which is shown to involve thousands of common alleles of very small effect.
Abstract: Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
4,573 citations
TL;DR: For example, this article found that exposure to multiple types and repeated episodes of maltreatment is associated with increased risks of severe maltreatment and psychological consequences, which has longlasting effects on mental health, drug and alcohol misuse (especially in girls), risky sexual behaviour, obesity, and criminal behaviour.
3,034 citations
Cardiff University1, Medical Research Council2, University of Bristol3, National Institute for Health Research4, King's College5, Trinity College, Dublin6, University of Cambridge7, University of Nottingham8, Queen's University Belfast9, University of Southampton10, University of Manchester11, John Radcliffe Hospital12, UCL Institute of Neurology13, University of Bonn14, University of Hamburg15, Charité16, University of Erlangen-Nuremberg17, University of Duisburg-Essen18, Ludwig Maximilian University of Munich19, Heidelberg University20, University College Dublin21, University of Freiburg22, Washington University in St. Louis23, Brigham Young University24, University of Antwerp25, University College London26, Wellcome Trust Sanger Institute27, King's College London28, Aristotle University of Thessaloniki29, National Institutes of Health30, Mayo Clinic31
TL;DR: A two-stage genome-wide association study of Alzheimer's disease involving over 16,000 individuals, the most powerful AD GWAS to date, produced compelling evidence for association with Alzheimer's Disease in the combined dataset.
Abstract: We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 10-157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 10-9) and 5' to the PICALM gene (rs3851179, P = 1.9 10-8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 10-10, odds ratio = 0.86; rs3851179, P = 1.3 10-9, odds ratio = 0.86).
2,956 citations
TL;DR: A Swedish patient of Indian origin traveled to New Delhi, India, and acquired a urinary tract infection caused by a carbapenem-resistant Klebsiella pneumoniae strain that typed to the sequence type 14 complex, showing broad resistance carried on these plasmids.
Abstract: A Swedish patient of Indian origin traveled to New Delhi, India, and acquired a urinary tract infection caused by a carbapenem-resistant Klebsiella pneumoniae strain that typed to the sequence type 14 complex. The isolate, Klebsiella pneumoniae 05-506, was shown to possess a metallo-β-lactamase (MBL) but was negative for previously known MBL genes. Gene libraries and amplification of class 1 integrons revealed three resistance-conferring regions; the first contained blaCMY-4 flanked by ISEcP1 and blc. The second region of 4.8 kb contained a complex class 1 integron with the gene cassettes arr-2, a new erythromycin esterase gene; ereC; aadA1; and cmlA7. An intact ISCR1 element was shown to be downstream from the qac/sul genes. The third region consisted of a new MBL gene, designated blaNDM-1, flanked on one side by K. pneumoniae DNA and a truncated IS26 element on its other side. The last two regions lie adjacent to one another, and all three regions are found on a 180-kb region that is easily transferable to recipient strains and that confers resistance to all antibiotics except fluoroquinolones and colistin. NDM-1 shares very little identity with other MBLs, with the most similar MBLs being VIM-1/VIM-2, with which it has only 32.4% identity. As well as possessing unique residues near the active site, NDM-1 also has an additional insert between positions 162 and 166 not present in other MBLs. NDM-1 has a molecular mass of 28 kDa, is monomeric, and can hydrolyze all β-lactams except aztreonam. Compared to VIM-2, NDM-1 displays tighter binding to most cephalosporins, in particular, cefuroxime, cefotaxime, and cephalothin (cefalotin), and also to the penicillins. NDM-1 does not bind to the carbapenems as tightly as IMP-1 or VIM-2 and turns over the carbapenems at a rate similar to that of VIM-2. In addition to K. pneumoniae 05-506, blaNDM-1 was found on a 140-kb plasmid in an Escherichia coli strain isolated from the patient's feces, inferring the possibility of in vivo conjugation. The broad resistance carried on these plasmids is a further worrying development for India, which already has high levels of antibiotic resistance.
2,144 citations
TL;DR: It is concluded that stem-cell-specific loss of Apc results in progressively growing neoplasia in long-lived intestinal stem cells.
Abstract: Intestinal cancer is initiated by Wnt-pathway-activating mutations in genes such as adenomatous polyposis coli (APC). As in most cancers, the cell of origin has remained elusive. In a previously established Lgr5 (leucine-rich-repeat containing G-protein-coupled receptor 5) knockin mouse model, a tamoxifen-inducible Cre recombinase is expressed in long-lived intestinal stem cells. Here we show that deletion of Apc in these stem cells leads to their transformation within days. Transformed stem cells remain located at crypt bottoms, while fuelling a growing microadenoma. These microadenomas show unimpeded growth and develop into macroscopic adenomas within 3-5weeks. The distribution of Lgr5(+) cells within stem-cell-derived adenomas indicates that a stem cell/progenitor cell hierarchy is maintained in early neoplastic lesions. When Apc is deleted in short-lived transit-amplifying cells using a different cre mouse, the growth of the induced microadenomas rapidly stalls. Even after 30weeks, large adenomas are very rare in these mice. We conclude that stem-cell-specific loss of Apc results in progressively growing neoplasia.
1,992 citations
TL;DR: This synthesis first highlights, that dynamic capabilities are shaped by enabling and inhibiting variables within and outside the firm, including the perceptions and motivations of managers; secondly, it identifies processes that create dynamic capabilities; and thirdly, it explains thatynamic capabilities do not automatically lead to performance improvements.
Abstract: The dynamic capability perspective extends the resource-based view argument by addressing how valuable, rare, difficult to imitate and imperfectly substitutable resources can be created and how the current stock of valuable resources can be refreshed in changing environments. The concept of dynamic capabilities emerged in the 1990s, and the field has advanced considerably since. This paper presents a review as well as a synthesis of the extant literature. This synthesis first highlights, that dynamic capabilities are shaped by enabling and inhibiting variables within and outside the firm, including the perceptions and motivations of managers; secondly, it identifies processes that create dynamic capabilities; and thirdly, it explains that dynamic capabilities do not automatically lead to performance improvements. Finally, the paper addresses some areas of confusion and contradiction that hamper the development of the literature.
1,357 citations
TL;DR: A systematic study to investigate the effect of neglecting to reorient the B‐matrix on DTI data during motion correction is presented and the consequences for diffusion fiber tractography are discussed.
Abstract: To estimate diffusion tensor MRI (DTI) measures, such as fractional anisotropy and fiber orientation, reliably, a large number of diffusion-encoded images is needed, preferably cardiac gated to reduce pulsation artifacts. However, the concomitant longer acquisition times increase the chances of subject motion adversely affecting the estimation of these measures. While correcting for motion artifacts improves the accuracy of DTI, an often overlooked step in realigning the images is to reorient the B-matrix so that orientational information is correctly preserved. To the best of our knowledge, most research groups and software packages currently omit this reorientation step. Given the recent explosion of DTI applications including, for example, neurosurgical planning (in which errors can have drastic consequences), it is important to investigate the impact of neglecting to perform the B-matrix reorientation. In this work, a systematic study to investigate the effect of neglecting to reorient the B-matrix on DTI data during motion correction is presented. The consequences for diffusion fiber tractography are also discussed. Magn Reson Med 61:1336–1349, 2009.
1,263 citations
Christopher Newton-Cheh1, Christopher Newton-Cheh2, Toby Johnson3, Toby Johnson4 +359 more•Institutions (64)
TL;DR: In this paper, the association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2(P = 1 × 10-23), FGF5 (P=1 × 10 -21), SH2B3(P= 3 × 10−18), MTHFR(MTHFR), c10orf107(P), ZNF652(ZNF652), PLCD3 (P,P = 5 × 10 −9),
Abstract: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
1,205 citations
TL;DR: Advances on multiple fronts that have highlighted the importance of the retrosplenial cortex for cognition are reviewed, and why specifying its precise functions remains problematic are considered.
Abstract: The past decade has seen a transformation in research on the retrosplenial cortex (RSC). This cortical area has emerged as a key member of a core network of brain regions that underpins a range of cognitive functions, including episodic memory, navigation, imagination and planning for the future. It is now also evident that the RSC is consistently compromised in the most common neurological disorders that impair memory. Here we review advances on multiple fronts, most notably in neuroanatomy, animal studies and neuroimaging, that have highlighted the importance of the RSC for cognition, and consider why specifying its precise functions remains problematic.
1,194 citations
Stanford University1, NorthShore University HealthSystem2, Columbia University3, Medical Research Council4, Cardiff University5, Centre for Mental Health6, University of Colorado Denver7, Emory University8, Washington University in St. Louis9, Icahn School of Medicine at Mount Sinai10, LSU Health Sciences Center New Orleans11, University of California, San Francisco12, Roy J. and Lucille A. Carver College of Medicine13, Massachusetts Institute of Technology14, Virginia Commonwealth University15
TL;DR: It is demonstrated that common schizophrenia susceptibility alleles can be detected and the characterization of these signals will suggest important directions for research on susceptibility mechanisms.
Abstract: Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5-1%, with high heritability (80-85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 x 10(-9)). This region includes a histone gene cluster and several immunity-related genes--possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.
1,151 citations
TL;DR: Those on insulin or insulin secretagogues were more likely to develop solid cancers than those on metformin, and combination with met formin abolished most of this excess risk.
Abstract: Aims/hypothesis The risk of developing a range of solid tumours is increased in type 2 diabetes, and may be influenced by glucose-lowering therapies. We examined the risk of development of solid tumours in relation to treatment with oral agents, human insulin and insulin analogues. Methods This was a retrospective cohort study of people treated in UK general practices. Those included in the analysis developed diabetes >40 years of age, and started treatment with oral agents or insulin after 2000. A total of 62,809 patients were divided into four groups according to whether they received monotherapy with metformin or sulfonylurea, combined therapy (metformin plus sulfonylurea), or insulin. Insulin users were grouped according to treatment with insulin glargine, long-acting human insulin, biphasic analogue and human biphasic insulin. The outcome measures were progression to any solid tumour, or cancer of the breast, colon, pancreas or prostate. Confounding factors were accounted for using Cox proportional hazards models. Results Metformin monotherapy carried the lowest risk of cancer. In comparison, the adjusted HR was 1.08 (95% CI 0.96–1.21) for metformin plus sulfonylurea, 1.36 (95% CI 1.19–1.54) for sulfonylurea monotherapy, and 1.42 (95% CI 1.27–1.60) for insulin-based regimens. Adding metformin to insulin reduced progression to cancer (HR 0.54, 95% CI 0.43–0.66). Theriskforthoseonbasalhumaninsulin alone vs insulin glargine alone was 1.24 (95% CI 0.90–1.70). Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69, 95% CI 1.23–2.33) or pancreatic cancer(HR 4.63,95% CI2.64–8.10),but did not influencethe riskofbreastorprostatecancer.Sulfonylureaswereassociated with a similar pattern of risk as insulin. Conclusions/interpretation Those on insulin or insulin secretagogues were more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk. Metformin use was associated with lower risk of cancer of the colon or pancreas, but did not affect the risk of breast or prostate cancer. Use of insulin analogues was not associated with increased cancer risk as compared with human insulin.
TL;DR: The results show that this form of early life stress results in an altered brain-gut axis and is therefore an important model for investigating potential mechanistic insights into stress-related disorders including depression and IBS.
TL;DR: The taxonomy provides end users with a mechanism by which they can assess the suitability of workflow in general and how they might use these features to make an informed choice about which workflow system would be a good choice for their particular application.
TL;DR: Normalization Process Theory explains how new technologies, ways of acting, and ways of working become routinely embedded in everyday practice, and has applications in the study of implementation processes.
Abstract: Theories are important tools in the social and natural sciences. The methods by which they are derived are rarely described and discussed. Normalization Process Theory explains how new technologies, ways of acting, and ways of working become routinely embedded in everyday practice, and has applications in the study of implementation processes. This paper describes the process by which it was built. Between 1998 and 2008, we developed a theory. We derived a set of empirical generalizations from analysis of data collected in qualitative studies of healthcare work and organization. We developed an applied theoretical model through analysis of empirical generalizations. Finally, we built a formal theory through a process of extension and implication analysis of the applied theoretical model. Each phase of theory development showed that the constructs of the theory did not conflict with each other, had explanatory power, and possessed sufficient robustness for formal testing. As the theory developed, its scope expanded from a set of observed regularities in data with procedural explanations, to an applied theoretical model, to a formal middle-range theory. Normalization Process Theory has been developed through procedures that were properly sceptical and critical, and which were opened to review at each stage of development. The theory has been shown to merit formal testing.
TL;DR: Based on confusions that have arisen in publications and presentations regarding MI, the authors compiled a list of 10 concepts and procedures with which MI should not be addled.
Abstract: Background: In the 26 years since it was first introduced in this journal, motivational interviewing (MI) has become confused with various other ideas and approaches, owing in part to its rapid international diffusion. Methods: Based on confusions that have arisen in publications and presentations regarding MI, the authors compiled a list of 10 concepts and procedures with which MI should not be addled. Results: This article discusses 10 things that MI is not: (1) the transtheoretical model of change; (2) a way of tricking people into doing what you want them to do; (3) a technique; (4) decisional balance; (5) assessment feedback; (6) cognitive-behavior therapy; (7) client-centered therapy; (8) easy to learn; (9) practice as usual; and (10) a panacea. Conclusion: Clarity about what does (and does not) constitute MI promotes quality assurance in scientific research, clinical practice, and training.
TL;DR: Although originally established for the scientific study of mutational mechanisms in human genes, HGMD has since acquired a much broader utility for researchers, physicians, clinicians and genetic counselors as well as for companies specializing in biopharmaceuticals, bioinformatics and personalized genomics.
Abstract: The Human Gene Mutation Database (HGMD®) is a comprehensive core collection of germline mutations in nuclear genes that underlie or are associated with human inherited disease. Here, we summarize the history of the database and its current resources. By December 2008, the database contained over 85,000 different lesions detected in 3,253 different genes, with new entries currently accumulating at a rate exceeding 9,000 per annum. Although originally established for the scientific study of mutational mechanisms in human genes, HGMD has since acquired a much broader utility for researchers, physicians, clinicians and genetic counselors as well as for companies specializing in biopharmaceuticals, bioinformatics and personalized genomics. HGMD was first made publicly available in April 1996, and a collaboration was initiated in 2006 between HGMD and BIOBASE GmbH. This cooperative agreement covers the exclusive worldwide marketing of the most up-to-date (subscription) version of HGMD, HGMD Professional, to academic, clinical and commercial users.
TL;DR: The most likely sources of gravitational waves are studied and the data analysis methods that are used to extract their signals from detector noise are reviewed, and the consequences of gravitational wave detections and observations for physics, astrophysics, and cosmology are considered.
Abstract: Gravitational wave detectors are already operating at interesting sensitivity levels, and they have an upgrade path that should result in secure detections by 2014. We review the physics of gravitational waves, how they interact with detectors (bars and interferometers), and how these detectors operate. We study the most likely sources of gravitational waves and review the data analysis methods that are used to extract their signals from detector noise. Then we consider the consequences of gravitational wave detections and observations for physics, astrophysics, and cosmology.
TL;DR: This review contains specific recommendations for the identification and management of most important complications such as the bleeding disorder, APL differentiation syndrome, QT prolongation and other ATRA- and ATO-related toxicities, as well as for molecular assessment of response to treatment.
TL;DR: The contribution of cognitive neuroscience, molecular genetics and clinical investigations to understanding how response inhibition is mediated in the human brain is reviewed.
Northwestern University1, Princeton University2, Lawrence University3, Catholic University of Leuven4, The Chinese University of Hong Kong5, University of Poitiers6, Leiden University7, Japan Women's University8, Ewha Womans University9, Cardiff University10, University of Tromsø11, University of Granada12, University of Costa Rica13, University of Lisbon14, University of Tübingen15
TL;DR: The stereotype content model (SCM) can serve as a pancultural tool for predicting group stereotypes from structural relations with other groups in society, and comparing across societies.
Abstract: The stereotype content model (SCM) proposes potentially universal principles of societal stereotypes and their relation to social structure. Here, the SCM reveals theoretically grounded, cross-cultural, cross-groups similarities and one difference across 10 non-US nations. Seven European (individualist) and three East Asian (collectivist) nations (N=1,028) support three hypothesized cross-cultural similarities: (a) perceived warmth and competence reliably differentiate societal group stereotypes; (b) many out-groups receive ambivalent stereotypes (high on one dimension; low on the other); and (c) high status groups stereotypically are competent, whereas competitive groups stereotypically lack warmth. Data uncover one consequential cross-cultural difference: (d) the more collectivist cultures do not locate reference groups (in-groups and societal prototype groups) in the most positive cluster (high-competence/high-warmth), unlike individualist cultures. This demonstrates out-group derogation without obvious reference-group favouritism. The SCM can serve as a pancultural tool for predicting group stereotypes from structural relations with other groups in society, and comparing across societies.
TL;DR: It is suggested that there are three levels of dynamic capabilities which are related to managers' perceptions of environmental dynamism, and that regenerative dynamic capabilities may either come from inside the firm or enter the firm from outside, via changes in leadership or the intervention of external change agents.
Abstract: The aim of this paper is to extend the concept of dynamic capabilities. Building on prior research, we suggest that there are three levels of dynamic capabilities which are related to managers' perceptions of environmental dynamism. At the first level we find incremental dynamic capabilities: those capabilities concerned with the continuous improvement of the firm's resource base. At the second level are renewing dynamic capabilities, those that refresh, adapt and augment the resource base. These two levels are usually conceived as one and represent what the literature refers to as dynamic capabilities. At the third level are regenerative dynamic capabilities, which impact, not on the firm's resource base, but on its current set of dynamic capabilities, i.e. these change the way the firm changes its resource base. We explore the three levels using illustrative examples and conclude that regenerative dynamic capabilities may either come from inside the firm or enter the firm from outside, via changes in leadership or the intervention of external change agents.
University College London1, St Bartholomew's Hospital2, Nottingham City Hospital3, St Mary's Hospital4, Royal Free Hospital5, St. Michael's GAA, Sligo6, Belfast City Hospital7, Cardiff University8, James Cook University Hospital9, London School of Economics and Political Science10, Brighton and Sussex Medical School11, Queen Mary University of London12, Harvard University13, Medical Research Council14
TL;DR: The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) as mentioned in this paper was a randomized controlled trial designed to assess the effect of screening on mortality, and the outcome of the initial screening was summarised in the report.
Abstract: Background: Ovarian cancer has a high case–fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS.
Methods: Between 2001 and 2005, a total of 202 638 post-menopausal women aged 50–74 years were randomly assigned to no treatment (control; n=101 359); annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50 640); or annual screening with transvaginal ultrasound (USS; n=50 639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032.
Findings: In the prevalence screen, 50 078 (98·9%) women underwent MMS, and 48 230 (95·2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1490 USS). Overall, 4355 of 50 078 (8.7%) women in the MMS group and 5779 of 48 230 (12·0%) women in the USS group required a repeat test, and 167 (0·3%) women in the MMS group and 1894 (3·9%) women in the USS group required clinical evaluation. 97 of 50 078 (0·2%) women from the MMS group and 845 of 48 230 (1·8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48·3%; 95% CI 35·0–61·8) of the invasive cancers were stage I/II, with no difference (p=0·396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89·4%, 99·8%, and 43·3% for MMS, and 84·9%, 98·2%, and 5·3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89·5%, 99·8%, and 35·1% for MMS, and 75·0%, 98·2%, and 2·8% for USS, respectively. There was a significant difference in specificity (p<0·0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers.
Interpretation: The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined.
Funding: Medical Research Council, Cancer Research UK and the Department of Health, UK; with additional support from the Eve Appeal, Special Trustees of Bart's and the London, and Special Trustees of University College London Hospital.
TL;DR: It is shown that acid pretreatment of a carbon support for gold-palladium alloy catalysts switches off the decomposition of H2O2, and the acid-pretreated catalysts give high yields of H 2O2 with hydrogen selectivities greater than 95%.
Abstract: Hydrogen peroxide (H2O2) is an important disinfectant and bleach and is currently manufactured from an indirect process involving sequential hydrogenation/oxidation of anthaquinones. However, a direct process in which H2 and O2 are reacted would be preferable. Unfortunately, catalysts for the direct synthesis of H2O2 are also effective for its subsequent decomposition, and this has limited their development. We show that acid pretreatment of a carbon support for gold-palladium alloy catalysts switches off the decomposition of H2O2. This treatment decreases the size of the alloy nanoparticles, and these smaller nanoparticles presumably decorate and inhibit the sites for the decomposition reaction. Hence, when used in the direct synthesis of H2O2, the acid-pretreated catalysts give high yields of H2O2 with hydrogen selectivities greater than 95%.
Pennsylvania State University1, Otto-von-Guericke University Magdeburg2, University of Ferrara3, Johns Hopkins University4, University of Pennsylvania5, SUNY Downstate Medical Center6, Cornell University7, Cardiff University8, University of Chile9, University of Buenos Aires10, Kyoto University11, Federal University of Rio de Janeiro12, Women's College, Kolkata13, Baylor College of Medicine14
TL;DR: This update reviews new information about acne pathophysiology and treatment-such as lasers and light therapy-and relevant topics where published data were sparse in 2003 but are now available including combination therapy, revision of acne scarring, and maintenance therapy.
Abstract: The Global Alliance to Improve Outcomes in Acne published recommendations for the management of acne as a supplement to the Journal of the American Academy of Dermatology in 2003. The recommendations incorporated evidence-based strategies when possible and the collective clinical experience of the group when evidence was lacking. This update reviews new information about acne pathophysiology and treatment–such as lasers and light therapy–and relevant topics where published data were sparse in 2003 but are now available including combination therapy, revision of acne scarring, and maintenance therapy. The update also includes a new way of looking at acne as a chronic disease, a discussion of the changing role of antibiotics in acne management as a result of concerns about microbial resistance, and factors that affect adherence to acne treatments. Summary statements and recommendations are provided throughout the update along with an indication of the level of evidence that currently supports each finding. As in the original supplement, the authors have based recommendations on published evidence as much as possible.
TL;DR: In this paper, the authors consider the potential of the discipline of marketing to contribute to consumption reduction from a social marketing perspective, and review the difficulties of applying conventional marketing theory and practice in pursuit of more sustainable consumption, and the logic of applying an adapted form of social marketing to promote more sustainable lifestyles and reductions in consumption.
TL;DR: This overview of available motor tasks aims to aid researchers in making the correct choice of test when attempting to tease out a transgenic phenotype or when assessing the recovery of motor function following therapeutic intervention.
Abstract: The characterization of mouse models of human disease is essential for understanding the underlying pathophysiology and developing new therapeutics. Many diseases are often associated with more than one model, and so there is a need to determine which model most closely represents the disease state or is most suited to the therapeutic approach under investigation. In the case of neurological disease, motor tests provide a good read-out of neurological function. This overview of available motor tasks aims to aid researchers in making the correct choice of test when attempting to tease out a transgenic phenotype or when assessing the recovery of motor function following therapeutic intervention.
TL;DR: The results are supportive of recent theories suggesting that these functional neuroimaging metrics are dependent on the excitation/inhibition balance in an individual's cortex and have important implications for the interpretation of functional imaging results, particularly when making between-group comparisons in clinical research.
Abstract: Functional imaging of the human brain is an increasingly important technique for clinical and cognitive neuroscience research, with functional MRI (fMRI) of the blood oxygen level-dependent (BOLD) response and electroencephalography or magnetoencephalography (MEG) recordings of neural oscillations being 2 of the most popular approaches. However, the neural and physiological mechanisms that generate these responses are only partially understood and sources of interparticipant variability in these measures are rarely investigated. Here, we test the hypothesis that the properties of these neuroimaging metrics are related to individual levels of cortical inhibition by combining magnetic resonance spectroscopy to quantify resting GABA concentration in the visual cortex, MEG to measure stimulus-induced visual gamma oscillations and fMRI to measure the BOLD response to a simple visual grating stimulus. Our results demonstrate that across individuals gamma oscillation frequency is positively correlated with resting GABA concentration in visual cortex (R = 0.68; P < 0.02), BOLD magnitude is inversely correlated with resting GABA (R = −0.64; P < 0.05) and that gamma oscillation frequency is strongly inversely correlated with the magnitude of the BOLD response (R = −0.88; P < 0.001). Our results are therefore supportive of recent theories suggesting that these functional neuroimaging metrics are dependent on the excitation/inhibition balance in an individual's cortex and have important implications for the interpretation of functional imaging results, particularly when making between-group comparisons in clinical research.
Cardiff University1, University of Alberta2, University Centre in Svalbard3, University of Oslo4, University of Zurich5, Karlsruhe Institute of Technology6, Norwegian Meteorological Institute7, University of Tsukuba8, University of Sussex9, University of Edinburgh10, University of Helsinki11, ETH Zurich12
TL;DR: In this article, the authors present a review of the changing state of European permafrost within a spatial zone that includes the continuous high latitude arctic permfrost of Svalbard and the discontinuous high altitude mountain permaffrost of Iceland, Fennoscandia and the Alps.
Wellcome Trust Sanger Institute1, University of Edinburgh2, Wellcome Trust3, Peninsula College4, King's College London5, Central Manchester University Hospitals NHS Foundation Trust6, University of Manchester7, James Cook University8, Newcastle University9, University of Oxford10, University of London11, Trinity College, Dublin12, Cardiff University13, Queen Mary University of London14, St George's, University of London15, University of Dundee16, University of Cambridge17, University of Leicester18, University College London19, Moorfields Eye Hospital20, NHS Blood and Transplant21, University of Bristol22
TL;DR: The Wellcome Trust Case Control Consortium 2 performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls as mentioned in this paper, finding significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A), 16q22 (CDH1 and CDH3), and 7q31 (LAMB1).
Abstract: Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 x 10(-5) were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 x 10(-17)), 16q22 (CDH1 and CDH3; P = 2.8 x 10(-8)) and 7q31 (LAMB1; P = 3.0 x 10(-8)). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.
TL;DR: New records from the South Atlantic are presented that show rapid changes during the last deglaciation that were instantaneous (within dating uncertainty) and of opposite sign to those observed in the North Atlantic.
Abstract: The asynchronous relationship between millennial-scale temperature changes over Greenland and Antarctica during the last glacial period has led to the notion of a bipolar seesaw which acts to redistribute heat depending on the state of meridional overturning circulation within the Atlantic Ocean. Here we present new records from the South Atlantic that show rapid changes during the last deglaciation that were instantaneous (within dating uncertainty) and of opposite sign to those observed in the North Atlantic. Our results demonstrate a direct link between the abrupt changes associated with variations in the Atlantic meridional overturning circulation and the more gradual adjustments characteristic of the Southern Ocean. These results emphasize the importance of the Southern Ocean for the development and transmission of millennial-scale climate variability and highlight its role in deglacial climate change and the associated rise in atmospheric carbon dioxide.