Isocitrate dehydrogenase 1 mutations (IDH1) and p16/CDKN2A copy number change in conventional chondrosarcomas.

To determine whether IDH1 mutations are present in primary and relapsed (local and distal) conventional central chondrosarcomas; and secondly, to assess if loss of p16/CDKN2A is associated with tumour grade progression, 102 tumour samples from 37 patients, including material from presenting and relapse events, were assessed. All wild-type cases for IDH1 R132 substitutions were also tested for IDH2 R172 and R140 alterations. The primary tumour and the most recent relapse sample were tested for p16/CDKN2A by interphase fluorescence in situ hybridisation. An additional 120 central cartilaginous tumours from different patients were also tested for p16/CDKN2A copy number. The study shows that if an IDH1 mutation were detected in a primary central chondrosarcoma, it is always detected at the time of presentation, and the same mutation is detected in local recurrences and metastatic events. We show that p16/CDKN2A copy number variation occurs subsequent to the IDH1 mutation, and confirm that p16/CDKN2A copy number variation occurs in 75 % of high grade central chondrosarcomas, and not in low grade cartilaginous tumours. Finally, p16/CDKN2A copy number variation is seen in both the IDH1 wild-type and mutant cartilaginous central tumours

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

Economics methods in Cochrane systematic reviews of health promotion and public health related interventions.

Peer reviewedPublisher PD

The convective storm initiation project

Copyright @ 2007 AMSThe Convective Storm Initiation Project (CSIP) is an international project to understand precisely where, when, and how convective clouds form and develop into showers in the mainly maritime environment of southern England. A major aim of CSIP is to compare the results of the very high resolution Met Office weather forecasting model with detailed observations of the early stages of convective clouds and to use the newly gained understanding to improve the predictions of the model. A large array of ground-based instruments plus two instrumented aircraft, from the U.K. National Centre for Atmospheric Science (NCAS) and the German Institute for Meteorology and Climate Research (IMK), Karlsruhe, were deployed in southern England, over an area centered on the meteorological radars at Chilbolton, during the summers of 2004 and 2005. In addition to a variety of ground-based remote-sensing instruments, numerous rawin-sondes were released at one- to two-hourly intervals from six closely spaced sites. The Met Office weather radar network and Meteosat satellite imagery were used to provide context for the observations made by the instruments deployed during CSIP. This article presents an overview of the CSIP field campaign and examples from CSIP of the types of convective initiation phenomena that are typical in the United Kingdom. It shows the way in which certain kinds of observational data are able to reveal these phenomena and gives an explanation of how the analyses of data from the field campaign will be used in the development of an improved very high resolution NWP model for operational use.This work is funded by the National Environment Research Council following an initial award from the HEFCE Joint Infrastructure Fund

A re-randomisation design for clinical trials

Background: Recruitment to clinical trials is often problematic, with many trials failing to recruit to their target sample size. As a result, patient care may be based on suboptimal evidence from underpowered trials or non-randomised studies. Methods: For many conditions patients will require treatment on several occasions, for example, to treat symptoms of an underlying chronic condition (such as migraines, where treatment is required each time a new episode occurs), or until they achieve treatment success (such as fertility, where patients undergo treatment on multiple occasions until they become pregnant). We describe a re-randomisation design for these scenarios, which allows each patient to be independently randomised on multiple occasions. We discuss the circumstances in which this design can be used. Results: The re-randomisation design will give asymptotically unbiased estimates of treatment effect and correct type I error rates under the following conditions: (a) patients are only re-randomised after the follow-up period from their previous randomisation is complete; (b) randomisations for the same patient are performed independently; and (c) the treatment effect is constant across all randomisations. Provided the analysis accounts for correlation between observations from the same patient, this design will typically have higher power than a parallel group trial with an equivalent number of observations. Conclusions: If used appropriately, the re-randomisation design can increase the recruitment rate for clinical trials while still providing an unbiased estimate of treatment effect and correct type I error rates. In many situations, it can increase the power compared to a parallel group design with an equivalent number of observations

Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia

Peer reviewe

Expansion of Canopy-Forming Willows Over the Twentieth Century on Herschel Island, Yukon Territory, Canada

Canopy-forming shrubs are reported to be increasing at sites around the circumpolar Arctic. Our results indicate expansion in canopy cover and height of willows on Herschel Island located at 70° north on the western Arctic coast of the Yukon Territory. We examined historic photographs, repeated vegetation surveys, and conducted monitoring of long-term plots and found evidence of increases of each of the dominant canopy-forming willow species (Salix richardsonii, Salix glauca and Salix pulchra), during the twentieth century. A simple model of patch initiation indicates that the majority of willow patches for each of these species became established between 1910 and 1960, with stem ages and maximum growth rates indicating that some patches could have established as late as the 1980s. Collectively, these results suggest that willow species are increasing in canopy cover and height on Herschel Island. We did not find evidence that expansion of willow patches is currently limited by herbivory, disease, or growing conditions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13280-011-0168-y) contains supplementary material, which is available to authorized users

Sex matters during adolescence: Testosterone-related cortical thickness maturation differs between boys and girls

Age-related changes in cortical thickness have been observed during adolescence, including thinning in frontal and parietal cortices, and thickening in the lateral temporal lobes. Studies have shown sex differences in hormone-related brain maturation when boys and girls are age-matched, however, because girls mature 1-2 years earlier than boys, these sex differences could be confounded by pubertal maturation. To address puberty effects directly, this study assessed sex differences in testosterone-related cortical maturation by studying 85 boys and girls in a narrow age range and matched on sexual maturity. We expected that testosterone-by-sex interactions on cortical thickness would be observed in brain regions known from the animal literature to be high in androgen receptors. We found sex differences in associations between circulating testosterone and thickness in left inferior parietal lobule, middle temporal gyrus, calcarine sulcus, and right lingual gyrus, all regions known to be high in androgen receptors. Visual areas increased with testosterone in boys, but decreased in girls. All other regions were more impacted by testosterone levels in girls than boys. The regional pattern of sex-by-testosterone interactions may have implications for understanding sex differences in behavior and adolescent-onset neuropsychiatric disorders. © 2012 Bramen et al