An investigation of minimisation criteria

Minimisation can be used within treatment trials to ensure that prognostic factors are evenly distributed between treatment groups. The technique is relatively straightforward to apply but does require running tallies of patient recruitments to be made and some simple calculations to be performed prior to each allocation. As computing facilities have become more widely available, minimisation has become a more feasible option for many. Although the technique has increased in popularity, the mode of application is often poorly reported and the choice of input parameters not justified in any logical way

Population-level transcriptome sequencing of nonmodel organisms Erynnis propertius and Papilio zelicaon

<p>Abstract</p> <p>Background</p> <p>Several recent studies have demonstrated the use of Roche 454 sequencing technology for <it>de novo </it>transcriptome analysis. Low error rates and high coverage also allow for effective SNP discovery and genetic diversity estimates. However, genetically diverse datasets, such as those sourced from natural populations, pose challenges for assembly programs and subsequent analysis. Further, estimating the effectiveness of transcript discovery using Roche 454 transcriptome data is still a difficult task.</p> <p>Results</p> <p>Using the Roche 454 FLX Titanium platform, we sequenced and assembled larval transcriptomes for two butterfly species: the Propertius duskywing, <it>Erynnis propertius </it>(Lepidoptera: Hesperiidae) and the Anise swallowtail, <it>Papilio zelicaon </it>(Lepidoptera: Papilionidae). The Expressed Sequence Tags (ESTs) generated represent a diverse sample drawn from multiple populations, developmental stages, and stress treatments.</p> <p>Despite this diversity, > 95% of the ESTs assembled into long (> 714 bp on average) and highly covered (> 9.6× on average) contigs. To estimate the effectiveness of transcript discovery, we compared the number of bases in the hit region of unigenes (contigs and singletons) to the length of the best match silkworm (<it>Bombyx mori</it>) protein--this "ortholog hit ratio" gives a close estimate on the amount of the transcript discovered relative to a model lepidopteran genome. For each species, we tested two assembly programs and two parameter sets; although CAP3 is commonly used for such data, the assemblies produced by Celera Assembler with modified parameters were chosen over those produced by CAP3 based on contig and singleton counts as well as ortholog hit ratio analysis. In the final assemblies, 1,413 <it>E. propertius </it>and 1,940 <it>P. zelicaon </it>unigenes had a ratio > 0.8; 2,866 <it>E. propertius </it>and 4,015 <it>P. zelicaon </it>unigenes had a ratio > 0.5.</p> <p>Conclusions</p> <p>Ultimately, these assemblies and SNP data will be used to generate microarrays for ecoinformatics examining climate change tolerance of different natural populations. These studies will benefit from high quality assemblies with few singletons (less than 26% of bases for each assembled transcriptome are present in unassembled singleton ESTs) and effective transcript discovery (over 6,500 of our putative orthologs cover at least 50% of the corresponding model silkworm gene).</p

Aerosol size distribution and radiative forcing response to anthropogenically driven historical changes in biogenic secondary organic aerosol formation

Emissions of biogenic volatile organic compounds (BVOCs) have changed in the past millennium due to changes in land use, temperature, and CO2 concentrations. Recent reconstructions of BVOC emissions have predicted that global isoprene emissions have decreased, while monoterpene and sesquiterpene emissions have increased; however, all three show regional variability due to competition between the various influencing factors. In this work, we use two modeled estimates of BVOC emissions from the years 1000 to 2000 to test the effect of anthropogenic changes to BVOC emissions on secondary organic aerosol (SOA) formation, global aerosol size distributions, and radiative effects using the GEOS-Chem-TOMAS (Goddard Earth Observing System; TwO-Moment Aerosol Sectional) global aerosol microphysics model. With anthropogenic emissions (e.g., SO2, NOx, primary aerosols) turned off and BVOC emissions changed from year 1000 to year 2000 values, decreases in the number concentration of particles of size Dp > 80 nm (N80) of > 25% in year 2000 relative to year 1000 were predicted in regions with extensive land-use changes since year 1000 which led to regional increases in the combined aerosol radiative effect (direct and indirect) of > 0.5 W m−2 in these regions. We test the sensitivity of our results to BVOC emissions inventory, SOA yields, and the presence of anthropogenic emissions; however, the qualitative response of the model to historic BVOC changes remains the same in all cases. Accounting for these uncertainties, we estimate millennial changes in BVOC emissions cause a global mean direct effect of between +0.022 and +0.163 W m−2 and the global mean cloud-albedo aerosol indirect effect of between −0.008 and −0.056 W m−2. This change in aerosols, and the associated radiative forcing, could be a largely overlooked and important anthropogenic aerosol effect on regional climates

The impact of signal-to-noise ratio, diffusion-weighted directions and image resolution in cardiac diffusion tensor imaging - insights from the ex-vivo rat heart

Background: Cardiac diffusion tensor imaging (DTI) is limited by scan time and signal-to-noise (SNR) restrictions. This invariably leads to a trade-off between the number of averages, diffusion-weighted directions (ND), and image resolution. Systematic evaluation of these parameters is therefore important for adoption of cardiac DTI in clinical routine where time is a key constraint. Methods: High quality reference DTI data were acquired in five ex-vivo rat hearts. We then retrospectively set 2 ≤ SNR ≤ 97, 7 ≤ ND ≤ 61, varied the voxel volume by up to 192-fold and investigated the impact on the accuracy and precision of commonly derived parameters. Results: For maximal scan efficiency, the accuracy and precision of the mean diffusivity is optimised when SNR is maximised at the expense of ND. With typical parameter settings used clinically, we estimate that fractional anisotropy may be overestimated by up to 13% with an uncertainty of ±30%, while the precision of the sheetlet angles may be as poor as ±31°. Although the helix angle has better precision of ±14°, the transmural range of helix angles may be under-estimated by up to 30° in apical and basal slices, due to partial volume and tapering myocardial geometry. Conclusions: These findings inform a baseline of understanding upon which further issues inherent to in-vivo cardiac DTI, such as motion, strain and perfusion, can be considered. Furthermore, the reported bias and reproducibility provides a context in which to assess cardiac DTI biomarkers

Priority setting for new technologies in medicine: A transdisciplinary study

BACKGROUND: Decision makers in health care organizations struggle with how to set priorities for new technologies in medicine. Traditional approaches to priority setting for new technologies in medicine are insufficient and there is no widely accepted model that can guide decision makers. DISCUSSION: Daniels and Sabin have developed an ethically based account about how priority setting decisions should be made. We have developed an empirically based account of how priority setting decisions are made. In this paper, we integrate these two accounts into a transdisciplinary model of priority setting for new technologies in medicine that is both ethically and empirically based. SUMMARY: We have developed a transdisciplinary model of priority setting that provides guidance to decision makers that they can operationalize to help address priority setting problems in their institution

BRCA2 gene mutations in families with aggregations of breast and stomach cancers

Stomach cancer ranks second to lung cancer in the global cancer burden. It is estimated that 25% of families meeting the criteria for hereditary diffuse gastric carcinoma (HDCG) will have germline mutations in the E-cadherin gene. Evidence suggests that stomach cancer might also be a malignant manifestation of other inherited predispositions to disease. Recently, it has been reported that the incidence of stomach cancer is significantly increased in BRCA2 gene mutation carriers. We analysed by direct sequencing the BRCA2 gene in 29 breast cancer patients derived from 29 families with an aggregation of at least one female breast cancer diagnosed before the age of 50 years and one male stomach cancer diagnosed before the age of 55 years. In all but one of these families at least one additional relative was also affected by a malignant tumour. We identified three frameshift mutations and three sequence variants – potentially missense mutations, in six unrelated patients representing 20.7% (six out of 29) of the families investigated. Our results confirm that BRCA2 gene mutations are also associated with familial aggregations of not only breast but also of stomach cancer. In comparison to the number of cancers expected in the study population compared to the general population there is an over-representation of several cancers with significant confidence intervals to suggest that the associations are real and not a selection artefact

A simple and rapid flow cytometry-based assay to identify a competent embryo prior to embryo transfer

Multiple pregnancy is a risk for prematurity and preterm birth. The goal of assisted reproduction is to achieve a single pregnancy, by transferring a single embryo. This requires improved methods to identify the competent embryo. Here, we describe such a test, based on flow cytometric determination of the nucleic acid (PI+) containing extracellular vesicle (EV) count in day 5 embryo culture media. 88 women undergoing IVF were included in the study. More than 1 embryos were transferred to most patients. In 58 women, the transfer resulted in clinical pregnancy, whereas in 30 women in implantation failure. In 112 culture media of embryos from the "clinical pregnancy" group, the number of PI+ EVs was significantly lower than in those of 49 embryos, from the "implantation failure" group. In 14 women, transfer of a single embryo resulted in a singleton pregnancy, or, transfer of two embryos in twin pregnancy. The culture media of 19 out of the 20 "confirmed competent" embryos contained a lower level of PI+ EVs than the cut off level, suggesting that the competent embryo can indeed be identified by low PI+ EV counts. We developed a noninvasive, simple, inexpensive, quick test, which identifies the embryos that are most likely to implant

The Ecm11-Gmc2 complex promotes synaptonemal complex formation through assembly of transverse filaments in budding yeast

During meiosis, homologous chromosomes pair at close proximity to form the synaptonemal complex (SC). This association is mediated by transverse filament proteins that hold the axes of homologous chromosomes together along their entire length. Transverse filament proteins are highly aggregative and can form an aberrant aggregate called the polycomplex that is unassociated with chromosomes. Here, we show that the Ecm11-Gmc2 complex is a novel SC component, functioning to facilitate assembly of the yeast transverse filament protein, Zip1. Ecm11 and Gmc2 initially localize to the synapsis initiation sites, then throughout the synapsed regions of paired homologous chromosomes. The absence of either Ecm11 or Gmc2 substantially compromises the chromosomal assembly of Zip1 as well as polycomplex formation, indicating that the complex is required for extensive Zip1 polymerization. We also show that Ecm11 is SUMOylated in a Gmc2-dependent manner. Remarkably, in the unSUMOylatable ecm11 mutant, assembly of chromosomal Zip1 remained compromised while polycomplex formation became frequent. We propose that the Ecm11-Gmc2 complex facilitates the assembly of Zip1 and that SUMOylation of Ecm11 is critical for ensuring chromosomal assembly of Zip1, thus suppressing polycomplex formation

Variants in KCNQ1 increase type II diabetes susceptibility in South Asians: A study of 3,310 subjects from India and the US

<p>Abstract</p> <p>Background</p> <p>Polymorphisms in intron 15 of potassium voltage-gated channel, KQT-like subfamily member 1 (<it>KCNQ1</it>) gene have been associated with type II diabetes (T2D) in Japanese genome-wide association studies (GWAS). More recently a meta-analysis of European GWAS has detected a new independent signal associated with T2D in intron 11 of the <it>KCNQ1 </it>gene. The purpose of this investigation is to examine the role of these variants with T2D in populations of Asian Indian descent from India and the US.</p> <p>Methods</p> <p>We examined the association between four variants in the <it>KCNQ1 </it>gene with T2D and related quantitative traits in a total of 3,310 Asian Indian participants from two different cohorts comprising 2,431 individuals of the Punjabi case-control cohort from the Sikh Diabetes Study and 879 migrant Asian Indians living in the US.</p> <p>Results</p> <p>Our data confirmed the association of a new signal at the <it>KCNQ1 </it>locus (rs231362) with T2D showing an allelic odds ratio (OR) of 1.24 95%CI [1.08-1.43], p = 0.002 in the Punjabi cohort. A moderate association with T2D was also seen for rs2237895 in the Punjabi (OR 1.14; p = 0.036) and combined cohorts (meta-analysis OR 1.14; p = 0.018). Three-site haplotype analysis of rs231362, rs2237892, rs2237895 exhibited considerably stronger evidence of association of the GCC haplotype with T2D showing OR of 1.24 95%CI [1.00-1.53], p = 0.001, permutation p = 8 × 10^-4in combined cohorts. The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008) as well as in combined cohort in meta-analysis (p = 0.009).</p> <p>Conclusions</p> <p>Our investigation has confirmed that the variation within the <it>KCNQ1 </it>locus confers a significant risk to T2D among Asian Indians. Haplotype analysis further suggested that the T2D risk associated with <it>KCNQ1 </it>SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through β cell function.</p