The Trail, 1964-11-05

https://soundideas.pugetsound.edu/thetrail_all/1896/thumbnail.jp

Cost-Effectiveness of Parallel Versus Sequential Testing of Genetic Aberrations for Stage IV Non-Small-Cell Lung Cancer in the Netherlands

PURPOSE: A large number of targeted treatment options for stage IV nonsquamous non–small-cell lung cancer with specific genetic aberrations in tumor DNA is available. It is therefore important to optimize diagnostic testing strategies, such that patients receive adequate personalized treatment that improves survival and quality of life. The aim of this study is to assess the efficacy (including diagnostic costs, turnaround time (TAT), unsuccessful tests, percentages of correct findings, therapeutic costs, and therapeutic effectiveness) of parallel next generation sequencing (NGS)–based versus sequential single-gene–based testing strategies routinely used in patients with metastasized non–small-cell lung cancer in the Netherlands. METHODS: A diagnostic microsimulation model was developed to simulate 100,000 patients with prevalence of genetic aberrations, extracted from real-world data from the Dutch Pathology Registry. These simulated patients were modeled to undergo different testing strategies composed of multiple tests with different test characteristics including single-gene and panel tests, test accuracy, the probability of an unsuccessful test, and TAT. Diagnostic outcomes were linked to a previously developed treatment model, to predict average long-term survival, quality-adjusted life-years (QALYs), costs, and cost-effectiveness of parallel versus sequential testing. RESULTS: NGS-based parallel testing for all actionable genetic aberrations is on average €266 cheaper than single-gene–based sequential testing, and detects additional relevant targetable genetic aberrations in 20.5% of the cases, given a TAT of maximally 2 weeks. Therapeutic costs increased by €8,358, and 0.12 QALYs were gained, leading to an incremental cost-effectiveness ratio of €69,614/QALY for parallel versus sequential testing. CONCLUSION: NGS-based parallel testing is diagnostically superior over single-gene–based sequential testing, as it is cheaper and more effective than sequential testing. Parallel testing remains cost-effective with an incremental cost-effectiveness ratio of 69,614 €/QALY upon inclusion of therapeutic costs and long-term outcomes

Transcriptome characterization and polymorphism detection between subspecies of big sagebrush (Artemisia tridentata)

<p>Abstract</p> <p>Background</p> <p>Big sagebrush (<it>Artemisia tridentata</it>) is one of the most widely distributed and ecologically important shrub species in western North America. This species serves as a critical habitat and food resource for many animals and invertebrates. Habitat loss due to a combination of disturbances followed by establishment of invasive plant species is a serious threat to big sagebrush ecosystem sustainability. Lack of genomic data has limited our understanding of the evolutionary history and ecological adaptation in this species. Here, we report on the sequencing of expressed sequence tags (ESTs) and detection of single nucleotide polymorphism (SNP) and simple sequence repeat (SSR) markers in subspecies of big sagebrush.</p> <p>Results</p> <p>cDNA of <it>A. tridentata </it>sspp. <it>tridentata </it>and <it>vaseyana </it>were normalized and sequenced using the 454 GS FLX Titanium pyrosequencing technology. Assembly of the reads resulted in 20,357 contig consensus sequences in ssp. <it>tridentata </it>and 20,250 contigs in ssp. <it>vaseyana</it>. A BLASTx search against the non-redundant (NR) protein database using 29,541 consensus sequences obtained from a combined assembly resulted in 21,436 sequences with significant blast alignments (≤ 1e^-15). A total of 20,952 SNPs and 119 polymorphic SSRs were detected between the two subspecies. SNPs were validated through various methods including sequence capture. Validation of SNPs in different individuals uncovered a high level of nucleotide variation in EST sequences. EST sequences of a third, tetraploid subspecies (ssp. <it>wyomingensis</it>) obtained by Illumina sequencing were mapped to the consensus sequences of the combined 454 EST assembly. Approximately one-third of the SNPs between sspp. <it>tridentata </it>and <it>vaseyana </it>identified in the combined assembly were also polymorphic within the two geographically distant ssp. <it>wyomingensis </it>samples.</p> <p>Conclusion</p> <p>We have produced a large EST dataset for <it>Artemisia tridentata</it>, which contains a large sample of the big sagebrush leaf transcriptome. SNP mapping among the three subspecies suggest the origin of ssp. <it>wyomingensis </it>via mixed ancestry. A large number of SNP and SSR markers provide the foundation for future research to address questions in big sagebrush evolution, ecological genetics, and conservation using genomic approaches.</p

Role of nitrogen lewis basicity in boronate affinity chromatography of nucleosides. Anal

Urinary modified nucleosides have a potential role as cancer biomarkers, and most of the methods used in their study have utilized low-pressure phenylboronate affinity chromatography materials for the purification of the cisdiol-containing nucleosides. In this study, a boronate HPLC column was surprisingly shown not to trap the nucleosides as would be expected from experience with the classic Affigel 601 resin but showed only partial selectivity toward cis-diol groups while other groups exhibited better retention. In aprotic conditions, trapping of nucleosides was possible; however, the selectivity toward cis-diol-containing compounds was lost with the Lewis basicity of available nitrogens being the main determinant of retention. The experimental findings are compared to and confirmed by DFT calculations. Modified nucleosides are naturally occurring modifications of the &quot;normal&quot; nucleosides. They have various roles within many nucleic acids but are mainly found in transfer RNA. They are excreted from the body via the urine as they cannot be salvaged; moreover, some are toxic when allowed to accumulate. Many past reports have investigated the modified nucleosides as potential cancer biomarkers and indicate considerable promise. [1][2][3][4][5] The methodologies used in these studies are wide ranging; however, since the introduction of boronate affinity chromatography as a ribonucleoside-selective cleanup step, on Affi-Gel 601 (Bio-Rad), utilized by Gehrke et al., 1,2 most research employed this off-line cleanup step process in the analysis. The subsequent identification/quantification of the ribonucleosides was almost exclusively carried out via RPLC-UV methods. More recently, some CE-UV methods have also been developed. [6][7][8][9] The further potential/ demand to obtain unambiguous identification via mass spectrometric detection led to the development of some off-line boronate chromatography GC/MS procedures. 3,5,10 However, the most natural choice for the analysis of the prepurified urinary nucleosides analysis is found in LC-MS. 11 Yet, the development of LC-MS procedures for urinary nucleosides only advanced 12 when electrospray mass spectrometry (ESI-MS) became available. Past studies by our group have considered the cleanup samples prior to ESI-MS analysis, 13 the optimization of the detection conditions, 14 comparison of various mass spectrometric methods, 15 and identification of the excreted nucleosides. 16,17 Other groups have taken advantage of mass spectrometry in the study of these compounds

A critical review of mathematical models and data used in diabetology

The literature dealing with mathematical modelling for diabetes is abundant. During the last decades, a variety of models have been devoted to different aspects of diabetes, including glucose and insulin dynamics, management and complications prevention, cost and cost-effectiveness of strategies and epidemiology of diabetes in general. Several reviews are published regularly on mathematical models used for specific aspects of diabetes. In the present paper we propose a global overview of mathematical models dealing with many aspects of diabetes and using various tools. The review includes, side by side, models which are simple and/or comprehensive; deterministic and/or stochastic; continuous and/or discrete; using ordinary differential equations, partial differential equations, optimal control theory, integral equations, matrix analysis and computer algorithms

Protocol for a randomised controlled trial of a decision aid for the management of pain in labour and childbirth [ISRCTN52287533]

BACKGROUND: Women report fear of pain in childbirth and often lack complete information on analgesic options prior to labour. Preferences for pain relief should be discussed before labour begins. A woman's antepartum decision to use pain relief is likely influenced by her cultural background, friends, family, the media, literature and her antenatal caregivers. Pregnant women report that information about analgesia was most commonly derived from hearsay and least commonly from health professionals. Decision aids are emerging as a promising tool to assist practitioners and their patients in evidence-based decision making. Decision aids are designed to assist patients and their doctors in making informed decisions using information that is unbiased and based on high quality research evidence. Decision aids are non-directive in the sense that they do not aim to steer the user towards any one option, but rather to support decision making which is informed and consistent with personal values. METHODS/DESIGN: We aim to evaluate the effectiveness of a Pain Relief for Labour decision aid, with and without an audio-component, compared to a pamphlet in a three-arm randomised controlled trial. Approximately 600 women expecting their first baby and planning a vaginal birth will be recruited for the trial. The primary outcomes of the study are decisional conflict (uncertainty about a course of action), knowledge, anxiety and satisfaction with decision-making and will be assessed using self-administered questionnaires. The decision aid is not intended to influence the type of analgesia used during labour, however we will monitor health service utilisation rates and maternal and perinatal outcomes. This study is funded by a competitive peer-reviewed grant from the Australian National Health and Medical Research Council (No. 253635). DISCUSSION: The Pain Relief for Labour decision aid was developed using the Ottawa Decision Support Framework and systematic reviews of the evidence about the benefits and risks of the non-pharmacological and pharmacological methods of pain relief for labour. It comprises a workbook and worksheet and has been developed in two forms – with and without an audio-component (compact disc). The format allows women to take the decision aid home and discuss it with their partner

Classification of Protein Kinases on the Basis of Both Kinase and Non-Kinase Regions

BACKGROUND: Protein phosphorylation is a generic way to regulate signal transduction pathways in all kingdoms of life. In many organisms, it is achieved by the large family of Ser/Thr/Tyr protein kinases which are traditionally classified into groups and subfamilies on the basis of the amino acid sequence of their catalytic domains. Many protein kinases are multi-domain in nature but the diversity of the accessory domains and their organization are usually not taken into account while classifying kinases into groups or subfamilies. METHODOLOGY: Here, we present an approach which considers amino acid sequences of complete gene products, in order to suggest refinements in sets of pre-classified sequences. The strategy is based on alignment-free similarity scores and iterative Area Under the Curve (AUC) computation. Similarity scores are computed by detecting common patterns between two sequences and scoring them using a substitution matrix, with a consistent normalization scheme. This allows us to handle full-length sequences, and implicitly takes into account domain diversity and domain shuffling. We quantitatively validate our approach on a subset of 212 human protein kinases. We then employ it on the complete repertoire of human protein kinases and suggest few qualitative refinements in the subfamily assignment stored in the KinG database, which is based on catalytic domains only. Based on our new measure, we delineate 37 cases of potential hybrid kinases: sequences for which classical classification based entirely on catalytic domains is inconsistent with the full-length similarity scores computed here, which implicitly consider multi-domain nature and regions outside the catalytic kinase domain. We also provide some examples of hybrid kinases of the protozoan parasite Entamoeba histolytica. CONCLUSIONS: The implicit consideration of multi-domain architectures is a valuable inclusion to complement other classification schemes. The proposed algorithm may also be employed to classify other families of enzymes with multi-domain architecture

An Experimental and Computational Study of Effects of Microtubule Stabilization on T-Cell Polarity

T-killer cells eliminate infected and cancerous cells with precision by positioning their centrosome near the interface (immunological synapse) with the target cell. The mechanism of centrosome positioning has remained controversial, in particular the role of microtubule dynamics in it. We re-examined the issue in the experimental model of Jurkat cells presented with a T cell receptor-binding artificial substrate, which permits controlled stimulation and reproducible measurements. Neither 1-µM taxol nor 100-nM nocodazole inhibited the centrosome positioning at the “synapse” with the biomimetic substrate. At the same time, in micromolar taxol but not in nanomolar nocodazole the centrosome adopted a distinct peripheral rather than the normally central position within the synapse. This effect was reproduced in a computational energy-minimization model that assumed no microtubule dynamics, but only a taxol-induced increase in the length of the microtubules. Together, the experimental and computational results indicate that microtubule dynamics are not essential for the centrosome positioning, but that the fit of the microtubule array in the deformed body of the conjugated T cell is a major factor. The possibility of modulating the T-cell centrosome position with well-studied drugs and of predicting their effects in silico appears attractive for designing anti-cancer and antiviral therapies

The Maunder minimum (1645-1715) was indeed a grand minimum: a reassessment of multiple datasets

Aims. Although the time of the Maunder minimum (1645–1715) is widely known as a period of extremely low solar activity, it is still being debated whether solar activity during that period might have been moderate or even higher than the current solar cycle (number 24). We have revisited all existing evidence and datasets, both direct and indirect, to assess the level of solar activity during the Maunder minimum. Methods. We discuss the East Asian naked-eye sunspot observations, the telescopic solar observations, the fraction of sunspot active days, the latitudinal extent of sunspot positions, auroral sightings at high latitudes, cosmogenic radionuclide data as well as solar eclipse observations for that period. We also consider peculiar features of the Sun (very strong hemispheric asymmetry of the sunspot location, unusual differential rotation and the lack of the K-corona) that imply a special mode of solar activity during the Maunder minimum. Results. The level of solar activity during the Maunder minimum is reassessed on the basis of all available datasets. Conclusions. We conclude that solar activity was indeed at an exceptionally low level during the Maunder minimum. Although the exact level is still unclear, it was definitely lower than during the Dalton minimum of around 1800 and significantly below that of the current solar cycle #24. Claims of a moderate-to-high level of solar activity during the Maunder minimum are rejected with a high confidence level