CAD in mammography: lesion-level versus case-level analysis of the effects of prompts on human decisions

Object: To understand decision processes in CAD-supported breast screening by analysing how prompts affect readers’ judgements of individual mammographic features (lesions). To this end we analysed hitherto unexamined details of reports completed by mammogram readers in an earlier evaluation of a CAD tool. Material and methods: Assessments of lesions were extracted from 5,839 reports for 59 cancer cases. Statistical analyses of these data focused on what features readers considered when recalling a cancer case and how readers reacted to CAD prompts. Results: About 13.5% of recall decisions were found to be caused by responses to features other than those indicating actual cancer. Effects of CAD: lesions were more likely to be examined if prompted; the presence of a prompt on a cancer increased the probability of both detection and recall especially for less accurate readers in subtler cases; lack of prompts made cancer features less likely to be detected; false prompts made non-cancer features more likely to be classified as cancer. Conclusion: The apparent lack of impact reported for CAD in some studies is plausibly due to CAD systematically affecting readers’ identification of individual features, in a beneficial way for certain combinations of readers and features and a damaging way for others. Mammogram readers do not ignore prompts. Methodologically, assessing CAD by numbers of recalled cancer cases may be misleading

The effectiveness and cost-effectiveness of telephone triage of patients requesting same day consultations in general practice: study protocol for a cluster randomised controlled trial comparing nurse-led and GP-led management systems (ESTEEM)

notes: PMCID: PMC3574027This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Recent years have seen an increase in primary care workload, especially following the introduction of a new General Medical Services contract in 2004. Telephone triage and telephone consultation with patients seeking health care represent initiatives aimed at improving access to care. Some evidence suggests that such approaches may be feasible but conclusions regarding GP workload, cost, and patients' experience of care, safety, and health status are equivocal. The ESTEEM trial aims to assess the clinical- and cost-effectiveness of nurse-led computer-supported telephone triage and GP-led telephone triage, compared to usual care, for patients requesting same-day consultations in general practice.UK National Institute of Health Research Health Technology Assessment programmeDepartment of Healt

Mapping 6D N = 1 supergravities to F-theory

We develop a systematic framework for realizing general anomaly-free chiral 6D supergravity theories in F-theory. We focus on 6D (1, 0) models with one tensor multiplet whose gauge group is a product of simple factors (modulo a finite abelian group) with matter in arbitrary representations. Such theories can be decomposed into blocks associated with the simple factors in the gauge group; each block depends only on the group factor and the matter charged under it. All 6D chiral supergravity models can be constructed by gluing such blocks together in accordance with constraints from anomalies. Associating a geometric structure to each block gives a dictionary for translating a supergravity model into a set of topological data for an F-theory construction. We construct the dictionary of F-theory divisors explicitly for some simple gauge group factors and associated matter representations. Using these building blocks we analyze a variety of models. We identify some 6D supergravity models which do not map to integral F-theory divisors, possibly indicating quantum inconsistency of these 6D theories.Comment: 37 pages, no figures; v2: references added, minor typos corrected; v3: minor corrections to DOF counting in section

Epigenetics as a mechanism driving polygenic clinical drug resistance

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance

Comparison of DC Bead-irinotecan and DC Bead-topotecan drug eluting beads for use in locoregional drug delivery to treat pancreatic cancer

DC Bead is a drug delivery embolisation system that can be loaded with doxorubicin or irinotecan for the treatment of a variety of liver cancers. In this study we demonstrate that the topoisomerase I inhibitor topotecan hydrochloride can be successfully loaded into the DC Bead sulfonate-modified polyvinyl alcohol hydrogel matrix, resulting in a sustained-release drug eluting bead (DEBTOP) useful for therapeutic purposes. The in vitro drug loading capacity, elution characteristics and the effects on mechanical properties of the beads are described with reference to our previous work with irinotecan hydrochloride (DEBIRI). Results showed that drug loading was faster when the solution was agitated compared to static loading and a maximum loading of ca. 40–45 mg topotecan in 1 ml hydrated beads was achievable. Loading the drug into the beads altered the size, compressibility moduli and colour of the bead. Elution was shown to be reliant on the presence of ions to perform the necessary exchange with the electrostatically bound topotecan molecules. Topotecan was shown by MTS assay to have an IC50 for human pancreatic adenocarcinoma cells (PSN-1) of 0.22 and 0.27 lM compared to 28.1 and 19.2 lM for irinotecan at 48 and 72 h, respectively. The cytotoxic efficacy of DEBTOP on PSN-1 was compared to DEBIRI. DEPTOP loaded at 6 & 30 mg ml-1, like its free drug form, was shown to be more potent than DEBIRI of comparable doses at 24, 48 & 72 h using a slightly modified MTS assay. Using a PSN-1 mouse xenograft model, DEBIRI doses of 3.3–6.6 mg were shown to be well tolerated (even with repeat administration) and effective in reducing the tumour size. DEBTOP however, was lethal after 6 days at doses of 0.83–1.2 mg but demonstrated reasonable efficacy and tolerability (again with repeat injection possible) at 0.2–0.4 mg doses. Care must therefore be taken when selecting the dose of topotecan to be loaded into DC Bead given its greater potency and potential toxicity

Planar and Nonplanar Konishi Anomalies and Effective Superpotential for Noncommutative N=1 Supersymmetric U(1)

The Konishi anomalies for noncommutative N=1 supersymmetric U(1) gauge theory arising from planar and nonplanar diagrams are calculated. Whereas planar Konishi anomaly is the expected \star-deformation of the commutative anomaly, nonplanar anomaly reflects the important features of nonplanar diagrams of noncommutative gauge theories, such as UV/IR mixing and the appearance of nonlocal open Wilson lines. We use the planar and nonplanar Konishi anomalies to calculate the effective superpotential of the theory. In the limit of vanishing |\Theta p|, with \Theta the noncommutativity parameter, the noncommutative effective superpotential depends on a gauge invariant superfield, which includes supersymmetric Wilson lines, and has nontrivial dependence on the gauge field supermultiplet.Comment: LaTeX, 36 pages. Version 2: Typos Corrected. Version 3: Extensively revised version, 42 pages, to be published in Int. J. Mod. Phys. A. (2005

Structural insights into RNA processing by the human RISC-loading complex.

Targeted gene silencing by RNA interference (RNAi) requires loading of a short guide RNA (small interfering RNA (siRNA) or microRNA (miRNA)) onto an Argonaute protein to form the functional center of an RNA-induced silencing complex (RISC). In humans, Argonaute2 (AGO2) assembles with the guide RNA-generating enzyme Dicer and the RNA-binding protein TRBP to form a RISC-loading complex (RLC), which is necessary for efficient transfer of nascent siRNAs and miRNAs from Dicer to AGO2. Here, using single-particle EM analysis, we show that human Dicer has an L-shaped structure. The RLC Dicer's N-terminal DExH/D domain, located in a short 'base branch', interacts with TRBP, whereas its C-terminal catalytic domains in the main body are proximal to AGO2. A model generated by docking the available atomic structures of Dicer and Argonaute homologs into the RLC reconstruction suggests a mechanism for siRNA transfer from Dicer to AGO2

6D supergravity without tensor multiplets

We systematically investigate the finite set of possible gauge groups and matter content for N = 1 supergravity theories in six dimensions with no tensor multiplets, focusing on nonabelian gauge groups which are a product of SU(N) factors. We identify a number of models which obey all known low-energy consistency conditions, but which have no known string theory realization. Many of these models contain novel matter representations, suggesting possible new string theory constructions. Many of the most exotic matter structures arise in models which precisely saturate the gravitational anomaly bound on the number of hypermultiplets. Such models have a rigid symmetry structure, in the sense that there are no moduli which leave the full gauge group unbroken.Comment: 31 pages, latex; v2, v3: minor corrections, references adde

Nonperturbative aspects of ABJM theory

Using the matrix model which calculates the exact free energy of ABJM theory on S^3 we study non-perturbative effects in the large N expansion of this model, i.e., in the genus expansion of type IIA string theory on AdS4xCP^3. We propose a general prescription to extract spacetime instanton actions from general matrix models, in terms of period integrals of the spectral curve, and we use it to determine them explicitly in the ABJM matrix model, as exact functions of the 't Hooft coupling. We confirm numerically that these instantons control the asymptotic growth of the genus expansion. Furthermore, we find that the dominant instanton action at strong coupling determined in this way exactly matches the action of an Euclidean D2-brane instanton wrapping RP^3.Comment: 26 pages, 14 figures. v2: small corrections, final version published in JHE