Self-controlled case series with multiple event types

Self-controlled case series methods for events that may be classified as one of several types are described. When the event is non-recurrent, the different types correspond to competing risks. It is shown that, under circumstances that are likely to arise in practical applications, the SCCS multi-type likelihood reduces to the product of the type-specific likelihoods. For recurrent events, this applies whether or not the marginal type-specific counts are dependent. As for the standard SCCS method, a rare disease assumption is required for non-recurrent events. Several forms of this assumption are investigated by simulation. The methods are applied to data on MMR vaccine and convulsions (febrile and non-febrile), and to data on thiazolidinediones and fractures (at different sites)

Formal techniques in the safety analysis of software components of a new dialysis machine

The paper is concerned with the practical use of formal techniques to contribute to the risk analysis of a new neonatal dialysis machine. The described formal analysis focuses on the controller component of the software implementation. The controller drives the dialysis cycle and deals with error management. The logic was analysed using model checking techniques and the source code was analysed formally, checking type correctness conditions, use of pointers and shared memory. The analysis provided evidence of the verification of risk control measures relating to the software component. The productive dialogue between the developers of the device, who had no experience or knowledge of formal methods, and the analyst using the formal analysis tools, provided a basis for the development of rationale for the effectiveness of the evidence. (C) 2019 Elsevier B.V. All rights reserved.This work has been funded by: EPSRC research grants EP/G059063/1 and EP/J008133/1: CHI+MED (Computer -Human Interaction for Medical Devices); and NanoSTIMA (ref. NORTE-01-0145-FEDER-000016) financed by the North Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, and through the European Regional Development Fund (ERDF). Leo Freitas would like to acknowledge EPSRC Trams2 project for financial support, Andrew Sims for providing access to the dialyser, which was used as our case study and Aleksandrs Baklanovs for doing some of the source analysis as part of an undergraduate project

Antipsychotic drugs and risks of myocardial infarction: a self-controlled case series study.

AIM: Antipsychotics increase the risk of stroke. Their effect on myocardial infarction remains uncertain because people prescribed and not prescribed antipsychotic drugs differ in their underlying vascular risk making between-person comparisons difficult to interpret. The aim of our study was to investigate this association using the self-controlled case series design that eliminates between-person confounding effects. METHODS AND RESULTS: All the patients with a first recorded myocardial infarction and prescription for an antipsychotic identified in the Clinical Practice Research Datalink linked to the Myocardial Ischaemia National Audit Project were selected for the self-controlled case series. The incidence ratio of myocardial infarction during risk periods following the initiation of antipsychotic use relative to unexposed periods was estimated within individuals. A classical case-control study was undertaken for comparative purposes comparing antipsychotic exposure among cases and matched controls. We identified 1546 exposed cases for the self-controlled case series and found evidence of an association during the first 30 days after the first prescription of an antipsychotic, for first-generation agents [incidence rate ratio (IRR) 2.82, 95% confidence interval (CI) 2.0-3.99] and second-generation agents (IRR: 2.5, 95% CI: 1.18-5.32). Similar results were found for the case-control study for new users of first- (OR: 3.19, 95% CI: 1.9-5.37) and second-generation agents (OR: 2.55, 95% CI: 0.93-7.01) within 30 days of their myocardial infarction. CONCLUSION: We found an increased risk of myocardial infarction in the period following the initiation of antipsychotics that was not attributable to differences between people prescribed and not prescribed antipsychotics

Cross section and transverse single-spin asymmetry of muons from open heavy-flavor decays in polarized p plus p collisions at root s=200 GeV

The cross section and transverse single-spin asymmetries of mu(-) and mu(+) from open heavy-flavor decays in polarized p + p collisions at root s = 200 GeV were measured by the PHENIX experiment during 2012 at the Relativistic Heavy Ion Collider. Because heavy-flavor production is dominated by gluon-gluon interactions at root s = 200 GeV, these measurements offer a unique opportunity to obtain information on the trigluon correlation functions. The measurements are performed at forward and backward rapidity (1.4 \u3c vertical bar y vertical bar \u3c 2.0) over the transverse momentum range of 1.25 \u3c p(T) \u3c 7 GeV/c for the cross section and 1.25 \u3c p(T) \u3c 5 GeV/c for the asymmetry measurements. The obtained cross section is compared to a fixed-order-plus-next-to-leading-log perturbative-quantum-chromodynamics calculation. The asymmetry results are consistent with zero within uncertainties, and a model calculation based on twist-3 three-gluon correlations agrees with the data

Noncommutative quantum mechanics and Bohm's ontological interpretation

We carry out an investigation into the possibility of developing a Bohmian interpretation based on the continuous motion of point particles for noncommutative quantum mechanics. The conditions for such an interpretation to be consistent are determined, and the implications of its adoption for noncommutativity are discussed. A Bohmian analysis of the noncommutative harmonic oscillator is carried out in detail. By studying the particle motion in the oscillator orbits, we show that small-scale physics can have influence at large scales, something similar to the IR-UV mixing

The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine

Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk

Genome-wide characterization of simple sequence repeats in cucumber (Cucumis sativus L.)

<p>Abstract</p> <p>Background</p> <p>Cucumber, <it>Cucumis sativus </it>L. is an important vegetable crop worldwide. Until very recently, cucumber genetic and genomic resources, especially molecular markers, have been very limited, impeding progress of cucumber breeding efforts. Microsatellites are short tandemly repeated DNA sequences, which are frequently favored as genetic markers due to their high level of polymorphism and codominant inheritance. Data from previously characterized genomes has shown that these repeats vary in frequency, motif sequence, and genomic location across taxa. During the last year, the genomes of two cucumber genotypes were sequenced including the Chinese fresh market type inbred line '9930' and the North American pickling type inbred line 'Gy14'. These sequences provide a powerful tool for developing markers in a large scale. In this study, we surveyed and characterized the distribution and frequency of perfect microsatellites in 203 Mbp assembled Gy14 DNA sequences, representing 55% of its nuclear genome, and in cucumber EST sequences. Similar analyses were performed in genomic and EST data from seven other plant species, and the results were compared with those of cucumber.</p> <p>Results</p> <p>A total of 112,073 perfect repeats were detected in the Gy14 cucumber genome sequence, accounting for 0.9% of the assembled Gy14 genome, with an overall density of 551.9 SSRs/Mbp. While tetranucleotides were the most frequent microsatellites in genomic DNA sequence, dinucleotide repeats, which had more repeat units than any other SSR type, had the highest cumulative sequence length. Coding regions (ESTs) of the cucumber genome had fewer microsatellites compared to its genomic sequence, with trinucleotides predominating in EST sequences. AAG was the most frequent repeat in cucumber ESTs. Overall, AT-rich motifs prevailed in both genomic and EST data. Compared to the other species examined, cucumber genomic sequence had the highest density of SSRs (although comparable to the density of poplar, grapevine and rice), and was richest in AT dinucleotides. Using an electronic PCR strategy, we investigated the polymorphism between 9930 and Gy14 at 1,006 SSR loci, and found unexpectedly high degree of polymorphism (48.3%) between the two genotypes. The level of polymorphism seems to be positively associated with the number of repeat units in the microsatellite. The <it>in silico </it>PCR results were validated empirically in 660 of the 1,006 SSR loci. In addition, primer sequences for more than 83,000 newly-discovered cucumber microsatellites, and their exact positions in the Gy14 genome assembly were made publicly available.</p> <p>Conclusions</p> <p>The cucumber genome is rich in microsatellites; AT and AAG are the most abundant repeat motifs in genomic and EST sequences of cucumber, respectively. Considering all the species investigated, some commonalities were noted, especially within the monocot and dicot groups, although the distribution of motifs and the frequency of certain repeats were characteristic of the species examined. The large number of SSR markers developed from this study should be a significant contribution to the cucurbit research community.</p

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials

Two Genes on A/J Chromosome 18 Are Associated with Susceptibility to Staphylococcus aureus Infection by Combined Microarray and QTL Analyses

Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N2 backcross mice (F1 [C18A]×C57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus–challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 β and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases