Estimating the burden of minor ailment consultations in general practices and emergency departments through retrospective review of routine data in North East Scotland

Minor ailment attendances in general practices and emergency departments (EDs) place significant burden on health care resources

The compound Poisson limit ruling periodic extreme behaviour of non-uniformly hyperbolic dynamics

We prove that the distributional limit of the normalised number of returns to small neighbourhoods of periodic points of non-uniformly hyperbolic dynamical systems is compound Poisson. The returns to small balls around a fixed point in the phase space correspond to the occurrence of rare events, or exceedances of high thresholds, so that there is a connection between the laws of Return Times Statistics and Extreme Value Laws. The fact that the fixed point in the phase space is a repelling periodic point implies that there is a tendency for the exceedances to appear in clusters whose average sizes is given by the Extremal Index, which depends on the expansion of the system at the periodic point. We recall that for generic points, the exceedances, in the limit, are singular and occur at Poisson times. However, around periodic points, the picture is different: the respective point processes of exceedances converge to a compound Poisson process, so instead of single exceedances, we have entire clusters of exceedances occurring at Poisson times with a geometric distribution ruling its multiplicity. The systems to which our results apply include: general piecewise expanding maps of the interval (Rychlik maps), maps with indifferent fixed points (Manneville-Pomeau maps) and Benedicks-Carleson quadratic maps.Comment: To appear in Communications in Mathematical Physic

Thermodynamic formalism for contracting Lorenz flows

We study the expansion properties of the contracting Lorenz flow introduced by Rovella via thermodynamic formalism. Specifically, we prove the existence of an equilibrium state for the natural potential $\hat\phi_t(x,y, z):=-t\log J_{(x, y, z)}^{cu}$ for the contracting Lorenz flow and for $t$ in an interval containing $[0,1]$. We also analyse the Lyapunov spectrum of the flow in terms of the pressure

Identifying component modules

A computer-based system for modelling component dependencies and identifying component modules is presented. A variation of the Dependency Structure Matrix (DSM) representation was used to model component dependencies. The system utilises a two-stage approach towards facilitating the identification of a hierarchical modular structure. The first stage calculates a value for a clustering criterion that may be used to group component dependencies together. A Genetic Algorithm is described to optimise the order of the components within the DSM with the focus of minimising the value of the clustering criterion to identify the most significant component groupings (modules) within the product structure. The second stage utilises a 'Module Strength Indicator' (MSI) function to determine a value representative of the degree of modularity of the component groupings. The application of this function to the DSM produces a 'Module Structure Matrix' (MSM) depicting the relative modularity of available component groupings within it. The approach enabled the identification of hierarchical modularity in the product structure without the requirement for any additional domain specific knowledge within the system. The system supports design by providing mechanisms to explicitly represent and utilise component and dependency knowledge to facilitate the nontrivial task of determining near-optimal component modules and representing product modularity

Rapid tests and urine sampling techniques for the diagnosis of urinary tract infection (UTI) in children under five years: a systematic review

Background: Urinary tract infection (UTI) is one of the most common sources of infection in children under five. Prompt diagnosis and treatment is important to reduce the risk of renal scarring. Rapid, cost-effective, methods of UTI diagnosis are required as an alternative to culture. Methods: We conducted a systematic review to determine the diagnostic accuracy of rapid tests for detecting UTI in children under five years of age. Results: The evidence supports the use of dipstick positive for both leukocyte esterase and nitrite (pooled LR+ = 28.2, 95% CI: 17.3, 46.0) or microscopy positive for both pyuria and bacteriuria (pooled LR+ = 37.0, 95% CI: 11.0, 125.9) to rule in UTI. Similarly dipstick negative for both LE and nitrite (Pooled LR- = 0.20, 95% CI: 0.16, 0.26) or microscopy negative for both pyuria and bacteriuria (Pooled LR- = 0.11, 95% CI: 0.05, 0.23) can be used to rule out UTI. A test for glucose showed promise in potty-trained children. However, all studies were over 30 years old. Further evaluation of this test may be useful. Conclusion: Dipstick negative for both LE and nitrite or microscopic analysis negative for both pyuria and bacteriuria of a clean voided urine, bag, or nappy/pad specimen may reasonably be used to rule out UTI. These patients can then reasonably be excluded from further investigation, without the need for confirmatory culture. Similarly, combinations of positive tests could be used to rule in UTI, and trigger further investigation

546 Results from Phase Ib study of tebentafusp (tebe) in combination with durvalumab (durva) and/or tremelimumab (treme) in metastatic cutaneous melanoma (mCM)

BackgroundTebe, a T cell receptor fused to an anti-CD3 effector, can redirect T cells to target gp100+ cells and in Ph3, demonstrated overall survival (OS) benefit as monotherapy in metastatic uveal melanoma. In Ph2, any tumor shrinkage (44% of patients) was a better predictor of OS than response rate. In Ph1, Tebe had monotherapy activity in mCM, also a gp100+ tumor, with 1-year OS ~74% in PD-1 naïve mCM. A Ph1 dose escalation of tebe with durva (anti-PD-L1) and/or treme (anti-CTLA4) was conducted in pre-treated mCM [NCT02535078], with nearly all patients having prior PD1-treatment, and where recently reported therapies have 1-yr OS of ~55%.MethodsHeavily pre-treated HLA-A2+ mCM patients received weekly IV tebe alone (Arm 4) or with increasing doses of durva and/or treme (Arm 1–3) administered IV monthly starting day 15 of each cycle. Primary objective was to identify RP2D of combination therapy. Secondary objectives included adverse events (AE) and efficacy.Results112 pts received ≥1 tebe dose. Median age was 59, 77% were ECOG 0, and 37% were BRAFm (of which 71% received prior BRAFi/MEKi). 91% of pts were 2L+, while 74% were 3L+. 103 (92%) received prior PD-1 inhibitor, of which 87% also received prior ipilimumab. 43 pts received tebe + durva (Arm 1), 13 received tebe + treme (Arm 2), 29 received triplet therapy (Arm 3), and 27 received tebe alone (Arm 4). Maximum target doses of tebe (68 mcg) + durva (20 mg/kg) and treme (1 mg/kg) were tolerated. MTD was not formally identified for any arm. Two DLTs occurred: prolonged grade 3 rash (Arm 1) and grade 2 diarrhea leading to treatment delay (Arm 2). Related AEs that were Grade ≥3 or led to discontinuations were: 44%/0% (Arm 1), 23%/0% (Arm2), 38%/7% (Arm3), 26%/4% (Arm 4). There were no treatment-related deaths.In prior PD-1 pts, tumor shrinkage occurred in 36% and 1-yr OS was 68%. Of 51 evaluable PD-1 resistant pts (best response CR/PR/SD to prior PD1), tumor shrinkage occurred in 28% and 1-yr OS was 73% (figure 1). In 35 evaluable PD-1 refractory pts (prior best response PD), tumor shrinkage occurred in 49% and 1-yr OS was 61%. For 38 prior PD-1 pts who received ≥10mg/kg durva, 1-yr OS was 81%.Abstract 546 Figure 1% tumor change from baseline in evaluable patients with known response to prior PD1 exposureConclusionsTebe with anti-PD-L1 and/or anti-CTLA4 had an acceptable safety profile. Tebe + durva demonstrated durable tumor shrinkage and promising 1-yr OS rates in prior-PD1 treated mCM relative to recent reports.Trial RegistrationNCT02535078Ethics ApprovalThe institutional review board or independent ethics committee at each center approved the trial. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines

The 2006 NESCent Phyloinformatics Hackathon: A Field Report

In December, 2006, a group of 26 software developers from some of the most widely used life science programming toolkits and phylogenetic software projects converged on Durham, North Carolina, for a Phyloinformatics Hackathon, an intense five-day collaborative software coding event sponsored by the National Evolutionary Synthesis Center (NESCent). The goal was to help researchers to integrate multiple phylogenetic software tools into automated workflows. Participants addressed deficiencies in interoperability between programs by implementing “glue code” and improving support for phylogenetic data exchange standards (particularly NEXUS) across the toolkits. The work was guided by use-cases compiled in advance by both developers and users, and the code was documented as it was developed. The resulting software is freely available for both users and developers through incorporation into the distributions of several widely-used open-source toolkits. We explain the motivation for the hackathon, how it was organized, and discuss some of the outcomes and lessons learned. We conclude that hackathons are an effective mode of solving problems in software interoperability and usability, and are underutilized in scientific software development

Disentangling a group of lensed submm galaxies at z∼ 2.9

MS0451.6−0305 is a rich galaxy cluster whose strong lensing is particularly prominent at submm wavelengths. We combine new Submillimetre Common-User Bolometer Array (SCUBA)-2 data with imaging from Herschel Spectral and Photometric Imaging Receiver (SPIRE) and PACS and Hubble Space Telescope in order to try to understand the nature of the sources being lensed. In the region of the ‘giant submm arc', we uncover seven multiply imaged galaxies (up from the previously known four), of which six are found to be at a redshift of z∼2.9, and possibly constitute an interacting system. Using a novel forward-modelling approach, we are able to simultaneously deblend and fit spectral energy distributions to the individual galaxies that contribute to the giant submm arc, constraining their dust temperatures, far-infrared luminosities, and star formation rates (SFRs). The submm arc first identified by SCUBA can now be seen to be composed of at least five distinct sources, four of these within a galaxy group at z∼2.9. Only a handful of lensed galaxy groups at this redshift are expected on the sky, and thus this is a unique opportunity for studying such systems in detail. The total unlensed luminosity for this galaxy group is (3.1±0.3)×1012 L⊙, which gives an unlensed SFR of (450±50) M⊙yr−1. This finding suggests that submm source multiplicity, due to physically associated groupings as opposed to chance alignment, extends to fainter flux densities than previously discovered. Many of these systems may also host optical companions undetected in the submm, as is the case her

A novel endonuclease IV post-PCR genotyping system

Here we describe a novel endonuclease IV (Endo IV) based assay utilizing a substrate that mimics the abasic lesions that normally occur in double-stranded DNA. The three component substrate is characterized by single-stranded DNA target, an oligonucleotide probe, separated from a helper oligonucleotide by a one base gap. The oligonucleotide probe contains a non-fluorescent quencher at the 5′ end and fluorophore attached to the 3′ end through a special rigid linker. Fluorescence of the oligonucleotide probe is efficiently quenched by the interaction of terminal dye and quencher when not hybridized. Upon hybridization of the oligonucleotide probe and helper probe to their complementary target, the phosphodiester linkage between the rigid linker and the 3′ end of the probe is efficiently cleaved, generating a fluorescent signal. In this study, the use of the Endo IV assay as a post-PCR amplification detection system is demonstrated. High sensitivity and specificity are illustrated using single nucleotide polymorphism detection