Signalling paediatric side effects using an ensemble of simple study designs

Background: Children are frequently prescribed medication `o-label', meaning there has not been sucient testing of the medication to determine its safety or eectiveness. The main reason this safety knowledge is lacking is due to ethical restrictions that prevent children from being included in the majority of clinical trials. Methods: Multiple measures of association are calculated for each drug and medical event pair and these are used as features that are fed into a classifier to determine the likelihood of the drug and medical event pair corresponding to an adverse drug reaction. The classier is trained using known adverse drug reactions or known non-adverse drug reaction relationships. Results: The novel ensemble framework obtained a false positive rate of 0:149, a sensitivity of 0:547 and a specificity of 0:851 when implemented on a reference set of drug and medical event pairs. The novel framework consistently outperformed each individual simple study design. Conclusion: This research shows that it is possible to exploit the mechanism of causality and presents a framework for signalling adverse drug reactions eectively

A novel semi-supervised algorithm for rare prescription side effect discovery

Drugs are frequently prescribed to patients with the aim of improving each patient's medical state, but an unfortunate consequence of most prescription drugs is the occurrence of undesirable side effects. Side effects that occur in more than one in a thousand patients are likely to be signalled efficiently by current drug surveillance methods, however, these same methods may take decades before generating signals for rarer side effects, risking medical morbidity or mortality in patients prescribed the drug while the rare side effect is undiscovered. In this paper we propose a novel computational meta-analysis framework for signalling rare side effects that integrates existing methods, knowledge from the web, metric learning and semi-supervised clustering. The novel framework was able to signal many known rare and serious side effects for the selection of drugs investigated, such as tendon rupture when prescribed Ciprofloxacin or Levofloxacin, renal failure with Naproxen and depression associated with Rimonabant. Furthermore, for the majority of the drug investigated it generated signals for rare side effects at a more stringent signalling threshold than existing methods and shows the potential to become a fundamental part of post marketing surveillance to detect rare side effects

Does the presence of connective tissue disease modify survival in patients with pulmonary fibrosis?

SummaryObjectivesPrevious studies into the survival differences between individuals with idiopathic pulmonary fibrosis and those with connective tissue disease associated pulmonary fibrosis (CTD-PF) have yielded mixed results. The aim of this study is to compare the survival of individuals with CTD-PF to those with idiopathic pulmonary fibrosis clinical syndrome (IPF-CS) using data derived from The Health Improvement network, a large primary care database in the UK.MethodsIncident cases of CTD-PF and IPF-CS between the years 2000–2009 were identified. Survival analysis was performed using Kaplan–Meier methods, stratified by type of connective tissue disease. Cox regression was then used to compare mortality rates between the groups, adjusting for age, gender and year of diagnosis.ResultsA total of 324 cases of CTD-PF and 2209 cases of IPF-CS were followed up over a mean period of 2.3 years. During this period, 113 (34.9%) cases of CTD-PF and 1073 (48.6%) cases of IPF-CS died. The mortality rates for cases with CTD-PF and IPF-CS were 123.6 per 1000 person years (95%CI: 102.8–148.9) and 229.8 per 1000 person years (95% CI: 216.4–244.0) respectively. After adjusting for age, sex and year of diagnosis, cases with CTD-PF had a better prognosis compared to those with IPF-CS (HR 0.76,95%CI: 0.62–0.92).ConclusionThe prognosis of individuals with CTD-PF appears to be significantly better than those with IPF-CS, but remains an important cause of death in patients with connective tissue disease, and requires more effective treatment options

Complications and mortality in hereditary hemorrhagic telangiectasia: a population-based study

OBJECTIVES: Studies report that the risks of significant neurologic complications (including stroke, cerebral abscess, and migraine) and hemorrhagic sequelae are high in patients with hereditary hemorrhagic telangiectasia (HHT), and that life expectancy in this cohort is reduced. However, most published cohorts derive from specialist centers, which may be susceptible to bias. METHODS: We used a population-based approach to estimate the risks of developing neurologic and hemorrhagic complications of HHT, the association of a diagnosis of HHT with common cardiovascular and malignant comorbidities, and also long-term survival of those with the disease. RESULTS: From a UK primary care database of 3.5 million patients (The Health Improvement Network), we identified 675 cases with a diagnosis of HHT and compared them with 6,696 controls matched by age, sex, and primary care practice. Risks of stroke (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.2-2.6), cerebral abscess (OR 30.0, CI 3.1-288), and migraine (OR 1.7, CI 1.3-2.2) were elevated over controls. Bleeding complications including epistaxis (OR 11.6, CI 9.1-14.7) and gastrointestinal hemorrhage (OR 6.1, CI 2.8-13.4) were more common in cases with HHT. Survival of cases with HHT was poorer than controls with a hazard ratio for death of 2.0 (CI 1.6-2.6) and a median age at death 3 years younger. CONCLUSIONS: Patients with HHT are at substantially increased risk of serious neurologic and hemorrhagic complications of the disease. Because a diagnosis of HHT is associated with a significantly poorer survival compared with those who have no disease, evaluation of new strategies to improve clinical management is required

A local families index formula for d-bar operators on punctured Riemann surfaces

Using heat kernel methods developed by Vaillant, a local index formula is obtained for families of d-bar operators on the Teichmuller universal curve of Riemann surfaces of genus g with n punctures. The formula also holds on the moduli space M{g,n} in the sense of orbifolds where it can be written in terms of Mumford-Morita-Miller classes. The degree two part of the formula gives the curvature of the corresponding determinant line bundle equipped with the Quillen connection, a result originally obtained by Takhtajan and Zograf.Comment: 47 page

Use of variability in national and regional data to estimate the prevalence of lymphangioleiomyomatosis

Background: Understanding the true prevalence of lymphangioleiomyomatosis (LAM) is important in estimating disease burden and targeting specific interventions. As with all rare diseases, obtaining reliable epidemiological data is difficult and requires innovative approaches. Aim: To determine the prevalence and incidence of LAM using data from patient organizations in seven countries, and to use the extent to which the prevalence of LAM varies regionally and nationally to determine whether prevalence estimates are related to health-care provision. Methods: Numbers of women with LAM were obtained from patient groups and national databases from seven countries (n = 1001). Prevalence was calculated for regions within countries using female population figures from census data. Incidence estimates were calculated for the USA, UK and Switzerland. Regional variation in prevalence and changes in incidence over time were analysed using Poisson regression and linear regression. Results: Prevalence of LAM in the seven countries ranged from 3.4 to 7.8/million women with significant variation, both between countries and between states in the USA. This variation did not relate to the number of pulmonary specialists in the region nor the percentage of population with health insurance, but suggests a large number of patients remain undiagnosed. The incidence of LAM from 2004 to 2008 ranged from 0.23 to 0.31/million women/per year in the USA, UK and Switzerland. Conclusions: Using this method, we have found that the prevalence of LAM is higher than that previously recorded and that many patients with LAM are undiagnose

Methane Flux in Cropland and Adjacent Riparian Buff ers with Different Vegetation Covers

While water quality functions of conservation buffers established adjacent to cropped fields have been widely documented, the relative contribution of these re-established perennial plant systems to greenhouse gases has not been completely documented. In the case of methane (CH(4)), these systems have the potential to serve as sinks of CH(4) or may provide favorable conditions for CH(4) production. This study quantifies CH(4) flux from soils of riparian buffer systems comprised of three vegetation types and compares these fluxes with those of adjacent crop fields. We measured soil properties and diel and seasonal variations of CH(4) flux in 7 to 17 yr-old re-established riparian forest buffers, warm-season and cool-season grass filters, and an adjacent crop field located in the Bear Creek watershed in central Iowa. Forest buffer and grass filter soils had significantly lower bulk density (P \u3c 0.01); and higher pH (P \u3c 0.01), total carbon (TC) (P \u3c 0.01), and total nitrogen (TN) (P \u3c 0.01) than crop field soils. There was no significant relationship between CH(4) flux and soil moisture or soil temperature among sites within the range of conditions observed. Cumulative CH(4) flux was -0.80 kg CH(4)-C ha(-1) yr(-1) in the cropped field, -0.46 kg CH(4)-C ha(-1) yr(-1) within the forest buffers, and 0.04 kg CH(4)-C ha(-1) yr(-1) within grass filters, but difference among vegetation covers was not significant. Results suggest that CH(4) flux was not changed after establishment of perennial vegetation on cropped soils, despite significant changes in soil properties

The Extended Coupled Cluster Treatment of Correlations in Quantum Magnets

The spin-half XXZ model on the linear chain and the square lattice are examined with the extended coupled cluster method (ECCM) of quantum many-body theory. We are able to describe both the Ising-Heisenberg phase and the XY-Heisenberg phase, starting from known wave functions in the Ising limit and at the phase transition point between the XY-Heisenberg and ferromagnetic phases, respectively, and by systematically incorporating correlations on top of them. The ECCM yields good numerical results via a diagrammatic approach, which makes the numerical implementation of higher-order truncation schemes feasible. In particular, the best non-extrapolated coupled cluster result for the sublattice magnetization is obtained, which indicates the employment of an improved wave function. Furthermore, the ECCM finds the expected qualitatively different behaviours of the linear chain and the square lattice cases.Comment: 22 pages, 3 tables, and 15 figure

Universality, the QCD critical/tricritical point and the quark number susceptibility

The quark number susceptibility near the QCD critical end-point (CEP), the tricritical point (TCP) and the O(4) critical line at finite temperature and quark chemical potential is investigated. Based on the universality argument and numerical model calculations we propose a possibility that the hidden tricritical point strongly affects the critical phenomena around the critical end-point. We made a semi-quantitative study of the quark number susceptibility near CEP/TCP for several quark masses on the basis of the Cornwall-Jackiw-Tomboulis (CJT) potential for QCD in the improved-ladder approximation. The results show that the susceptibility is enhanced in a wide region around CEP inside which the critical exponent gradually changes from that of CEP to that of TCP, indicating a crossover of different universality classes.Comment: 18 pages, 10 figure

Horizontal Branch Stars: The Interplay between Observations and Theory, and Insights into the Formation of the Galaxy

We review HB stars in a broad astrophysical context, including both variable and non-variable stars. A reassessment of the Oosterhoff dichotomy is presented, which provides unprecedented detail regarding its origin and systematics. We show that the Oosterhoff dichotomy and the distribution of globular clusters (GCs) in the HB morphology-metallicity plane both exclude, with high statistical significance, the possibility that the Galactic halo may have formed from the accretion of dwarf galaxies resembling present-day Milky Way satellites such as Fornax, Sagittarius, and the LMC. A rediscussion of the second-parameter problem is presented. A technique is proposed to estimate the HB types of extragalactic GCs on the basis of integrated far-UV photometry. The relationship between the absolute V magnitude of the HB at the RR Lyrae level and metallicity, as obtained on the basis of trigonometric parallax measurements for the star RR Lyrae, is also revisited, giving a distance modulus to the LMC of (m-M)_0 = 18.44+/-0.11. RR Lyrae period change rates are studied. Finally, the conductive opacities used in evolutionary calculations of low-mass stars are investigated. [ABRIDGED]Comment: 56 pages, 22 figures. Invited review, to appear in Astrophysics and Space Scienc