The introduction and rapidly expanding range of Aedes albopictus in Europe is an iconic example of the growing risk of the globalization of vectors and vector-borne diseases. The history of yellow ...fever and dengue in temperate regions confirms that transmission of both diseases could recur, particularly if Ae. aegypti, a more effective vector, were to be re-introduced. The article is a broad overview of the natural history and epidemiology of both diseases in the context of these risks.
In many observational studies, analysts estimate treatment effects using propensity scores, e.g. by matching or sub-classifying on the scores. When some values of the covariates are missing, analysts ...can use multiple imputation to fill in the missing data, estimate propensity scores based on the m completed datasets, and use the propensity scores to estimate treatment effects. We compare two approaches to implement this process. In the first, the analyst estimates the treatment effect using propensity score matching within each completed data set, and averages the m treatment effect estimates. In the second approach, the analyst averages the m propensity scores for each record across the completed datasets, and performs propensity score matching with these averaged scores to estimate the treatment effect. We compare properties of both methods via simulation studies using artificial and real data. The simulations suggest that the second method has greater potential to produce substantial bias reductions than the first, particularly when the missing values are predictive of treatment assignment.
The appearance of West Nile virus in New York in 1999 and the unprecedented panzootic that followed, have stimulated a major research effort in the western hemisphere and a new interest in the ...presence of this virus in the Old World. This review considers current understanding of the natural history of this pathogen, with particular regard to transmission in Europe.
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•There is an urgent need for novel drugs for PSC.•In this phase II clinical trial, norUDCA reduced serum ALP levels within 12weeks.•norUDCA’s effects on liver enzymes were ...dose-dependent.•The safety profile of norUDCA was excellent.
Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500mg/d, 1,000mg/d or 1,500mg/d) compared with placebo in patients with PSC.
One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit.
norUDCA reduced ALP levels by −12.3%, −17.3%, and −26.0% in the 500, 1,000, and 1,500mg/d groups (p=0.029, p=0.003, and p<0.0001 when compared to placebo), respectively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary endpoints, such as ALT, AST, γ-GT, or the rate of patients achieving ALP levels <1.5× ULN. Serious adverse events occurred in seven patients in the 500mg/d, five patients in the 1,000mg/d, two patients in the 1500mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups.
norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients.
Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study.
ClinicalTrials.gov number: NCT01755507.
Global atmospheric temperatures are presently in a warming phase that began 250-300 years ago. Speculations on the potential impact of continued warming on human health often focus on mosquito-borne ...diseases. Elementary models suggest that higher global temperatures will enhance their transmission rates and extend their geographic ranges. However, the histories of three such diseases-malaria, yellow fever, and dengue-reveal that climate has rarely been the principal determinant of their prevalence or range; human activities and their impact on local ecology have generally been much more significant. It is therefore inappropriate to use climate-based models to predict future prevalence.
The MINIBALL spectrometer utilizes successfully a variety of post-accelerated radioactive ion beams provided by the new HIE-ISOLDE accelerator at CERN. In-beam γ-ray spectroscopy after Coulomb ...excitation (CE) or transfer reactions is performed with optimized setups of ancillary detectors for particle detection. The physics program covers a wide range of shell model investigations. Exotic heavy ion beams will enable unique studies of collective properties up to the actinide region. First data taking with HIE-ISOLDE beams started recently. The higher energies and intensities of the new post-accelerator provides a promising perspective for a new generation of MINIBALL experiments. Intriguing first results were obtained by employing beams of 74,76,78Zn, 110,132Sn, 144Xe with beam energies in the range of 4.0 - 5.5 MeV/u for CE experiments at 'safe' energies. In all cases first results for various B(Eλ) values for these isotopes were obtained.
Multiple imputation is particularly well suited to deal with missing data in large epidemiologic studies, because typically these studies support a wide range of analyses by many data users. Some of ...these analyses may involve complex modeling, including interactions and nonlinear relations. Identifying such relations and encoding them in imputation models, for example, in the conditional regressions for multiple imputation via chained equations, can be daunting tasks with large numbers of categorical and continuous variables. The authors present a nonparametric approach for implementing multiple imputation via chained equations by using sequential regression trees as the conditional models. This has the potential to capture complex relations with minimal tuning by the data imputer. Using simulations, the authors demonstrate that the method can result in more plausible imputations, and hence more reliable inferences, in complex settings than the naive application of standard sequential regression imputation techniques. They apply the approach to impute missing values in data on adverse birth outcomes with more than 100 clinical and survey variables. They evaluate the imputations using posterior predictive checks with several epidemiologic analyses of interest.
Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular carcinoma (HCC), sorafenib is ...currently an effective first-line therapy. Unfortunately, the development of drug resistance to sorafenib is becoming increasingly common. This study aims to identify factors contributing to resistance and ways to mitigate resistance. Recent studies have shown that epigenetics, transport processes, regulated cell death, and the tumor microenvironment are involved in the development of sorafenib resistance in HCC and subsequent HCC progression. This study summarizes discoveries achieved recently in terms of the principles of sorafenib resistance and outlines approaches suitable for improving therapeutic outcomes for HCC patients.
There is strong circumstantial evidence that certain heavy, unstable atomic nuclei are 'octupole deformed', that is, distorted into a pear shape. This contrasts with the more prevalent rugby-ball ...shape of nuclei with reflection-symmetric, quadrupole deformations. The elusive octupole deformed nuclei are of importance for nuclear structure theory, and also in searches for physics beyond the standard model; any measurable electric-dipole moment (a signature of the latter) is expected to be amplified in such nuclei. Here we determine electric octupole transition strengths (a direct measure of octupole correlations) for short-lived isotopes of radon and radium. Coulomb excitation experiments were performed using accelerated beams of heavy, radioactive ions. Our data on (220)Rn and (224)Ra show clear evidence for stronger octupole deformation in the latter. The results enable discrimination between differing theoretical approaches to octupole correlations, and help to constrain suitable candidates for experimental studies of atomic electric-dipole moments that might reveal extensions to the standard model.
In categorical data, it is typically the case that some combinations of variables are theoretically impossible, such as a 3-year-old child who is married or a man who is pregnant. In practice, ...however, reported values often include such structural zeros due to, for example, respondent mistakes or data processing errors. To purge data of such errors, many statistical organizations use a process known as edit-imputation. The basic idea is first to select reported values to change according to some heuristic or loss function, and second to replace those values with plausible imputations. This two-stage process typically does not fully use information in the data when determining locations of errors, nor does it appropriately reflect uncertainty resulting from the edits and imputations. We present an alternative approach to editing and imputation for categorical microdata with structural zeros that addresses these shortcomings. Specifically, we use a Bayesian hierarchical model that couples a stochastic model for the measurement error process with a Dirichlet process mixture of multinomial distributions for the underlying, error-free values. The latter model is restricted to have support only on the set of theoretically possible combinations. We illustrate this integrated approach to editing and imputation using simulation studies with data from the 2000 U. S. census, and compare it to a two-stage edit-imputation routine. Supplementary material is available online.
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