Molecular dynamics study of orientational cooperativity in water

Recent experiments on liquid water show collective dipole orientation fluctuations dramatically slower than expected (with relaxation time >tation, the self-dipole randomization time tr, which is an upper limit on ta; we find that tr5ta. Third, to check if there are correlated domains of dipoles in water which have large relaxation times compared to the individual dipoles, we calculate the randomization time tbox of the site-dipole field, the net dipole moment formed by a set of molecules belonging to a box of edge Lbox. We find that the site-dipole randomization time tbox2.5ta for Lbox3 , i.e., it is shorter than the same quantity calculated for the self-dipole. Finally, we find that the orientational correlation length is short even at low T.

A Phase IIB, Randomized, Double-Blind, Multicenter, Immunogenicity Study of Vacc-4x Versus Placebo in HIV-1-infected Patients

Background: Vacc-4x is a peptide-based HIV therapeutic vaccine to conserved domains on p24Gag. Recently conserved 'sectors' on HIV p24, critical for virus viability and thereby immunologically vulnerable have been identified. Elite controllers target immune responses to such regions. The Vacc-4x peptides lie within a number of these conserved sectors of HIV p24. The co-primary endpoints of this study were to compare changes in CD4 counts and return to ART between treatmentand placebo groups during a 24 week treatment interruption. Secondary endpoints included safety, viral load and immunogenicity.Methods: This prospective, randomized, double blind phase IIB clinical study (NCT00659789) was carried out in 13 European and 5 US centers recruiting 135 patients on ART. After 6 immunizations on ART over 28 weeks, treatment was interrupted for up to 24 weeks (to week 52) (Vacc-4x n = 88; placebo n = 38). Immunological analyses (ELISPOT, proliferation, intracellular cytokine staining) were carried out at central laboratories.Results: There were no Vacc-4x-related serious adverse events. Of the 135 patients recruited (male n = 92; female n = 43), 126 patients completed the study. Median prestudy CD4 count was 712 (Vacc-4x) and 619 cells/mm3 (placebo), and median CD4 nadir 300 (Vacc-4x) and 285 cells/mm3 (placebo). There was no statistically significant difference between the two groups regarding change in CD4 counts (p = 0.12) or ART resumption (p = 0.89) during treatment interruption. A statistically significant treatment difference between Vacc-4x and placebo groupsfor viral load (VL) was found for patients who achieved a 6 month ART-free period (p = 0.0022). There was a positive correlation between ELISPOT responses and lower viral load in the Vacc-4x group compared to placebo (p = 0.02). Long-term follow-up of patients up t o week 104 was completed in June 2011.Conclusion: Vacc-4x was found to be safe and well tolerated. TheVacc-4x group experienced a significant reduction in viral load compared to placebo.

Molecular dynamics study of the longitudinal modes in disparate-mass binaryliquid mixtures.

A series of molecular dynamics simulations of simple liquid binary mixtures of soft spheres with disparate-mass particles were carried out to investigate the origin of the marked differences between the dynamic structure factors of some liquid binary mixtures such as the Li0.7Mg0.3 and Li0.8Pb0.2 alloys. It is shown that the facility for observing peaks associated with fast-propagating modes in the partial Li-Li dynamic structure factor of Li0.8Pb0.2 should be mainly attributed to the structure of this alloy, which is characterized by an incipient ABAB ordering as found in molten salts. The longitudinal dispersion relations at intermediate wave vectors obtained from the longitudinal current spectra are very similar for the two alloys and reflect the existence of both fast-and slow-propagating modes of kinetic character associated with light and heavy particles, respectively. The influence of the hardness of the repulsive potential cores as well as the composition of the mixture on the longitudinal collective modes is also discussed.

Self and cross-velocity correlation functions and diffusion coefficients in liquids: a molecular dynamics study of binary mixtures of soft spheres

Molecular dynamics simulation is applied to the study of the diffusion properties in binary liquid mixtures made up of soft-sphere particles with different sizes and masses. Self- and distinct velocity correlation functions and related diffusion coefficients have been calculated. Special attention has been paid to the dynamic cross correlations which have been computed through recently introduced relative mean molecular velocity correlation functions which are independent on the reference frame. The differences between the distinct velocity correlations and diffusion coefficients in different reference frames (mass-fixed, number-fixed, and solvent-fixed) are discussed.

Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.

BACKGROUND: Atazanavir-associated hyperbilirubinemia can cause premature discontinuation of atazanavir and avoidance of its initial prescription. We used genomewide genotyping and clinical data to characterize determinants of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202. METHODS: Plasma atazanavir pharmacokinetics and indirect bilirubin concentrations were characterized in HIV-1-infected patients randomized to atazanavir/ritonavir-containing regimens. A subset had genomewide genotype data available. RESULTS: Genomewide assay data were available from 542 participants, of whom 475 also had data on estimated atazanavir clearance and relevant covariates available. Peak bilirubin concentration and relevant covariates were available for 443 participants. By multivariate analysis, higher peak on-treatment bilirubin levels were found to be associated with the UGT1A1 rs887829 T allele (P=6.4×10), higher baseline hemoglobin levels (P=4.9×10), higher baseline bilirubin levels (P=6.7×10), and slower plasma atazanavir clearance (P=8.6×10). For peak bilirubin levels greater than 3.0 mg/dl, the positive predictive value of a baseline bilirubin level of 0.5 mg/dl or higher with hemoglobin concentrations of 14 g/dl or higher was 0.51, which increased to 0.85 with rs887829 TT homozygosity. For peak bilirubin levels of 3.0 mg/dl or lower, the positive predictive value of a baseline bilirubin level less than 0.5 mg/dl with a hemoglobin concentration less than 14 g/dl was 0.91, which increased to 0.96 with rs887829 CC homozygosity. No polymorphism predicted atazanavir pharmacokinetics at genomewide significance. CONCLUSION: Atazanavir-associated hyperbilirubinemia is best predicted by considering UGT1A1 genotype, baseline bilirubin level, and baseline hemoglobin level in combination. Use of ritonavir as a pharmacokinetic enhancer may have abrogated genetic associations with atazanavir pharmacokinetics.

Retention half times in the skeleton of plutonium and Sr-90 from above-ground nuclear tests: A retrospective study of the Swiss population

Plutonium and Sr-90 are considered to be among the most radiotoxic nuclides produced by the nuclear fission process. In spite of numerous studies on mammals and humans there is still no general agreement on the retention half time of both radionuclides in the skeleton in the general population. Here we determined plutonium and Sr-90 in human vertebrae in individuals deceased between 1960 and 2004 in Switzerland. Plutonium was measured by sensitive SF-ICP-MS techniques and Sr-90 by radiometric methods. We compared our results to the ones obtained for other environmental compartments to reveal the retention half time of NBT fallout Pu-239 and Sr-90 in trabecular bones of the Swiss population. Results show that plutonium has a retention half time of 40 +/- 14 years. In contrast Sr-90 has a shorter retention half time of 13.5 +/- 1.0 years. Moreover Sr-90 retention half time in vertebrae is shown to be linked to the retention half time in food and other environmental compartments. These findings demonstrate that the renewal of the vertebrae through calcium homeostatic control is faster for Sr-90 excretion than for plutonium excretion. The precise determination of the retention half time of plutonium in the skeleton will improve the biokinetic model of plutonium metabolism in humans. (C) 2010 Elsevier Ltd. All rights reserved.

Affective state and voice : cross-cultural assessment of speaking behavior and voice sound characteristics : a normative multicenter study of 577 + 36 healthy subjects

BACKGROUND: Human speech is greatly influenced by the speakers' affective state, such as sadness, happiness, grief, guilt, fear, anger, aggression, faintheartedness, shame, sexual arousal, love, amongst others. Attentive listeners discover a lot about the affective state of their dialog partners with no great effort, and without having to talk about it explicitly during a conversation or on the phone. On the other hand, speech dysfunctions, such as slow, delayed or monotonous speech, are prominent features of affective disorders. METHODS: This project was comprised of four studies with healthy volunteers from Bristol (English: n = 117), Lausanne (French: n = 128), Zurich (German: n = 208), and Valencia (Spanish: n = 124). All samples were stratified according to gender, age, and education. The specific study design with different types of spoken text along with repeated assessments at 14-day intervals allowed us to estimate the 'natural' variation of speech parameters over time, and to analyze the sensitivity of speech parameters with respect to form and content of spoken text. Additionally, our project included a longitudinal self-assessment study with university students from Zurich (n = 18) and unemployed adults from Valencia (n = 18) in order to test the feasibility of the speech analysis method in home environments. RESULTS: The normative data showed that speaking behavior and voice sound characteristics can be quantified in a reproducible and language-independent way. The high resolution of the method was verified by a computerized assignment of speech parameter patterns to languages at a success rate of 90%, while the correct assignment to texts was 70%. In the longitudinal self-assessment study we calculated individual 'baselines' for each test person along with deviations thereof. The significance of such deviations was assessed through the normative reference data. CONCLUSIONS: Our data provided gender-, age-, and language-specific thresholds that allow one to reliably distinguish between 'natural fluctuations' and 'significant changes'. The longitudinal self-assessment study with repeated assessments at 1-day intervals over 14 days demonstrated the feasibility and efficiency of the speech analysis method in home environments, thus clearing the way to a broader range of applications in psychiatry. © 2014 S. Karger AG, Basel.

Treatment patterns and health care resource utilization in a 1-year observational cohort study of outpatients with schizophrenia at risk of nonadherence treated with long-acting injectable antipsychotics

Purpose: To describe (1) the clinical profiles and the patterns of use of long-acting injectable (LAI) antipsychotics in patients with schizophrenia at risk of nonadherence with oral antipsychotics, and in those who started treatment with LAI antipsychotics, (2) health care resource utilization and associated costs. Patients and methods: A total of 597 outpatients with schizophrenia at risk of nonadherence, according to the psychiatrist's clinical judgment, were recruited at 59 centers in a noninterventional prospective observational study of 1-year follow-up when their treatment was modified. In a post hoc analysis, the profiles of patients starting LAI or continuing with oral antipsychotics were described, and descriptive analyses of treatments, health resource utilization, and direct costs were performed in those who started an LAI antipsychotic. Results: Therapy modifications involved the antipsychotic medications in 84.8% of patients, mostly because of insufficient efficacy of prior regimen. Ninety-two (15.4%) patients started an LAI antipsychotic at recruitment. Of these, only 13 (14.1%) were prescribed with first-generation antipsychotics. During 1 year, 16.3% of patients who started and 14.9% of patients who did not start an LAI antipsychotic at recruitment relapsed, contrasting with the 20.9% who had been hospitalized only within the prior 6 months. After 1 year, 74.3% of patients who started an LAI antipsychotic continued concomitant treatment with oral antipsychotics. The mean (median) total direct health care cost per patient per month during the study year among the patients starting any LAI antipsychotic at baseline was 1,407 ( 897.7). Medication costs (including oral and LAI antipsychotics and concomitant medication) represented almost 44%, whereas nonmedication costs accounted for more than 55% of the mean total direct health care costs. Conclusion: LAI antipsychotics were infrequently prescribed in spite of a psychiatrist-perceived risk of nonadherence to oral antipsychotics. Mean medication costs were lower than nonmedication costs.

A genome-wide association study of neuroticism in a population-based sample.

Neuroticism is a moderately heritable personality trait considered to be a risk factor for developing major depression, anxiety disorders and dementia. We performed a genome-wide association study in 2,235 participants drawn from a population-based study of neuroticism, making this the largest association study for neuroticism to date. Neuroticism was measured by the Eysenck Personality Questionnaire. After Quality Control, we analysed 430,000 autosomal SNPs together with an additional 1.2 million SNPs imputed with high quality from the Hap Map CEU samples. We found a very small effect of population stratification, corrected using one principal component, and some cryptic kinship that required no correction. NKAIN2 showed suggestive evidence of association with neuroticism as a main effect (p < 10(-6)) and GPC6 showed suggestive evidence for interaction with age (p approximately = 10(-7)). We found support for one previously-reported association (PDE4D), but failed to replicate other recent reports. These results suggest common SNP variation does not strongly influence neuroticism. Our study was powered to detect almost all SNPs explaining at least 2% of heritability, and so our results effectively exclude the existence of loci having a major effect on neuroticism.

Ab initio theoretical comparative study of magnetic coupling in KNiF3 and K2NiF4s

The origin of magnetic coupling in KNiF3 and K2 NiF4 is studied by means of an ab initio cluster model approach. By a detailed study of the mapping between eigenstates of the exact nonrelativistic and spin model Hamiltonians it is possible to obtain the magnetic coupling constant J and to compare ab initio cluster-model values with those resulting from ab initio periodic Hartree-Fock calculations. This comparison shows that J is strongly determined by two-body interactions; this is a surprising and unexpected result. The importance of the ligands surrounding the basic metal-ligand-metal interacting unit is reexamined by using two different partitions and the constrained space orbital variation method of analysis. This decomposition enables us to show that this effect is basically environmental. Finally, dynamical electronic correlation effects have found to be critical in determining the final value of the magnetic coupling constant.

Ab Initio study of magnetic interactions in the KCuF3 and K2CuF4 low-dimensional Systems

The ab initio cluster model approach has been used to study the electronic structure and magnetic coupling of KCuF3 and K2CuF4 in their various ordered polytype crystal forms. Due to a cooperative Jahn-Teller distortion these systems exhibit strong anisotropies. In particular, the magnetic properties strongly differ from those of isomorphic compounds. Hence, KCuF3 is a quasi-one-dimensional (1D) nearest neighbor Heisenberg antiferromagnet whereas K2CuF4 is the only ferromagnet among the K2MF4 series of compounds (M=Mn, Fe, Co, Ni, and Cu) behaving all as quasi-2D nearest neighbor Heisenberg systems. Different ab initio techniques are used to explore the magnetic coupling in these systems. All methods, including unrestricted Hartree-Fock, are able to explain the magnetic ordering. However, quantitative agreement with experiment is reached only when using a state-of-the-art configuration interaction approach. Finally, an analysis of the dependence of the magnetic coupling constant with respect to distortion parameters is presented.