Estimating time-to-onset of adverse drug reactions from spontaneous reporting databases.

International audienceBACKGROUND: Analyzing time-to-onset of adverse drug reactions from treatment exposure contributes to meeting pharmacovigilance objectives, i.e. identification and prevention. Post-marketing data are available from reporting systems. Times-to-onset from such databases are right-truncated because some patients who were exposed to the drug and who will eventually develop the adverse drug reaction may do it after the time of analysis and thus are not included in the data. Acknowledgment of the developments adapted to right-truncated data is not widespread and these methods have never been used in pharmacovigilance. We assess the use of appropriate methods as well as the consequences of not taking right truncation into account (naïve approach) on parametric maximum likelihood estimation of time-to-onset distribution. METHODS: Both approaches, naïve or taking right truncation into account, were compared with a simulation study. We used twelve scenarios for the exponential distribution and twenty-four for the Weibull and log-logistic distributions. These scenarios are defined by a set of parameters: the parameters of the time-to-onset distribution, the probability of this distribution falling within an observable values interval and the sample size. An application to reported lymphoma after anti TNF-¿ treatment from the French pharmacovigilance is presented. RESULTS: The simulation study shows that the bias and the mean squared error might in some instances be unacceptably large when right truncation is not considered while the truncation-based estimator shows always better and often satisfactory performances and the gap may be large. For the real dataset, the estimated expected time-to-onset leads to a minimum difference of 58 weeks between both approaches, which is not negligible. This difference is obtained for the Weibull model, under which the estimated probability of this distribution falling within an observable values interval is not far from 1. CONCLUSIONS: It is necessary to take right truncation into account for estimating time-to-onset of adverse drug reactions from spontaneous reporting databases

On the construction of model Hamiltonians for adiabatic quantum computation and its application to finding low energy conformations of lattice protein models

In this report, we explore the use of a quantum optimization algorithm for obtaining low energy conformations of protein models. We discuss mappings between protein models and optimization variables, which are in turn mapped to a system of coupled quantum bits. General strategies are given for constructing Hamiltonians to be used to solve optimization problems of physical/chemical/biological interest via quantum computation by adiabatic evolution. As an example, we implement the Hamiltonian corresponding to the Hydrophobic-Polar (HP) model for protein folding. Furthermore, we present an approach to reduce the resulting Hamiltonian to two-body terms gearing towards an experimental realization.Comment: 35 pages, 8 figure

Classical Ising model test for quantum circuits

We exploit a recently constructed mapping between quantum circuits and graphs in order to prove that circuits corresponding to certain planar graphs can be efficiently simulated classically. The proof uses an expression for the Ising model partition function in terms of quadratically signed weight enumerators (QWGTs), which are polynomials that arise naturally in an expansion of quantum circuits in terms of rotations involving Pauli matrices. We combine this expression with a known efficient classical algorithm for the Ising partition function of any planar graph in the absence of an external magnetic field, and the Robertson-Seymour theorem from graph theory. We give as an example a set of quantum circuits with a small number of non-nearest neighbor gates which admit an efficient classical simulation.Comment: 17 pages, 2 figures. v2: main result strengthened by removing oracular settin

Fluoride supplements (tablets, drops, lozenges or chewing gums) for preventing dental caries in children.

BACKGROUND: Dietary fluoride supplements were first introduced to provide systemic fluoride in areas where water fluoridation is not available. Since 1990, the use of fluoride supplements in caries prevention has been re-evaluated in several countries. OBJECTIVES: To evaluate the efficacy of fluoride supplements for preventing dental caries in children. SEARCH METHODS: We searched the Cochrane Oral Health Group's Trials Register (to 12 October 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE via OVID (1950 to 12 October 2011), EMBASE via OVID (1980 to 12 October 2011), WHOLIS/PAHO/MEDCARIB/LILACS/BBO via BIREME (1982 to 12 October 2011), and Current Controlled Trials (to 12 October 2011). We handsearched reference lists of articles and contacted selected authors. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials comparing, with minimum follow-up of 2 years, fluoride supplements (tablets, drops, lozenges) with no fluoride supplement or with other preventive measures such as topical fluorides in children less than 16 years of age at the start. The main outcome was caries increment measured by the change in decayed, missing and filled tooth surfaces (DMFS). DATA COLLECTION AND ANALYSIS: Two review authors, independently and in duplicate, assessed the eligibility of studies for inclusion, and carried out risk of bias assessment and data extraction. In the event of disagreement, we sought consensus and consulted a third review author. We contacted trial authors for missing information. We used the prevented fraction (PF) as a metric for evaluating the efficacy of the intervention. The PF is defined as the mean caries increment in controls minus mean caries increment in the treated group divided by mean caries increment in controls. We conducted random-effects meta-analyses when data could be pooled. We assessed heterogeneity in the results of the studies by examining forest plots and by using formal tests for homogeneity. We recorded adverse effects (fluorosis) when the studies provided relevant data. MAIN RESULTS: We included 11 studies in the review involving 7196 children.In permanent teeth, when fluoride supplements were compared with no fluoride supplement (three studies), the use of fluoride supplements was associated with a 24% (95% confidence interval (CI) 16 to 33%) reduction in decayed, missing and filled surfaces (D(M)FS). The effect of fluoride supplements was unclear on deciduous or primary teeth. In one study, no caries-inhibiting effect was observed on deciduous teeth while in another study, the use of fluoride supplements was associated with a substantial reduction in caries increment.When fluoride supplements were compared with topical fluorides or with other preventive measures, there was no differential effect on permanent or deciduous teeth.The review found limited information on the adverse effects associated with the use of fluoride supplements. AUTHORS' CONCLUSIONS: This review suggests that the use of fluoride supplements is associated with a reduction in caries increment when compared with no fluoride supplement in permanent teeth. The effect of fluoride supplements was unclear on deciduous teeth. When compared with the administration of topical fluorides, no differential effect was observed. We rated 10 trials as being at unclear risk of bias and one at high risk of bias, and therefore the trials provide weak evidence about the efficacy of fluoride supplements

Net Efficacy Adjusted for Risk (NEAR): A Simple Procedure for Measuring Risk:Benefit Balance

BACKGROUND: Although several mathematical models have been proposed to assess the risk:benefit of drugs in one measure, their use in practice has been rather limited. Our objective was to design a simple, easily applicable model. In this respect, measuring the proportion of patients who respond favorably to treatment without being affected by adverse drug reactions (ADR) could be a suitable endpoint. However, remarkably few published clinical trials report the data required to calculate this proportion. As an approach to the problem, we calculated the expected proportion of this type of patients. METHODOLOGY/PRINCIPAL FINDINGS: Theoretically, responders without ADR may be obtained by multiplying the total number of responders by the total number of subjects that did not suffer ADR, and dividing the product by the total number of subjects studied. When two drugs are studied, the same calculation may be repeated for the second drug. Then, by constructing a 2 x 2 table with the expected frequencies of responders with and without ADR, and non-responders with and without ADR, the odds ratio and relative risk with their confidence intervals may be easily calculated and graphically represented on a logarithmic scale. Such measures represent "net efficacy adjusted for risk" (NEAR). We assayed the model with results extracted from several published clinical trials or meta-analyses. On comparing our results with those originally reported by the authors, marked differences were found in some cases, with ADR arising as a relevant factor to balance the clinical benefit obtained. The particular features of the adverse reaction that must be weighed against benefit is discussed in the paper. CONCLUSION: NEAR representing overall risk-benefit may contribute to improving knowledge of drug clinical usefulness. As most published clinical trials tend to overestimate benefits and underestimate toxicity, our measure represents an effort to change this trend

Prevalence, intensity and extent of Oral Impacts on Daily Performances associated with self-perceived malocclusion in 11-12-year-old children

BACKGROUND: To determine the prevalence, intensity and extent of the Oral Impacts on Daily Performances associated with self-perceived malocclusion among Peruvian schoolchildren. METHODS: Eight hundred and five children aged 11 to 12 years attending 4 of 7 randomly selected schools linked to a Health Centre in Lima, Peru, participated in the study. The Spanish (Peru)Child-OIDP was used to assess the prevalence, intensity and extent of oral impacts on 8 daily performances (eating, speaking, teeth cleaning, sleeping, smiling, studying, emotion and social contact). Self-perceived malocclusion included complaints about position of teeth, spacing of teeth and deformity of mouth or face. The prevalence of oral impacts was compared by covariables using the Chi-square test, whereas the intensity and extent of oral impacts were compared by covariables through the Mann-Whitney test. RESULTS: Only 15.5% of children reported impacts associated with self-perceived malocclusion during the last 3 months. Of them, 18.4% reported impacts of severe or very severe intensity and 76.0% reported impacts on only one daily performance. Psychosocial activities such as smiling, emotion and social contact were the most frequently and severely impacted everyday activities. CONCLUSION: Impacts of self-perceived malocclusion primarily affected psychological and social everyday activities. These findings provide further evidence to support the importance of psychological and social components of oral health on children's lives

Socio-demographic and behavioural correlates of oral hygiene status and oral health related quality of life, the Limpopo - Arusha school health project (LASH): A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Promoting oral health of adolescents is important for improvement of oral health globally. This study used baseline-data from LASH-project targeting secondary students to; 1) assess frequency of poor oral hygiene status and oral impacts on daily performances, OIDP, by socio-demographic and behavioural characteristics, 2) examine whether socio-economic and behavioural correlates of oral hygiene status and OIDP differed by gender and 3) examine whether socio-demographic disparity in oral health was explained by oral health-related behaviours.</p> <p>Methods</p> <p>Cross-sectional study was conducted in 2009 using one-stage cluster sampling design. Total of 2412 students (mean age 15.2 yr) completed self-administered questionnaires, whereas 1077 (mean age 14.9 yr) underwent dental-examination. Bivariate analyses were conducted using cross-tabulations and chi-square statistics. Multiple variable analyses were conducted using stepwise standardized logistic regression (SLR) with odds ratios and 95% Confidence intervals (CI).</p> <p>Results</p> <p>44.8% presented with fair to poor OHIS and 48.2% reported any OIDP. Older students, those from low socio-economic status families, had parents who couldn't afford dental care and had low educational-level reported oral impacts, poor oral hygiene, irregular toothbrushing, less dental attendance and fewer intakes of sugar-sweetened drinks more frequently than their counterparts. Stepwise logistic regression revealed that reporting any OIDP was independently associated with; older age-groups, parents do not afford dental care, smoking experience, no dental visits and fewer intakes of sugar-sweetened soft drinks. Behavioural factors accounted partly for association between low family SES and OIDP. Low family SES, no dental attendance and smoking experience were most important in males. Low family SES and fewer intakes of sugar-sweetened soft drinks were the most important correlates in females.</p> <p>Socio-behavioural factors associated with higher odds ratios for poor OHIS were; older age, belonging to the poorest household category and having parents who did not afford dental care across both genders.</p> <p>Conclusion</p> <p>Disparities in oral hygiene status and OIDP existed in relation to age, affording dental care, smoking and intake of sugar sweetened soft drinks. Gender differences should be considered in intervention studies, and modifiable behaviours have some relevance in reducing social disparity in oral health.</p

A human ribonuclease induces apoptosis associated with p21WAF1/CIP1 induction and JNK inactivation

<p>Abstract</p> <p>Background</p> <p>Ribonucleases are promising agents for use in anticancer therapy. Among the different ribonucleases described to be cytotoxic, a paradigmatic example is onconase which manifests cytotoxic and cytostatic effects, presents synergism with several kinds of anticancer drugs and is currently in phase II/III of its clinical trial as an anticancer drug against different types of cancer. The mechanism of cytotoxicity of PE5, a variant of human pancreatic ribonuclease carrying a nuclear localization signal, has been investigated and compared to that of onconase.</p> <p>Methods</p> <p>Cytotoxicity was measured by the MTT method and by the tripan blue exclusion assay. Apoptosis was assessed by flow cytometry, caspase enzymatic detection and confocal microscopy. Cell cycle phase analysis was performed by flow cytometry. The expression of different proteins was analyzed by western blot.</p> <p>Results</p> <p>We show that the cytotoxicity of PE5 is produced through apoptosis, that it does not require the proapoptotic activity of p53 and is not prevented by the multiple drug resistance phenotype. We also show that PE5 and onconase induce cell death at the same extent although the latter is also able to arrest the cell growth. We have compared the cytotoxic effects of both ribonucleases in the NCI/ADR-RES cell line by measuring their effects on the cell cycle, on the activation of different caspases and on the expression of different apoptosis- and cell cycle-related proteins. PE5 increases the number of cells in S and G₂/M cell cycle phases, which is accompanied by the increased expression of cyclin E and p21^WAF1/CIP1together with the underphosphorylation of p46 forms of JNK. Citotoxicity of onconase in this cell line does not alter the cell cycle phase distribution and it is accompanied by a decreased expression of XIAP</p> <p>Conclusions</p> <p>We conclude that PE5 kills the cells through apoptosis associated with the p21^WAF1/CIP1induction and the inactivation of JNK. This mechanism is significantly different from that found for onconase.</p

The Foundations of Agency - and Ethics?

In this article, I take off from some central issues in Paul Katsafanas' recent book Agency and the Foundations of Ethics. I argue that Katsafanas' alleged aims of action fail to do the work he requires them to do. First, his approach to activity or control is deeply problematic in the light of counterexamples, but as the related issues are substantially under-theorized, we do not at present know what agential activity or control may imply. More importantly, the view of activity or control he needs to get his argument going is most likely false, as it requires our values to do work that they are too fickle to do. Second, I take issue with the Nietzschean drive psychology underlying the second agential aim, viz. power. I argue that ordinary desires better describe a number of phenomena that Katsafanas uses drives to explain, and that some actions can aim in the opposite direction. As only drive-motivated actions aim at power, action does not, therefore, constitutively aim at power. Finally, I sketch a Humean approach to constitutivism, and argue that it both explains the desiderata that Katsafanas posits as well as solves the problems for his view. Constitutivists should prefer it to his view and develop it further