An integrated analysis of five double-blind, randomized controlled trials evaluating the safety and efficacy of a hyaluronan product for intra-articular injection in osteoarthritis of the kneel

Objective: Five double-blind, randomized, saline-controlled trials (RCTs) were included in the United States marketing application for an intra-articular hyaluronan (IA-HA) product for the treatment of osteoarthritis (OA) of the knee. We report an integrated analysis of the primary Case Report Form (CRF) data from these trials. Method. Trials were similar in design, patient population and outcome measures - all included the Lequesne Algofunctional Index (LI), a validated composite index of pain and function, evaluating treatment over 3 months. Individual patient data were pooled; a repeated measures analysis of covariance was performed in the intent-to-treat (ITT) population. Analyses utilized both fixed and random effects models. Safety data from the five RCTs were summarized. Results: A total of 1155 patients with radiologically confirmed knee OA were enrolled: 619 received three or five IA-HA injections; 536 received. placebo saline injections. In the active and control groups, mean ages were 61.8 and 61.4 years; 62.4% and 58.8% were women; baseline total Lequesne scores 11.03 and 11.30, respectively. Integrated analysis of the pooled data set found a statistically significant reduction (P < 0.001) in total Lequesne score with hyaluronan (HA) (-2.68) vs placebo (-2.00); estimated difference -0.68 (95% CI: -0.56 to -0.79), effect size 0.20. Additional modeling approaches confirmed robustness of the analyses. Conclusions: This integrated analysis demonstrates that multiple design factors influence the results of RCTs assessing efficacy of intra-articular (IA) therapies, and that integrated analyses based on primary data differ from meta-analyses using transformed data. (C) 2006 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Physical activity and strength of the femoral neck during the adolescent growth spurt: A longitudinal analysis

Loading of the femoral neck (FN) is dominated by bending and compressive stresses. We hypothesize that adaptation of the FN to physical activity would be manifested in the cross-sectional area (CSA) and section modulus (Z) of bone, indices of axial and bending strength, respectively. We investigated the influence of physical activity on bone strength during adolescence using 7 years of longitudinal data from 109 boys and 121 girls from the Saskatchewan Paediatric Bone and Mineral Accrual Study (PBMAS). Physical activity data (PAC-Q physical activity inventory) and anthropometric measurements were taken every 6 months and DXA bone scans were measured annually (Hologic QDR2000, array mode). We applied hip structural analysis to derive strength and geometric indices of the femoral neck using DXA scans. To control for maturation, we determined a biological maturity age defined as years from age at peak height velocity (APHV). To account for the repeated measures within individual nature of longitudinal data, multilevel random effects regression analyses were used to analyze the data. When biological maturity age and body size (height and weight) were controlled, in both boys and girls, physical activity was a significant positive independent predictor of CSA and Z of the narrow region of the femoral neck (P < 0.05). There was no independent effect of physical activity on the subperiosteal width of the femoral neck. When leg length and leg lean mass were introduced into the random effects models to control for size and muscle mass of the leg (instead of height and weight), all significant effects of physical activity disappeared. Even among adolescents engaged in normal levels of physical activity, the statistically significant relationship between physical activity and indices of bone strength demonstrate that modifiable lifestyle factors like exercise play an important role in optimizing bone strength during the growing years. Physical activity differences were explained by the interdependence between activity and lean mass considerations. Physical activity is important for optimal development of bone strength. (c) 2005 Elsevier Inc. All rights reserved.

Relationships of activity and sugar drink intake on fat mass development in youths

Purpose: To determine whether a significant relationship exists between fat mass (FM) development and physical activity (PA) and/or sugar-sweetened drink (SD) consumption in healthy boys and girls aged 8-19 yr. Methods: A total of 105 males and 103 females were assessed during childhood and adolescence for a maximum of 7 yr and a median of 5 yr. Height was measured biannually. Fat-free mass (FFM) and FM were assessed annually by dual x-ray absorptiometry (DXA). PA was evaluated two to three times annually using the PAQ-C/A. Energy intake and SD were assessed using a 24-h dietary intake questionnaire also completed two to three times per year. Years from peak height velocity were used as a biological maturity age indicator. Multilevel random effects models were used to test the relationship. Results: When controlling for maturation, FFM, and energy intake adjusted for SD, PA level was negatively related to FM development in males (P < 0.05) but not in females (P > 0.05). In contrast, there was no relationship between SD and FM development of males or females (P > 0.05). There was also no interaction effect between SD and PA (P > 0.05) with FM development. Conclusion: This finding tends support to the idea that increasing PA in male youths aids in the control of FM development. Models employed showed no relationship between SD and FM in either gender.

Paediatric population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in cystic fibrosis and bone marrow transplant patients

Objectives: The aim of the study was to characterise the population pharmacokinetics (popPK) properties of itraconazole (ITRA) and its active metabolite hydroxy-ITRA in a representative paediatric population of cystic fibrosis (CF) and bone marrow transplant (BMT) patients. The goals were to determine the relative bioavailability between the two oral formulations, and to explore improved dosage regimens in these patients. Methods: All paediatric patients with CF taking oral ITRA for the treatment of allergic bronchopulmonary aspergillosis and patients undergoing BMT who were taking ITRA for prophylaxis of any fungal infection were eligible for the study. A minimum of two blood samples were drawn after the capsules and also after switching to oral solution, or vice versa. ITRA and hydroxy-ITRA plasma concentrations were measured by HPLC[1]. A nonlinear mixed-effect modelling approach (NONMEM 5.1.1) was used to describe the PK of ITRA and hydroxy-ITRA simultaneously. Simulations were used to assess dosing strategies in these patients. Results: Forty-nine patients (29CF, 20 BMT) were recruited to the study who provided 227 blood samples for the population analysis. A 1-compartment model with 1st order absorption and elimination best described ITRA kinetics, with 1st order conversion to hydroxy-ITRA. For ITRA, the apparent clearance (ClItra/F) and volume of distribution (Vitra/F) was 35.5L/h and 672L, respectively; the absorption rate constant for the capsule formulation was 0.0901 h-1 and for the oral solution formulation it was 0.959 h-1. The capsule comparative bioavailability (vs. solution) was 0.55. For hydroxy-ITRA, the apparent volume of distribution and clearance were 10.6 L and 5.28 L/h, respectively. Of several screened covariates only allometrically scaled total body weight significantly improved the fit to the data. No difference between the two populations was found. Conclusion: The developed popPK model adequately described the pharmacokinetics of ITRA and hydroxy-ITRA in paediatric patients with CF and patients undergoing BMT. High inter-patient variability confirmed previous data in CF[2], leukaemia and BMT[3] patients. From the population model, simulations showed the standard dose (5 mg/kg/day) needs to be doubled for the solution formulation and even 4 times more given of the capsules to achieve an adequate target therapeutic trough plasma concentration of 0.5 mg/L[4] in these patients.

Finite mixture regression model with random effects: application to neonatal hospital length of stay

A two-component mixture regression model that allows simultaneously for heterogeneity and dependency among observations is proposed. By specifying random effects explicitly in the linear predictor of the mixture probability and the mixture components, parameter estimation is achieved by maximising the corresponding best linear unbiased prediction type log-likelihood. Approximate residual maximum likelihood estimates are obtained via an EM algorithm in the manner of generalised linear mixed model (GLMM). The method can be extended to a g-component mixture regression model with the component density from the exponential family, leading to the development of the class of finite mixture GLMM. For illustration, the method is applied to analyse neonatal length of stay (LOS). It is shown that identification of pertinent factors that influence hospital LOS can provide important information for health care planning and resource allocation. (C) 2002 Elsevier Science B.V. All rights reserved.

Experimental tests of quantum nonlinear dynamics in atom optics

Cold atoms in optical potentials provide an ideal test bed to explore quantum nonlinear dynamics. Atoms are prepared in a magneto-optic trap or as a dilute Bose-Einstein condensate and subjected to a far detuned optical standing wave that is modulated. They exhibit a wide range of dynamics, some of which can be explained by classical theory while other aspects show the underlying quantum nature of the system. The atoms have a mixed phase space containing regions of regular motion which appear as distinct peaks in the atomic momentum distribution embedded in a sea of chaos. The action of the atoms is of the order of Planck's constant, making quantum effects significant. This tutorial presents a detailed description of experiments measuring the evolution of atoms in time-dependent optical potentials. Experimental methods are developed providing means for the observation and selective loading of regions of regular motion. The dependence of the atomic dynamics on the system parameters is explored and distinct changes in the atomic momentum distribution are observed which are explained by the applicable quantum and classical theory. The observation of a bifurcation sequence is reported and explained using classical perturbation theory. Experimental methods for the accurate control of the momentum of an ensemble of atoms are developed. They use phase space resonances and chaotic transients providing novel ensemble atomic beamsplitters. The divergence between quantum and classical nonlinear dynamics is manifest in the experimental observation of dynamical tunnelling. It involves no potential barrier. However a constant of motion other than energy still forbids classically this quantum allowed motion. Atoms coherently tunnel back and forth between their initial state of oscillatory motion and the state 180 out of phase with the initial state.

Hurt feelings in couple relationships: Towards integrative models of the negative effects of hurtful events

Previous research suggests that hurt feelings can have powerful effects on individual and relational outcomes. This study examined a typology of hurtful events in couple relationships, together with integrative models predicting ongoing effects on victims and relationships. Participants were 224 students from introductory and third-year psychology classes, who completed open-ended and structured measures concerning an event in which a partner had hurt their feelings. By tailoring Leary et al.'s (1998) typology to the context of romantic relationships, five categories of hurtful events were proposed: active disassociation, passive disassociation, criticism, infidelity, and deception. Analyses assessing similarities and differences among the categories confirmed the utility of the typology. Structural equation modeling showed that longer-term effects on the victim were predicted by relationship anxiety and by the victim's immediate reactions to the event (negative emotions and self-perceptions; feelings of rejection and powerlessness). In contrast, ongoing effects on the relationship were predicted by avoidance, the victim's attributions and perceptions of offender remorse, and the victim's own behavior. The results highlight the utility of an integrated approach to hurt, incorporating emotional, cognitive, and behavioral responses, and dimensions of attachment security.

Drying front in a sloping aquifer: Nonlinear effects

[1] The profiles for the water table height h(x, t) in a shallow sloping aquifer are reexamined with a solution of the nonlinear Boussinesq equation. We demonstrate that the previous anomaly first reported by Brutsaert [1994] that the point at which the water table h first becomes zero at x = L at time t = t(c) remains fixed at this point for all times t > t(c) is actually a result of the linearization of the Boussinesq equation and not, as previously suggested [Brutsaert, 1994; Verhoest and Troch, 2000], a result of the Dupuit assumption. Rather, by examination of the nonlinear Boussinesq equation the drying front, i.e., the point x(f) at which h is zero for times t greater than or equal to t(c), actually recedes downslope as physically expected. This points out that the linear Boussinesq equation should be used carefully when a zero depth is obtained as the concept of an average'' depth loses meaning at that time.

Effects of potential models on the adsorption of ethane and ethylene on graphitized thermal carbon black. Study of two-dimensional critical temperature and isosteric heat versus loading

Adsorption of ethylene and ethane on graphitized thermal carbon black and in slit pores whose walls are composed of graphene layers is studied in detail to investigate the packing efficiency, the two-dimensional critical temperature, and the variation of the isosteric heat of adsorption with loading and temperature. Here we used a Monte Carlo simulation method with a grand canonical Monte Carlo ensemble. A number of two-center Lennard-Jones (LJ) potential models are investigated to study the impact of the choice of potential models in the description of adsorption behavior. We chose two 2C-LJ potential models in our investigation of the (i) UA-TraPPE-LJ model of Martin and Siepmann (J. Phys. Chem. B 1998,102, 25692577) for ethane and Wick et al. (J. Phys. Chem. B 2000,104, 8008-8016) for ethylene and (ii) AUA4-LJ model of Ungerer et al. (J. Chem. Phys. 2000,112, 5499-5510) for ethane and Bourasseau et al. (J. Chem. Phys. 2003, 118, 3020-3034) for ethylene. These models are used to study the adsorption of ethane and ethylene on graphitized thermal carbon black. It is found that the solid-fluid binary interaction parameter is a function of adsorbate and temperature, and the adsorption isotherms and heat of adsorption are well described by both the UA-TraPPE and AUA models, although the UA-TraPPE model performs slightly better. However, the local distributions predicted by these two models are slightly different. These two models are used to explore the two-dimensional condensation for the graphitized thermal carbon black, and these values are 110 K for ethylene and 120 K for ethane.

Effects of potential models in the vapor-liquid equilibria and adsorption of simple gases on graphitized thermal carbon black

In this paper, we investigate the effects of various potential models in the description of vapor–liquid equilibria (VLE) and adsorption of simple gases on highly graphitized thermal carbon black. It is found that some potential models proposed in the literature are not suitable for the description of VLE (saturated gas and liquid densities and the vapor pressure with temperature). Simple gases, such as neon, argon, krypton, xenon, nitrogen, and methane are studied in this paper. To describe the isotherms on graphitized thermal carbon black correctly, the surface mediation damping factor introduced in our recent publication should be used to calculate correctly the fluid–fluid interaction energy between particles close to the surface. It is found that the damping constant for the noble gases family is linearly dependent on the polarizability, suggesting that the electric field of the graphite surface has a direct induction effect on the induced dipole of these molecules. As a result of this polarization by the graphite surface, the fluid–fluid interaction energy is reduced whenever two particles are near the surface. In the case of methane, we found that the damping constant is less than that of a noble gas having the similar polarizability, while in the case of nitrogen the damping factor is much greater and this could most likely be due to the quadrupolar nature of nitrogen.

Using epidemiological models to estimate the health effects of diet behaviour change: the example of tailored fruit and vegetable promotion

Objective: To explore the use of epidemiological modelling for the estimation of health effects of behaviour change interventions, using the example of computer-tailored nutrition education aimed at fruit and vegetable consumption in The Netherlands. Design: The effects of the intervention on changes in consumption were obtained from an earlier evaluation study. The effect on health outcomes was estimated using an epidemiological multi-state life table model. input data for the model consisted of relative risk estimates for cardiovascular disease and cancers, data on disease occurrence and mortality, and survey data on the consumption of fruits and vegetables. Results: if the computer-tailored nutrition education reached the entire adult population and the effects were sustained, it could result in a mortality decrease of 0.4 to 0.7% and save 72 to 115 life-years per 100000 persons aged 25 years or older. Healthy life expectancy is estimated to increase by 32.7 days for men and 25.3 days for women. The true effect is likely to lie between this theoretical maximum and zero effect, depending mostly on durability of behaviour change and reach of the intervention. Conclusion: Epidemiological models can be used to estimate the health impact of health promotion interventions.