Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: a randomized phase II study.

Vaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha-2a (Peg-IFN-α-2a) plus ribavirin (RBV). In this double-blind, placebo-controlled, dose-ranging study, treatment-naïve patients with HCV genotype 1 infection (n = 94) were randomized to receive open-label Peg-IFN-α-2a (180 μg/week) and RBV (1,000-1,200 mg/day) in combination with blinded placebo or vaniprevir (300 mg twice-daily [BID], 600 mg BID, 600 mg once-daily [QD], or 800 mg QD) for 28 days, then open-label Peg-IFN-α-2a and RBV for an additional 44 weeks. The primary efficacy endpoint was rapid viral response (RVR), defined as undetectable plasma HCV RNA at week 4. Across all doses, vaniprevir was associated with a rapid two-phase decline in viral load, with HCV RNA levels approximately 3 log(10) IU/mL lower in vaniprevir-treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%-83.3% versus 5.6%; P < 0.001 for all comparisons). There were numerically higher, but not statistically significant, early and sustained virologic response rates with vaniprevir, as compared to placebo. Resistance profile was predictable, with variants at R155 and D168 detected in a small number of patients. No relationship between interleukin-28B genotype and treatment outcomes was demonstrated in this study. The incidence of adverse events was generally comparable between vaniprevir and placebo recipients; however, vomiting appeared to be more common at higher vaniprevir doses. CONCLUSION: Vaniprevir is a potent HCV protease inhibitor with a predictable resistance profile and favorable safety profile that is suitable for QD or BID administration.

Utility of the mini-cog for detection of cognitive impairment in primary care: data from two spanish studies.

Objectives. To study the utility of the Mini-Cog test for detection of patients with cognitive impairment (CI) in primary care (PC). Methods. We pooled data from two phase III studies conducted in Spain. Patients with complaints or suspicion of CI were consecutively recruited by PC physicians. The cognitive diagnosis was performed by an expert neurologist, after formal neuropsychological evaluation. The Mini-Cog score was calculated post hoc, and its diagnostic utility was evaluated and compared with the utility of the Mini-Mental State (MMS), the Clock Drawing Test (CDT), and the sum of the MMS and the CDT (MMS + CDT) using the area under the receiver operating characteristic curve (AUC). The best cut points were obtained on the basis of diagnostic accuracy (DA) and kappa index. Results. A total sample of 307 subjects (176 CI) was analyzed. The Mini-Cog displayed an AUC (±SE) of 0.78 ± 0.02, which was significantly inferior to the AUC of the CDT (0.84 ± 0.02), the MMS (0.84 ± 0.02), and the MMS + CDT (0.86 ± 0.02). The best cut point of the Mini-Cog was 1/2 (sensitivity 0.60, specificity 0.90, DA 0.73, and kappa index 0.48 ± 0.05). Conclusions. The utility of the Mini-Cog for detection of CI in PC was very modest, clearly inferior to the MMS or the CDT. These results do not permit recommendation of the Mini-Cog in PC.

Using a single tablet daily to treat latent tuberculosis infection in Brazil: bioequivalence of two different isoniazid formulations (300 mg and 100 mg) demonstrated by a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry method in a randomised, crossover study

The recommended treatment for latent tuberculosis (TB) infection in adults is a daily dose of isoniazid (INH) 300 mg for six months. In Brazil, INH was formulated as 100 mg tablets. The treatment duration and the high pill burden compromised patient adherence to the treatment. The Brazilian National Programme for Tuberculosis requested a new 300 mg INH formulation. The aim of our study was to compare the bioavailability of the new INH 300 mg formulation and three 100 mg tablets of the reference formulation. We conducted a randomised, single dose, open label, two-phase crossover bioequivalence study in 28 healthy human volunteers. The 90% confidence interval for the INH maximum concentration of drug observed in plasma and area under the plasma concentration vs. time curve from time zero to the last measurable concentration “time t” was 89.61-115.92 and 94.82-119.44, respectively. The main limitation of our study was that neither adherence nor the safety profile of multiple doses was evaluated. To determine the level of INH in human plasma, we developed and validated a sensitive, simple and rapid high-performance liquid chromatography-tandem mass spectrometry method. Our results showed that the new formulation was bioequivalent to the 100 mg reference product. This finding supports the use of a single 300 mg tablet daily strategy to treat latent TB. This new formulation may increase patients’ adherence to the treatment and quality of life.

Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.

BACKGROUND: Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1β monoclonal antibody, in two trials. METHODS: In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA. RESULTS: At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo. CONCLUSIONS: These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).

Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.

BACKGROUND: Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1β monoclonal antibody, in two trials. METHODS: In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA. RESULTS: At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo. CONCLUSIONS: These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).

Thin Maintenance Surfaces - Phase I, TR-435, 1999

The first phase of a two-phase research project was conducted to develop guidelines for Iowa transportation officials on the use of thin maintenance surfaces (TMS) for asphaltic concrete and bituminous roads. Thin maintenance surfaces are seal coats (chip seals), slurry seals, and micro-surfacing. Interim guidelines were developed to provide guidance on which roads are good candidates for TMS, when TMS should be placed, and what type of thin maintenance surface should be selected. The guidelines were developed specifically for Iowa aggregates, weather, traffic conditions, road user expectations, and transportation official expectations. In addition to interim guidelines, this report presents recommendations for phase-two research. It is recommended that test section monitoring continue and that further investigations be conducted regarding thin maintenance surface aggregate, additional test sections, placed, and a design method adopted for seal coats.

ADVANCED NUMERICAL METHODS FOR SIMULATING MICROBUBBLE IN AN AERATED MIXING TANK

Fluid mixing in mechanically agitated tanks is one of the major unit operations in many industries. Bubbly flows have been of interest among researchers in physics, medicine, chemistry and technology over the centuries. The aim of this thesis is to use advanced numerical methods for simulating microbubble in an aerated mixing tank. Main components of the mixing tank are a cylindrical vessel, a rotating Rushton turbine and the air nozzle. The objective of Computational Fluid Dynamics (CFD) is to predict fluid flow, heat transfer, mass transfer and chemical reactions. The CFD simulations of a turbulent bubbly flow are carried out in a cylindrical mixing tank using large eddy simulation (LES) and volume of fluid (VOF) method. The Rushton turbine induced flow is modeled by using a sliding mesh method. Numerical results are used to describe the bubbly flows in highly complex liquid flow. Some of the experimental works related to turbulent bubbly flow in a mixing tank are briefly reported. Numerical simulations are needed to complete and interpret the results of the experimental work. Information given by numerical simulations has a major role in designing and scaling-up mixing tanks. The results of this work have been reported in the following scientific articles: ·Honkanen M., Koohestany A., Hatunen T., Saarenrinne P., Zamankhan P., Large eddy simulations and PIV experiments of a two-phase air-water mixer, in Proceedings of ASME Fluids Engineering Summer Conference (2005). ·Honkanen M., Koohestany A., Hatunen T., Saarenrinne P., Zamankhan P., Dynamical States of Bubbling in an Aerated Stirring Tank, submitted to J. Computational Physics.

Phase behavior and rheological analysis of reverse liquid crystals and W/I2, W/H2 gel emulsions using an amphiphilic block copolymer.

This article reports the phase behavior determi- nation of a system forming reverse liquid crystals and the formation of novel disperse systems in the two-phase region. The studied system is formed by water, cyclohexane, and Pluronic L-121, an amphiphilic block copolymer considered of special interest due to its aggregation and structural proper- ties. This system forms reverse cubic (I2) and reverse hexagonal (H2) phases at high polymer concentrations. These reverse phases are of particular interest since in the two-phase region, stable high internal phase reverse emulsions can be formed. The characterization of the I2 and H2 phases and of the derived gel emulsions was performed with small-angle X-ray scattering (SAXS) and rheometry, and the influence of temperature and water content was studied. TheH2 phase experimented a thermal transition to an I2 phase when temperature was increased, which presented an Fd3m structure. All samples showed a strong shear thinning behavior from low shear rates. The elasticmodulus (G0) in the I2 phase was around 1 order of magnitude higher than in theH2 phase. G0 was predominantly higher than the viscousmodulus (G00). In the gel emulsions,G0 was nearly frequency-independent, indicating their gel type nature. Contrarily to water-in-oil (W/O) normal emulsions, in W/I2 and W/H2 gel emulsions, G0, the complex viscosity (|η*|), and the yield stress (τ0) decreased with increasing water content, since the highly viscous microstructure of the con- tinuous phase was responsible for the high viscosity and elastic behavior of the emulsions, instead of the volumefraction of dispersed phase and droplet size. A rheological analysis, in which the cooperative flow theory, the soft glass rheology model, and the slip plane model were analyzed and compared, was performed to obtain one single model that could describe the non-Maxwellian behavior of both reverse phases and highly concentrated emulsions and to characterize their microstructure with the rheological properties.

Effects of condensation in microchannels with a porous boundary: analytical investigation on heat transfer and meniscus shape

In two-phase miniature and microchannel flows, the meniscus shape must be considered due to effects that are affected by condensation and/or evaporation and coupled with the transport phenomena in the thin film on the microchannel wall, when capillary forces drive the working fluid. This investigation presents an analytical model for microchannel condensers with a porous boundary, where capillary forces pump the fluid. Methanol was selected as the working fluid. Very low liquid Reynolds numbers were obtained (Re~6), but very high Nusselt numbers (Nu~150) could be found due to the channel size (1.5 mm) and the presence of the porous boundary. The meniscus calculation provided consistent results for the vapor interface temperature and pressure, as well as the meniscus curvature. The obtained results show that microchannel condensers with a porous boundary can be used for heat dissipation with reduced heat transfer area and very high heat dissipation capabilities.

Computational studies for the design of process equipment with complex geometries

This study combines several projects related to the flows in vessels with complex shapes representing different chemical apparata. Three major cases were studied. The first one is a two-phase plate reactor with a complex structure of intersecting micro channels engraved on one plate which is covered by another plain plate. The second case is a tubular microreactor, consisting of two subcases. The first subcase is a multi-channel two-component commercial micromixer (slit interdigital) used to mix two liquid reagents before they enter the reactor. The second subcase is a micro-tube, where the distribution of the heat generated by the reaction was studied. The third case is a conventionally packed column. However, flow, reactions or mass transfer were not modeled. Instead, the research focused on how to describe mathematically the realistic geometry of the column packing, which is rather random and can not be created using conventional computeraided design or engineering (CAD/CAE) methods. Several modeling approaches were used to describe the performance of the processes in the considered vessels. Computational fluid dynamics (CFD) was used to describe the details of the flow in the plate microreactor and micromixer. A space-averaged mass transfer model based on Fick’s law was used to describe the exchange of the species through the gas-liquid interface in the microreactor. This model utilized data, namely the values of the interfacial area, obtained by the corresponding CFD model. A common heat transfer model was used to find the heat distribution in the micro-tube. To generate the column packing, an additional multibody dynamic model was implemented. Auxiliary simulation was carried out to determine the position and orientation of every packing element in the column. This data was then exported into a CAD system to generate desirable geometry, which could further be used for CFD simulations. The results demonstrated that the CFD model of the microreactor could predict the flow pattern well enough and agreed with experiments. The mass transfer model allowed to estimate the mass transfer coefficient. Modeling for the second case showed that the flow in the micromixer and the heat transfer in the tube could be excluded from the larger model which describes the chemical kinetics in the reactor. Results of the third case demonstrated that the auxiliary simulation could successfully generate complex random packing not only for the column but also for other similar cases.

Modeling of Liquid-Solid Flow in Industrial Scale

In the present work, liquid-solid flow in industrial scale is modeled using the commercial software of Computational Fluid Dynamics (CFD) ANSYS Fluent 14.5. In literature, there are few studies on liquid-solid flow in industrial scale, but any information about the particular case with modified geometry cannot be found. The aim of this thesis is to describe the strengths and weaknesses of the multiphase models, when a large-scale application is studied within liquid-solid flow, including the boundary-layer characteristics. The results indicate that the selection of the most appropriate multiphase model depends on the flow regime. Thus, careful estimations of the flow regime are recommended to be done before modeling. The computational tool is developed for this purpose during this thesis. The homogeneous multiphase model is valid only for homogeneous suspension, the discrete phase model (DPM) is recommended for homogeneous and heterogeneous suspension where pipe Froude number is greater than 1.0, while the mixture and Eulerian models are able to predict also flow regimes, where pipe Froude number is smaller than 1.0 and particles tend to settle. With increasing material density ratio and decreasing pipe Froude number, the Eulerian model gives the most accurate results, because it does not include simplifications in Navier-Stokes equations like the other models. In addition, the results indicate that the potential location of erosion in the pipe depends on material density ratio. Possible sedimentation of particles can cause erosion and increase pressure drop as well. In the pipe bend, especially secondary flows, perpendicular to the main flow, affect the location of erosion.

Dyad function-based cognitive behavioural therapy as a treatment for obsessive compulsive disorder in two school aged children with high functioning autism

Children with High-Functioning Autism (HF A) are more vulnerable to developing Obsessive Compulsive Disorder (OCD) than typically developing children and those with Low-Functioning Autism (Gadow et al., 2005). This study used a multiple baseline design across behaviours (Cooper, Heron, & Heward, 2007) to investigate if a two phase function-based Cognitive Behaviour Therapy (CBT) would decrease obsessive compulsive behaviours (OCBs) in two children ages 7 and 9 who met criteria for OCD and HF A. This multimodal treatment package consisted of treatment enhancements to meet the children's cognitive, linguistic, and social challenges associated with their HF A diagnosis, as well as a manual and accompanied children's workbook (Vause, Neil, & Feldman, in progress). In line with previous research conducted on CBT as a treatment for OCD in this population (e.g., Wood et at, 2009), the children in this study experienced clinically significant decreases in their OCBs as a result of receiving the CBT protocol.

Flux difference splitting for open channel flows

A finite difference scheme based on flux difference splitting is presented for the solution of the one-dimensional shallow-water equations in open channels, together with an extension to two-dimensional flows. A linearized problem, analogous to that of Riemann for gas dynamics, is defined and a scheme, based on numerical characteristic decomposition, is presented for obtaining approximate solutions to the linearized problem. The method of upwind differencing is used for the resulting scalar problems, together with a flux limiter for obtaining a second-order scheme which avoids non-physical, spurious oscillations. The scheme is applied to a one-dimensional dam-break problem, and to a problem of flow in a river whose geometry induces a region of supercritical flow. The scheme is also applied to a two-dimensional dam-break problem. The numerical results are compared with the exact solution, or other numerical results, where available.

A moving-mesh finite element method and its application to the numerical solution of phase-change problems

A distributed Lagrangian moving-mesh finite element method is applied to problems involving changes of phase. The algorithm uses a distributed conservation principle to determine nodal mesh velocities, which are then used to move the nodes. The nodal values are obtained from an ALE (Arbitrary Lagrangian-Eulerian) equation, which represents a generalization of the original algorithm presented in Applied Numerical Mathematics, 54:450--469 (2005). Having described the details of the generalized algorithm it is validated on two test cases from the original paper and is then applied to one-phase and, for the first time, two-phase Stefan problems in one and two space dimensions, paying particular attention to the implementation of the interface boundary conditions. Results are presented to demonstrate the accuracy and the effectiveness of the method, including comparisons against analytical solutions where available.

The role of phase separation and feed cycle length in leach beds coupled to methanogenic reactors for digestion of a solid substrate (Part 1): Optimisation of reactors’ performance

A two-phase system composed by a leach bed and a methanogenic reactor was modified for the first time to improve volumetric substrate degradation and methane yields from a complex substrate (maize; Zea mays). The system, which was operated for consecutive feed cycles of different durations for 120 days, was highly flexible and its performance improved by altering operational conditions. Daily substrate degradation was higher the shorter the feed cycle, reaching 8.5 g TSdestroyed d�1 (7-day feed cycle) but the overall substrate degradation was higher by up to 55% when longer feed cycles (14 and 28 days) were applied. The same occurred with volumetric methane yields, reaching 0.839 m3 (m3)�1 d�1. The system performed better than others on specific methane yields, reaching 0.434 m3 kg�1 TSadded, in the 14-day and 28-day systems. The UASB and AF designs performed similarly as second stage reactors on methane yields, SCOD and VFA removal efficiencies.