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Background: Multicriteria decision analysis (MCDA) represents a promising method for benefit-risk assessment. Our goal was to develop features of pragmatic MCDA (EVIDEM [Evidence and Value: Impact on DEcisionMaking]) addressing real-life regulatory decision-making needs, incorporate advanced pharmacoepidemiology, and test the resulting benefit-risk framework using a case study. Methods: The Intervention Outcomes domain of EVIDEM was transformed into a generic benefit-risk framework including clinical efficacy, patient-reported outcomes, and adverse event (AE) criteria. The concept of relative benefit-risk balance (RBRB) was developed for comparability across products and therapeutic areas and over time. Evidence matrix was designed to include most relevant data from trials, observational studies, and models, including Bayesian and longitudinal modeling. The framework was tested with a panel of stakeholders using efalizumab for psoriasis as retrospective case study. Uncertainty was explored. Results: The MCDA benefit-risk tree was adapted with psoriasis-specific subcriteria. Panelists assigned similar weights to benefits (0.48; SD, 0.20-0.70) and risks (0.52; SD, 0.10-0.60), with large variations reflecting diverse perspectives. Panelist scores reflected higher efficacy versus placebo, lower efficacy versus active comparators, and serious and fatal AEs identified postlicensing. Efalizumab’s RBRB was positive at licensing in 2004 (0.29, scale -1 to +1) and ranged from -0.41 (vs active comparators) to 0.01 (vs placebo) in 2009, when its market authorization was withdrawn. Retesting indicated good reproducibility. Panelists acknowledged good face validity and the importance of criteria beyond benefit-risk in real-life assessments. Conclusions: The approach allows quantification and visualization of benefit-risk over time and across comparators. Combination of pragmatic MCDA designed to integrate criteria beyond benefit-risk and advanced statistics supports application of MCDA to further accountable benefit-risk assessments for real-life decision making.

Background: Multicriteria decision analysis (MCDA) represents a promising method for benefit-risk assessment. Our goal was to develop features of pragmatic MCDA (EVIDEM [Evidence and Value: Impact on DEcisionMaking]) addressing real-life regulatory decision-making needs, incorporate advanced pharmacoepidemiology, and test the resulting benefit-risk framework using a case study.Methods: The Intervention Outcomes domain of EVIDEM was transformed into a generic benefit-risk framework including clinical efficacy, patient-reported outcomes, and adverse event (AE) criteria. The concept of relative benefit-risk balance (RBRB) was developed for comparability across products and therapeutic areas and over time. Evidence matrix was designed to include most relevant data from trials, observational studies, and models, including Bayesian and longitudinal modeling. The framework was tested with a panel of stakeholders using efalizumab for psoriasis as retrospective case study. Uncertainty was explored.Results: The MCDA benefit-risk tree was adapted with psoriasis-specific subcriteria. Panelists assigned similar weights to benefits (0.48; SD, 0.20-0.70) and risks (0.52; SD, 0.10-0.60), with large variations reflecting diverse perspectives. Panelist scores reflected higher efficacy versus placebo, lower efficacy versus active comparators, and serious and fatal AEs identified postlicensing. Efalizumab’s RBRB was positive at licensing in 2004 (0.29, scale –1 to +1) and ranged from –0.41 (vs active comparators) to 0.01 (vs placebo) in 2009, when its market authorization was withdrawn. Retesting indicated good reproducibility. Panelists acknowledged good face validity and the importance of criteria beyond benefit-risk in real-life assessments.Conclusions: The approach allows quantification and visualization of benefit-risk over time and across comparators. Combination of pragmatic MCDA designed to integrate criteria beyond benefit-risk and advanced statistics supports application of MCDA to further accountable benefit-risk assessments for real-life decision making.

The Incremental Decrease in End-Points Through Aggressive Lipid-Lowering (IDEAL) trial demonstrated incremental cardiovascular benefit of treatment with high-dose atorvastatin (80mg/ day) versus standard-dose simvastatin (20mg/day to 40mg/day) in 8888 patients with a previous myocardial infarction (MI) over a median follow-up period of 4.8 years.

To assess the clinical and economic benefits of atorvastatin for Canadian patients with type 2 diabetes from a Canadian Ministry of Health perspective.

In the Berlin of the Weimar Republic, conflict raged not only over a new architecture corresponding to the optical culture but also over new forms of urban space. This essay, through a broad overview of the social spaces of Berlin, explores the tension between "artisanal" and "industrial" production and between collective and individual labor. It shows how different sociopolitical environments mobilized artisanal and industrial tropes and analyzes the ways in which they were construed iconographically.

In this work, we report measurements of viscosity and density near the liquid–liquid phase transition of the binary solution of the room temperature ionic liquid (RTIL) 1-methyl-3-hexylimidazolium tetrafluoroborate (C₆mim+BF₄−) in 1-pentanol. The density and the shear viscosity have been determined as function of the temperature and of the concentration. The critical point is located at the temperature T_c = 314.91 K and the mass fraction w_c = 0.31034 of the salt. For the critical concentration, the viscosity measurements yield an enhancement as expected for Ising criticality with a crossover to regular behaviour. The regular background is obtained by interpolation from the measurements at non-critical concentrations. The critical enhancement is well described by the mode-coupling crossover function of Bhattacharjee et al. (Phys. Rev. A, 1981, 24, 1469) .The closed form result of the limiting case q_D/q_c → 0 matches the data almost perfectly.

In this work, we report measurements of viscosity and density near the liquid–liquid phase transition of the binary solution of the room temperature ionic liquid RTIL 1-methyl-3-hexylimidazolium tetrafluoroborate C6mimBF4− in 1-pentanol. The density and the shear viscosity have been determined as function of the temperature and of the concentration. The critical point is located at the temperature Tc  314.91 K and the mass fraction wc  0.31034 of the salt. For the critical concentration, the viscosity measurements yield an enhancement as expected for Ising criticality with a crossover to regular behaviour. The regular background is obtained by interpolation from the measurements at non-critical concentrations. The critical enhancement is well described by the mode-coupling crossover function of Bhattacharjee et al.(Phys. Rev. A, 1981, 24, 1469) .The closed form result of the limiting case qDqc → 0 matches the data almost perfectly.

Precise coexistence curves are reported for the liquid–liquid phase transition of binary solutions of the room temperature ionic liquid RTIL 1-methyl-3-hexylimidazolium tetrafluoroborate C6mimBF4− in a series of alcohols 1-butanol, 1-pentanol, 2-butanol, and 2-pentanol. The phase diagrams are determined by measuring the temperature dependence of the refractive index in the two phases of samples of critical composition. The critical data of the systems are in the region predicted for the model fluid of equal-sized, charged, hard spheres in a dielectric continuum, the so-called restricted primitive model RPM. Therefore, the phase transition can be classified as essentially driven by Coulomb interactions. The effective exponents βeffdetermined are close to the universal Ising value, where the deviations are found to be negative, when the volume fraction or the mass fraction are chosen as concentration variable. The negative values of the first Wegner correction indicate non-uniform crossover from Ising to mean-field criticality. The diameter of the coexistence curves shows the non-analytic temperature dependence typical for Ising systems.

The existence of a tricritical point was postulated for the ternary system water3-methylpyridineNaBr J. Jacob et al., Phys. Rev. E, 1998, 58, 2188 because light-scattering measurements yielded the mean-field critical exponent γ  1 of the susceptibility at high concentrations of the salt, while the usual Ising value γ  1.24 was found at low salt concentrations. However, in the preceding papers we have reported measurements of the viscosities and of the coexistence curves, which for all salt concentrations showed normal Ising criticality with corrections to scaling at large separations from the critical temperatures. In this paper, we continue the research on this system and report now measurements of the scattering intensity in the homogeneous phase approaching the critical temperature from below. Micro-heterogeneities causing a background were observed, which required waiting times up to 8 days to decay. The data are corrected for multiple scattering using a Monte Carlo simulation of the photon-paths in the sample and also by using the 3D cross-correlation method that enables to separate the singly scattered light from the other contributions. The scattering intensities of the equilibrated samples are described by the Ornstein–Zernike expression. For all salt concentrations, 10–17 mass the critical exponents are consistent with Ising critical behaviour. No systematic variation with the concentration of the salt is found for the various properties determined as the effective values of the critical exponents γand νfor the susceptibility and the correlation length, respectively, and the corresponding amplitudes.

The existence of a tricritical point was postulated recently for the ternary system water/3-methylpyridine/NaBr (J. Jacob et al., Phys. Rev. E, 1998, 58, 2188) because light-scattering measurements showed at high concentrations of the salt purely mean field behaviour with a critical exponent of the susceptibility γ = 1 instead of the Ising value γ = 1.24, which is found at low salt concentrations. However, in a preceding paper (Wagner et al., Phys. Chem. Chem. Phys., 2002, 4, 5300) we have reported measurements of the viscosities, which for all salt concentrations showed normal Ising criticality with a crossover to non-critical behaviour at large separations from the critical temperatures. In this paper we continue the research on this system and report refractive index measurements of the coexisting phases. For all salt concentrations (10–17 mass%) the critical exponents are consistent with Ising critical behaviour where the Lorenz–Lorentz function is taken as order parameter. The effective value of the critical exponent β is found to depend on the concentration of the salt. In the region of high salt concentration mean field tricriticality was expected with an exponent β = 1 while a value somewhat below the Ising value is found. The effective value of β is reduced at lower salt content. Essentially the same results are obtained when the mole, mass or volume fractions of the different components are taken as order parameter, where the compositions in the two phases are estimated on the basis of the separation temperatures determined for previously given concentrations.

A systematic study of liquid–liquid phase transitions in mixtures of room temperature ionic liquids RTIL with nonionic solvents of different dielectric constant is presented. We report phase diagrams and the location of the critical points in the binary systems. The salts are 1-alkyl-3-methylimidazolium tetrafluoroborates and hexafluorophosphates with butyl-, hexyl-, octyl- side chains. The solvents are water, n-alcohols n  1 − 16, branched alcohols, and dialcohols. A corresponding state analysis of the data is carried out in terms of the variables of the restricted primitive model RPM, which considers ionic fluids as equal-sized charged hard spheres in a dielectric continuum. The reduced critical temperatures are found to depend almost linearly on the dielectric constant of the solvent. The data of all investigated systems are represented by a master plot, which indicates a continuous crossover from a Coulomb driven phase transition, reasonably described by the RPM, towards a phase transition determined by hydrophobic interactions.

A systematic study of liquid–liquid phase transitions in mixtures of room temperature ionic liquids (RTIL) with nonionic solvents of different dielectric constant is presented. We report phase diagrams and the location of the critical points in the binary systems. The salts are 1-alkyl-3-methylimidazolium tetrafluoroborates and hexafluorophosphates with butyl-, hexyl-, octyl- side chains. The solvents are water, n-alcohols (n = 1 − 16), branched alcohols, and dialcohols. A corresponding state analysis of the data is carried out in terms of the variables of the restricted primitive model (RPM), which considers ionic fluids as equal-sized charged hard spheres in a dielectric continuum. The reduced critical temperatures are found to depend almost linearly on the dielectric constant of the solvent. The data of all investigated systems are represented by a master plot, which indicates a continuous crossover from a Coulomb driven phase transition, reasonably described by the RPM, towards a phase transition determined by hydrophobic interactions.

A transition from Ising criticality to mean-field tricritical behaviour was concluded lately for the ternary system of NaBr in mixtures of water and 3-methylpyridine from light-scattering measurements (J. Jacob et al., Phys. Rev. E, 1998, 58, 2188). In this paper we report for this ternary system measurements of the phase diagram, of the line of lower critical points and of the critical viscosities for a set of concentrations of the salt in the range of 10–19 mass%. The critical line is found to depend linearly on the salt content without noticeable discontinuity. The viscosity measurements yield Ising criticality at all concentrations of the salt. The critical exponent found is y = ν z = 0.0398 ± 0.0007 (i.e. z = 0.0632) in accordance with the expectations [0.041 (0.065)] for an Ising system, while a vanishing of the critical divergence at a tricritical point was expected. Crossover to non-critical behaviour is observed, which is well described by the mode-coupling theory. While the value of the exponent is not influenced by the content of the salt, the cut-off wave number and hence the amplitude of the critical viscosity assume a minimum at compositions where the reported light-scattering measurements suggest mean-field tricriticality.

The Montreal Urban Community Wastewater Treatment Plant (MUCWTP) located in Montreal, Quebec, Canada, uses physicochemical treatment processes prior to discharging wastewater into the St. Lawrence River via an outfall tunnel of 2 hours retention time. Although chlorination facilities exist, they are not being used, and the MUCWTP is seeking alternative methods for disinfection to achieve a 2- to 3-log fecal coliform reduction. Liquid chemical disinfectants were attractive options because of their low capital costs. This led to an investigation of the feasibility of using hydrogen peroxide or peracetic acid.
A method for measuring peroxycompounds (hydrogen peroxide or peracetic acid plus hydrogen peroxide) was developed using the peroxidase-based oxidation of 2,2'-azino-bis(3-ethylbenz-thiazoline-6-sulfuric acid) diammonium salt (ABTS) with hydrogen peroxide. The validity of the method was confirmed using effluent from the MUCWTP. Recovery was higher than 90% for peracetic acid levels as low as 1.0 mg/L. Quenching of hydrogen peroxide was achieved with 50-mg/L catalase; quenching of peracetic acid was achieved with 100 mg/L of sodium thiosulfate, followed by 50 mg/L of catalase.
Batch disinfection tests were conducted on MUCWTP effluent. Hydrogen peroxide and peracetic acid in wastewater over time could be modeled as a second-order decay, with the decay “constant” being a function of the initial concentration of peroxycompounds. This function was the same for both hydrogen peroxide and peracetic acid, possibly indicating similar decomposition pathways in wastewater matrices.
Disinfection was modeled using a modified Hom equation. Required doses of hydrogen peroxide to reach the target fecal coliform levels ranged from 106 to 285 mg/L, with the higher doses occurring when ferric chloride instead of alum was used as the coagulant. Hence, hydrogen peroxide was infeasible as a disinfectant for this application. On the other hand, the peracetic acid dose needed to achieve the target fecal coliform level was only 0.6 to 1.6 mg/L. Therefore, peracetic acid seems to be a promising disinfectant for physicochemical or primary effluent, or combined sewer overflows.

BACKGROUND: Clostridium difficile infection (CDI) represents a public health problem with increasing incidence and severity.OBJECTIVE: To evaluate the clinical and economic consequences of vancomycin compared with fidaxomicin in the treatment of CDI from the Canadian health care system perspective.METHODS: A decision-tree model was developed to compare vancomycin and fidaxomicin for the treatment of severe CDI. The model assumed identical initial cure rates and included first recurrent episodes of CDI (base case). Treatment of patients presenting with recurrent CDI was examined as an alternative analysis. Costs included were for study medication, physician services and hospitalization. Cost effectiveness was measured as incremental cost per recurrence avoided. Sensitivity analyses of key input parameters were performed.RESULTS: In a cohort of 1000 patients with an initial episode of severe CDI, treatment with fidaxomicin led to 137 fewer recurrences at an incremental cost of $1.81 million, resulting in an incremental cost of $13,202 per recurrence avoided. Among 1000 patients with recurrent CDI, 113 second recurrences were avoided at an incremental cost of $18,190 per second recurrence avoided. Incremental costs per recurrence avoided increased with increasing proportion of cases caused by the NAP1/B1/027 strain. Results were sensitive to variations in recurrence rates and treatment duration but were robust to variations in other parameters.CONCLUSIONS: The use of fidaxomicin is associated with a cost increase for the Canadian health care system. Clinical benefits of fidaxomicin compared with vancomycin depend on the proportion of cases caused by the NAP1/B1/027 strain in patients with severe CDI.

For Abstract see ChemInform Abstract in Full Text.