Improving the Government of Canada’s response to flooding through the inclusion of pertinent economic information

At present, the methods by which costs of flood-related damages are estimated vary significantly across Canada, resulting in widely different and often incomplete quantification of these costs. I use the comprehensive flood-costing methodology that I co-developed in Adeel et al. (2020) to assess the economic impacts of flooding in Canada during 2013 – 2017. This methodology is meant to facilitate flood-planning investments by governments at different levels and allocation of resources to support real-time flood monitoring and response. Public Safety Canada, Indigenous Services Canada, and Natural Resources Canada should standardize and integrate pertinent economic information into existing disaster-response mechanisms, using the methodology proposed herein. Indigenous approaches for evaluating flood damages and losses must also be incorporated. Doing so would standardize the process of post-disaster assessments, facilitate enhancement of local resilience against flood impacts, and improve allocation of resources by the Government of Canada in response to flooding

Nondifferentiable energy minimization for cohesive fracture in a discontinuous Galerkin finite element framework

Until recently, most works on the computational modelling of fracture relied on a Newtonian mechanics approach, i.e., momentum balance equations describing the motion of the body along with fracture criteria describing the evolution of fractures. Robustness issues associated with this approach have been identified in the previous literature, several of which, as this thesis shows, due to the discontinuous dependence of stress field on the deformation field at the time of insertion of displacement discontinuities. Lack of continuity limits applicability of the models and undermines reliability of the numerical solutions. In particular, solutions often show non-convergent behaviour with time step refinement and exhibit nonphysical velocity fields and crack activation patterns. In addition, implicit time-stepping schemes, which are favoured in quasi-static and low-velocity problems, are challenging in such models. This is not a coincidence but a manifestation of algorithmic pitfalls of such methods. Continuity of stresses is in general hard to achieve in a computational model that employs a crack initiation criterion. Energy (variational) approaches to fracture have gained increased popularity in recent years. An energy approach has been shown to avoid introduction of a crack initiation criterion. The central idea of this model is the minimization of a mechanical energy functional, whose term representing the energy due to the cracks is a nondifferentiable function of the interface openings at zero opening displacement. A consequence of this formulation is that crack initiation happens automatically as a by-product of energy minimization. This avoids the complexities arising from the introduction of an extrinsic activation criterion but entails minimization of a nondifferentiable potential. The aim of this research is to develop robust and efficient computational algorithms for numerical implementation of the energy approach to cohesive fracture. Two computational algorithms have been proposed in a discontinuous Galerkin finite element framework, including a continuation algorithm which entails successive smooth approximations of the nondifferentiable functional and a block coordinate descent algorithm which uses generalized differential calculus for the treatment of nondifferentiability. These methods allow for a seamless transition from the uncracked to the cracked state, making possible the use of iterative solvers with implicit time-stepping, and completely sidestepping robustness issues of previous computational frameworks. A critical component of this work is validation of the robustness of the proposed numerical methods. Various numerical simulations are presented including time step and mesh size convergence studies and qualitative and quantitative comparison of simulations with experimental observations and theoretical findings. In addition, an energy-based hydro-mechanical model and computational algorithm is presented for hydraulic fracturing in impermeable media, which shows the crucial importance of continuity in multi-physics modelling. A search algorithm is developed on the basis of graph theory to identify the set of fluid-pressurized cracks among cracks in naturally fractured domains

Clinical outcomes and survival surrogacy studies of prostate-specific antigen declines following enzalutamide in men with metastatic castration-resistant prostate cancer previously treated with docetaxel.

Background In the AFFIRM trial, enzalutamide significantly increased overall survival (OS) for men with metastatic castration-resistant prostate cancer (mCRPC) after chemotherapy versus placebo and significantly decreased prostate-specific antigen (PSA) levels. The goal of this post hoc analysis was to associate levels of PSA decline from baseline after enzalutamide with clinical outcomes in the postchemotherapy mCRPC setting.Methods Men in the AFFIRM trial (n = 1199) were grouped by maximal PSA decline in the first 90 days of treatment. Kaplan-Meier estimates evaluated the association of defined PSA changes from baseline with OS, progression-free survival (PFS), radiographic PFS (rPFS), and pain response. Each PSA decline category was assessed for OS surrogacy using Prentice criteria, proportion of treatment effect explained (PTE), and proportion of variation explained.Results Men treated with enzalutamide had improved OS (hazard ratio, 0.63; P 19.0; P .20).Conclusions PSA declines of any, ≥30%, and ≥50% following enzalutamide were associated with greater clinical and pain response and improvements in PFS and OS. Surrogacy of PSA decline for OS was not fully established, possibly due to lack of PSA declines with placebo, and discordant results between PSA and imaging responses over time, and because some declines were not durable due to rapid resistance development. However, a lack of PSA decline by 90 days following enzalutamide treatment was a poor prognosis indicator in this setting. Conclusions from sensitivity analyses of maximal PSA decline from baseline over the entire treatment period are consistent with PSA declines restricted to the first 90 days. Cancer 2017;123:2303-2311. © 2017 American Cancer Society

Increased survival with enzalutamide in prostate cancer after chemotherapy

Contains fulltext : 108324.pdf (publisher's version ) (Open Access)BACKGROUND: Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. METHODS: In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. RESULTS: The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P<0.001). The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate (29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide. CONCLUSIONS: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy. (Funded by Medivation and Astellas Pharma Global Development; AFFIRM ClinicalTrials.gov number, NCT00974311.)

Antitumour Activity and Safety of Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Abiraterone Acetate Plus Prednisone for ≥24 weeks in Europe.

Background Enzalutamide and abiraterone acetate plus prednisone, which target the androgen receptor axis, have expanded the treatment of advanced prostate cancer. Retrospective analyses suggest some cross-resistance between these two drugs when used sequentially, but robust, prospective studies have not yet been reported.Objective To fulfil a regulatory postregistration commitment by evaluating the efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed following abiraterone acetate plus prednisone treatment.Design, setting, and participants Multicentre, single-arm, open-label study, enrolled patients with progressing mCRPC after ≥24 wk of abiraterone acetate plus prednisone treatment. All patients maintained castration therapy during the trial. Prior chemotherapy was allowed but not required.Intervention Patients received enzalutamide 160mg/d orally.Outcome measurements and statistical analysis The primary endpoint was radiographic progression-free survival. Secondary endpoints were overall survival, prostate-specific antigen (PSA) response, and time-to-PSA progression. Safety data were also assessed. Kaplan-Meier methods were used to descriptively analyse time-to-event endpoints.Results and limitations Overall, 214 patients received enzalutamide treatment, 145 of whom were chemotherapy-naïve. Median radiographic progression-free survival was 8.1 mo (95% confidence interval: 6.1-8.3); median overall survival had not been reached. Unconfirmed PSA response rate was 27% (48 of 181). Median time-to-PSA progression was 5.7 mo (95% confidence interval: 5.6-5.8). The most common treatment-emergent adverse events were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). No seizures were reported.Conclusions Enzalutamide showed antitumour activity in some patients with mCRPC who had previously progressed following ≥24 wk of abiraterone acetate plus prednisone treatment.Patient summary Patients with mCRPC who progressed on previous abiraterone acetate plus prednisone treatment, with or without prior chemotherapy, received enzalutamide. Although cross-resistance between the two agents was observed in a majority of patients, some still benefited from enzalutamide treatment

Current and Emerging Treatment Options for Castration-Resistant Prostate Cancer: A Focus on Immunotherapy

BACKGROUND: Castration-resistant prostate cancer is a disease with limited treatment options. However, the ongoing elucidation of the mechanisms underlying this disease continues to support the development of not only novel agents, but also innovative approaches. Among these therapies, immunotherapy has emerged as a promising strategy. DESIGN: This review article summarizes the most recent data from investigations of immunotherapies in castration-resistant prostate cancer (literature and congress searches current as of August 2011). RESULTS: Immunotherapeutic strategies such as passive immunization, vaccines, and particularly checkpoint blockade have demonstrated some efficacy as single agents. Elucidation of effective combinations of agents and drug regimens is ongoing but will require continued careful investigation, including the standardization of surrogate endpoints in clinical trials. CONCLUSIONS: It is hypothesized that the combination of immunotherapeutic agents with traditional and novel chemotherapeutics will potentiate the efficacy of the chemotherapeutics while maintaining manageable toxicity

Enzalutamide in European and North American men participating in the AFFIRM trial

Objective To explore any differences in efficacy and safety outcomes between European (EU) (n = 684) and North American (NA) (n = 395) patients in the AFFIRM trial (NCT00974311).Patients and Methods Phase III, double-blind, placebo-controlled, multinational AFFIRM trial in men with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel. Participants were randomly assigned in a 2:1 ratio to receive oral enzalutamide 160 mg/day or placebo. The primary end point was overall survival (OS) in a post hoc analysis.Results Enzalutamide significantly improved OS compared with placebo in both EU and NA patients. The median OS in EU patients was longer than NA patients in both treatment groups. However, the relative treatment effect, expressed as hazard ratio and 95% confidence interval, was similar in both regions: 0.64 (0.50, 0.82) for EU and 0.63 (0.47, 0.83) for NA. Significant improvements in other end points further confirmed the benefit of enzalutamide over placebo in patients from both regions. The tolerability profile of enzalutamide was comparable between EU and NA patients, with fatigue and nausea the most common adverse events. Four EU patients (4/461 enzalutamide-treated, 0.87%) and one NA patient (1/263 enzalutamide-treated, 0.38%) had seizures. The difference in median OS was related in part to the timing of development of mCRPC and baseline demographics on study entry.Conclusion This post hoc exploratory analysis of the AFFIRM trial showed a consistent OS benefit for enzalutamide in men with mCRPC who had previously progressed on docetaxel in both NA- and EU-treated patients, although the median OS was higher in EU relative to NA patients. Efficacy benefits were consistent across end points, with a comparable safety profile in both regions. © 2014 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International

Design and Development of a Direct-acting Piezoelectric Fuel Injector

Manufacturers face the challenge of enhancing fuel efficiency, engine performance, and reducing harmful emissions. Novel fuel injection technologies can assist in meeting such demands. This dissertation summarizes the stages in the design, prototyping and experimental analysis of a direct-acting piezoelectric fuel injector concept. In the proposed design, a piezoelectric stack actuator is used to directly control the injection of fuel in order to enhance the injection characteristics by utilizing the fast response time of the actuator. The direct-acting concept was implemented by developing a motion inverter in the form of a disc that reverses the direction of the input and allows the actuator to directly control injections. Tests with input signals similar to those used in diesel engines confirmed the theoretical calculations and verified the prototype’s performance. This design can control the quantity of injected fuel more precisely than currently available commercial injectors.MAS

Comparison of Unsupervised Machine Learning Approaches for Cluster Analysis to Define Subgroups of Heart Failure with Preserved Ejection Fraction with Different Outcomes

Heart failure with preserved ejection (HFpEF) is a heterogenous condition affecting nearly half of all patients with heart failure (HF). Artificial intelligence methodologies can be useful to identify patient subclassifications with important clinical implications. We sought a comparison of different machine learning (ML) techniques and clustering capabilities in defining meaningful subsets of patients with HFpEF. Three unsupervised clustering strategies, hierarchical clustering, K-prototype, and partitioning around medoids (PAM), were used to identify distinct clusters in patients with HFpEF, based on a wide range of demographic, laboratory, and clinical parameters. The study population had a median age of 77 years, with a female majority, and moderate diastolic dysfunction. Hierarchical clustering produced six groups but two were too small (two and seven cases) to be clinically meaningful. The K-prototype methods produced clusters in which several clinical and biochemical features did not show statistically significant differences and there was significant overlap between the clusters. The PAM methodology provided the best group separations and identified six mutually exclusive groups (HFpEF1-6) with statistically significant differences in patient characteristics and outcomes. Comparison of three different unsupervised ML clustering strategies, hierarchical clustering, K-prototype, and partitioning around medoids (PAM), was performed on a mixed dataset of patients with HFpEF containing clinical and numerical data. The PAM method identified six distinct subsets of patients with HFpEF with different long-term outcomes or mortality. By comparison, the two other clustering algorithms, the hierarchical clustering and K-prototype, were less optimal