Cost-effectiveness of Chimeric Antigen Receptor T-cell Therapy for Treating Large B-cell Lymphoma Patients in Canada

Background/Aim: Chimeric antigen receptor (CAR) T-cell therapy is a novel cell therapy for treating hematological cancers including multiply relapsed large B-cell lymphoma in adults. Although for some patients it can produce long-term remission who would have otherwise run out of treatment options, it is very expensive, costing $373,000 U.S. dollars per patient. There are also other additional hospital costs related to management of severe adverse events. The first two Health Canada approved CAR T-cell therapy products were reviewed by the Canadian Agency for Drugs and Technologies in Health (CADTH) and recommended for funding. Because CAR T-cell therapies have not been administered before in Canadian hospitals, there are certain logistical concerns with implementation that are unique. The first aim of this thesis is to describe processes of developing CAR T-cell therapy and administering it to patients, as well as describe the challenges to implementation and considerations for long-term sustainability of cell and gene therapy in Canada. The second aim is to evaluate the cost-effectiveness of axicabtagene ciloleucel, a CAR T-cell therapy for treating adult lymphoma patients, compared to salvage chemotherapy. Methods: A qualitative interview study was conducted with 13 CAR T-cell therapy stakeholders including scientists, clinicians, and policy-makers in Canada. Questions were asked related to CAR T-cell therapy development, treating patients, challenges to implementation, and suggestions for logistical planning at the healthcare system level. A partitioned survival model was developed in TreeAge Pro Software from a Canadian public payer perspective. Patients with large B-cell lymphomas were modeled and their health outcomes from being treated with axicabtagene ciloleucel or salvage chemotherapy were extrapolated over a lifetime time horizon. The cost-effectiveness was evaluated by the incremental cost-effectiveness ratio. Results: The results from the qualitative interviews were summarized into 4 main themes: novel, patient characteristics and experiences, processes from “bench to bedside”, and future state of CAR T-cell therapy in Canada, including both challenges and recommendations to ensure sustainability. The ICER generated for the cost-effectiveness analysis was$170,380 per QALY. At a willingness-to-pay threshold of $150,000 per QALY, CAR T-cell therapy is not cost-effective. There is some uncertainty in the long-term efficacy of CAR T-cell therapy and in the cost of CAR T-cell therapy. Conclusions: Valuable perspectives from CAR T-cell therapy stakeholders on the current and future state of CAR T-cell therapy were highlighted from a Canadian perspective. In addition, a reduction in price of CAR T-cell therapy and reduced uncertainty through collection of long-term health outcomes can improve the cost-effectiveness to ensure value-for-money

Noise-marginalized optimal statistic: A robust hybrid frequentist-Bayesian statistic for the stochastic gravitational-wave background in pulsar timing arrays

Observations have revealed that nearly all galaxies contain supermassive black holes (SMBHs) at their centers. When galaxies merge, these SMBHs form SMBH binaries (SMBHBs) that emit low-frequency gravitational waves (GWs). The incoherent superposition of these sources produce a stochastic GW background (GWB) that can be observed by pulsar timing arrays (PTAs). The optimal statistic is a frequentist estimator of the amplitude of the GWB that specifically looks for the spatial correlations between pulsars induced by the GWB. In this paper, we introduce an improved method for computing the optimal statistic that marginalizes over the red noise in individual pulsars. We use simulations to demonstrate that this method more accurately determines the strength of the GWB, and we use the noise-marginalized optimal statistic to compare the significance of monopole, dipole, and Hellings-Downs (HD) spatial correlations and perform sky scrambles.Comment: 8 pages, 7 figures. Published in PR

Preparation and characterization of multiwalled carbon nanotube (MWCNT)/polymer nanostructured materials

http://spiedigitallibrary.org/journals/doc/SPIEDL-home/proc

Preparation and characterisation of vertically aligned single-walled carbon nanotube arrays on porous silicon

http://spiedigitallibrary.org/journals/doc/SPIEDL-home/proc

Intestinal barrier function of Atlantic salmon (Salmo salar L.) post smolts is reduced by common sea cage environments and suggested as a possible physiological welfare indicator

<p>Abstract</p> <p>Background</p> <p>Fish farmed under high intensity aquaculture conditions are subjected to unnatural environments that may cause stress. Therefore awareness of how to maintain good health and welfare of farmed fish is important. For Atlantic salmon held in sea cages, water flow, dissolved oxygen (DO) levels and temperature will fluctuate over time and the fish can at times be exposed to detrimentally low DO levels and high temperatures. This experimental study investigates primary and secondary stress responses of Atlantic salmon post smolts to long-term exposure to reduced and fluctuating DO levels and high water temperatures, mimicking situations in the sea cages. Plasma cortisol levels and cortisol release to the water were assessed as indicators of the primary stress response and intestinal barrier integrity and physiological functions as indicators of secondary responses to changes in environmental conditions.</p> <p>Results</p> <p>Plasma cortisol levels were elevated in fish exposed to low (50% and 60% saturation) DO levels and low temperature (9°C), at days 9, 29 and 48. The intestinal barrier function, measured as electrical resistance (TER) and permeability of mannitol at the end of the experiment, were reduced at 50% DO, in both proximal and distal intestine. When low DO levels were combined with high temperature (16°C), plasma cortisol levels were elevated in the cyclic 1:5 h at 85%:50% DO group and fixed 50% DO group compared to the control (85% DO) group at day 10 but not at later time points. The intestinal barrier function was clearly disturbed in the 50% DO group; TER was reduced in both intestinal regions concomitant with increased paracellular permeability in the distal region.</p> <p>Conclusions</p> <p>This study reveals that adverse environmental conditions (low water flow, low DO levels at low and high temperature), that can occur in sea cages, elicits primary and secondary stress responses in Atlantic salmon post smolts. The intestinal barrier function was significantly affected by prolonged hypoxic stress even when no primary stress response was observed. This suggests that intestinal barrier function is a good experimental marker for evaluation of chronic stress and that it can be a valuable tool to study the impact of various husbandry conditions on health and welfare of farmed Atlantic salmon.</p

Noise-marginalized optimal statistic: A robust hybrid frequentist-Bayesian statistic for the stochastic gravitational-wave background in pulsar timing arrays

Observations have revealed that nearly all galaxies contain supermassive black holes (SMBHs) at their centers. When galaxies merge, these SMBHs form SMBH binaries (SMBHBs) that emit low-frequency gravitational waves (GWs). The incoherent superposition of these sources produce a stochastic GW background (GWB) that can be observed by pulsar timing arrays. The optimal statistic is a frequentist estimator of the amplitude of the GWB that specifically looks for the spatial correlations between pulsars induced by the GWB. In this paper, we introduce an improved method for computing the optimal statistic that marginalizes over the red noise in individual pulsars. We use simulations to demonstrate that this method more accurately determines the strength of the GWB, and we use the noise-marginalized optimal statistic to compare the significance of monopole, dipole, and Hellings-Downs (HD) spatial correlations and perform sky scrambles

Physician decision making in selection of second-line treatments in immune thrombocytopenia in children.

Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder which presents with isolated thrombocytopenia and risk of hemorrhage. While most children with ITP promptly recover with or without drug therapy, ITP is persistent or chronic in others. When needed, how to select second-line therapies is not clear. ICON1, conducted within the Pediatric ITP Consortium of North America (ICON), is a prospective, observational, longitudinal cohort study of 120 children from 21 centers starting second-line treatments for ITP which examined treatment decisions. Treating physicians reported reasons for selecting therapies, ranking the top three. In a propensity weighted model, the most important factors were patient/parental preference (53%) and treatment-related factors: side effect profile (58%), long-term toxicity (54%), ease of administration (46%), possibility of remission (45%), and perceived efficacy (30%). Physician, health system, and clinical factors rarely influenced decision-making. Patient/parent preferences were selected as reasons more often in chronic ITP (85.7%) than in newly diagnosed (0%) or persistent ITP (14.3%, P = .003). Splenectomy and rituximab were chosen for the possibility of inducing long-term remission (P < .001). Oral agents, such as eltrombopag and immunosuppressants, were chosen for ease of administration and expected adherence (P < .001). Physicians chose rituximab in patients with lower expected adherence (P = .017). Treatment choice showed some physician and treatment center bias. This study illustrates the complexity and many factors involved in decision-making in selecting second-line ITP treatments, given the absence of comparative trials. It highlights shared decision-making and the need for well-conducted, comparative effectiveness studies to allow for informed discussion between patients and clinicians

Exploring the dynamics of compliance with community penalties

In this paper, we examine how compliance with community penalties has been theorized hitherto and seek to develop a new dynamic model of compliance with community penalties. This new model is developed by exploring some of the interfaces between existing criminological and socio-legal work on compliance. The first part of the paper examines the possible definitions and dimensions of compliance with community supervision. Secondly, we examine existing work on explanations of compliance with community penalties, supplementing this by drawing on recent socio-legal scholarship on private individuals’ compliance with tax regimes. In the third part of the paper, we propose a dynamic model of compliance, based on the integration of these two related analyses. Finally, we consider some of the implications of our model for policy and practice concerning community penalties, suggesting the need to move beyond approaches which, we argue, suffer from compliance myopia; that is, a short-sighted and narrowly focused view of the issues