Budgetary policies and available actions: a generalisation of decision rules for allocation and research decisions

The allocation problem in health care can be characterised as a mathematical programming problem but attempts to incorporate uncertainty in costs and effect have suffered from important limitations. A two stage stochastic mathematical programming formulation is developed and applied to a numerical example to explore and demonstrate the implications of this more general and comprehensive approach. The solution to the allocation problem for different budgets, budgetary policies, and available actions are then demonstrated. This analysis is used to evaluate different budgetary policies and examine the adequacy of standard decision rules in cost-effectiveness analysis. The research decision is then considered alongside the allocation problem. This more general formulation demonstrates that the value of further research depends on: i) the budgetary policy in place; ii) the realisations revealed during the budget period; iii) remedial actions that may be available; and iv) variability in parameters values.

Colour depth-from-defocus incorporating experimental point spread function measurements

Depth-From-Defocus (DFD) is a monocular computer vision technique for creating depth maps from two images taken on the same optical axis with different intrinsic camera parameters. A pre-processing stage for optimally converting colour images to monochrome using a linear combination of the colour planes has been shown to improve the accuracy of the depth map. It was found that the first component formed using Principal Component Analysis (PCA) and a technique to maximise the signal-to-noise ratio (SNR) performed better than using an equal weighting of the colour planes with an additive noise model. When the noise is non-isotropic the Mean Square Error (MSE) of the depth map by maximising the SNR was improved by 7.8 times compared to an equal weighting and 1.9 compared to PCA. The fractal dimension (FD) of a monochrome image gives a measure of its roughness and an algorithm was devised to maximise its FD through colour mixing. The formulation using a fractional Brownian motion (mm) model reduced the SNR and thus produced depth maps that were less accurate than using PCA or an equal weighting. An active DFD algorithm to reduce the image overlap problem has been developed, called Localisation through Colour Mixing (LCM), that uses a projected colour pattern. Simulation results showed that LCM produces a MSE 9.4 times lower than equal weighting and 2.2 times lower than PCA. The Point Spread Function (PSF) of a camera system models how a point source of light is imaged. For depth maps to be accurately created using DFD a high-precision PSF must be known. Improvements to a sub-sampled, knife-edge based technique are presented that account for non-uniform illumination of the light box and this reduced the MSE by 25%. The Generalised Gaussian is presented as a model of the PSF and shown to be up to 16 times better than the conventional models of the Gaussian and pillbox

Kinematics and neuromuscular recruitment during vertical treadmill exercise

The vertical treadmill (VertiRun) is an unresearched, partial weight-bearing exercise mode for lower limb rehabilitation. The user undertakes a “running-like” action whilst body weight is supported by a bench and the limb is drawn downwards against overhanging resistance cables on a vertically hung nonmotorised treadmill. This study sought to describe the kinematics and neuromuscular recruitment during VertiRun exercise in the supine, 40°, and 70° postures. Twenty-one healthy male participants (age, 25±7 years; stature, 1.79±0.07 m; body mass, 77.7±8.8 kg) volunteered for sagittal plane kinematic analysis of the ankle, knee and hip and electromyography of lower limb musculature in all three postures. Results indicated similar kinematic and neuromuscular profiles in the 40° and 70° postures which differed from the supine. Regardless of posture, a basic movement pattern was observed where the hamstrings and gastrocnemius muscles were active to extend the hip, flex the knee, plantarflex the ankle and draw the leg down the treadmill belt in the contact phase. The rectus femoris and tibialis anterior were active to flex the hip and knee, and dorsiflex the ankle to draw the leg upwards during the swing phase. The vasti muscles were not active during VertiRun exercise. The VertiRun demonstrated similar kinematic and neuro-muscular patterns to overground gait, allows workload progression based on effort and posture changes, and is a low-impact exercise mode that could maintain physical fitness without loading injured tissues. This study suggests that the VertiRun could supplement rehabilitation programmes for lower-limb injuries

Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

BackgroundInternal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsIn this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing.FindingsBetween Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials.FundingAstellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro

Human polyomaviruses in children undergoing transplantation, United States, 2008-2010

Immunocompromised patients are at risk for disease caused by infection by some polyomaviruses. To define the prevalence of polyomaviruses in children undergoing transplantation, we collected samples from a longitudinal cohort and tested for the 9 known human polyomaviruses. All were detected; several were present in previously unreported specimen types

Challenges Associated with Estimating Utility in Wet Age-Related Macular Degeneration : A Novel Regression Analysis to Capture the Bilateral Nature of the Disease

INTRODUCTION: The estimation of utility values for the economic evaluation of therapies for wet age-related macular degeneration (AMD) is a particular challenge. Previous economic models in wet AMD have been criticized for failing to capture the bilateral nature of wet AMD by modelling visual acuity (VA) and utility values associated with the better-seeing eye only. METHODS: Here we present a de novo regression analysis using generalized estimating equations (GEE) applied to a previous dataset of time trade-off (TTO)-derived utility values from a sample of the UK population that wore contact lenses to simulate visual deterioration in wet AMD. This analysis allows utility values to be estimated as a function of VA in both the better-seeing eye (BSE) and worse-seeing eye (WSE). RESULTS: VAs in both the BSE and WSE were found to be statistically significant (p < 0.05) when regressed separately. When included without an interaction term, only the coefficient for VA in the BSE was significant (p = 0.04), but when an interaction term between VA in the BSE and WSE was included, only the constant term (mean TTO utility value) was significant, potentially a result of the collinearity between the VA of the two eyes. The lack of both formal model fit statistics from the GEE approach and theoretical knowledge to support the superiority of one model over another make it difficult to select the best model. CONCLUSION: Limitations of this analysis arise from the potential influence of collinearity between the VA of both eyes, and the use of contact lenses to reflect VA states to obtain the original dataset. Whilst further research is required to elicit more accurate utility values for wet AMD, this novel regression analysis provides a possible source of utility values to allow future economic models to capture the quality of life impact of changes in VA in both eyes. FUNDING: Novartis Pharmaceuticals UK Limited

Development of a transparent interactive decision interrogator to facilitate the decision-making process in health care.

BACKGROUND: Decisions about the use of new technologies in health care are often based on complex economic models. Decision makers frequently make informal judgments about evidence, uncertainty, and the assumptions that underpin these models. OBJECTIVES: Transparent interactive decision interrogator (TIDI) facilitates more formal critique of decision models by decision makers such as members of appraisal committees of the National Institute for Health and Clinical Excellence in the UK. By allowing them to run advanced statistical models under different scenarios in real time, TIDI can make the decision process more efficient and transparent, while avoiding limitations on pre-prepared analysis. METHODS: TIDI, programmed in Visual Basic for applications within Excel, provides an interface for controlling all components of a decision model developed in the appropriate software (e.g., meta-analysis in WinBUGS and the decision model in R) by linking software packages using RExcel and R2WinBUGS. TIDI's graphical controls allow the user to modify assumptions and to run the decision model, and results are returned to an Excel spreadsheet. A tool displaying tornado plots helps to evaluate the influence of individual parameters on the model outcomes, and an interactive meta-analysis module allows the user to select any combination of available studies, explore the impact of bias adjustment, and view results using forest plots. We demonstrate TIDI using an example of a decision model in antenatal care. CONCLUSION: Use of TIDI during the NICE appraisal of tumor necrosis factor-alpha inhibitors (in psoriatic arthritis) successfully demonstrated its ability to facilitate critiques of the decision models by decision makers

The Salmonella Mutagenicity Assay: The Stethoscope of Genetic Toxicology for the 21st Century

Objectives: According to the 2007 National Research Council report Toxicology for the Twenty-First Century, modern methods (e.g., "omics," in vitro assays, high-throughput testing, computational methods) will lead to the emergence of a new approach to toxicology. The Salmonella mammalian microsome mutagenicity assay has been central to the field of genetic toxicology since the 1970s. Here we document the paradigm shifts engendered by the assay, the validation and applications of the assay, and how the assay is a model for future in vitro toxicology assays. Data sources: We searched PubMed, Scopus, and Web of Knowledge using key words relevant to the Salmonella assay and additional genotoxicity assays. Data extraction: We merged the citations, removing duplicates, and categorized the papers by year and topic. Data synthesis: The Salmonella assay led to two paradigm shifts: that some carcinogens were mutagens and that some environmental samples (e.g., air, water, soil, food, combustion emissions) were mutagenic. Although there are > 10,000 publications on the Salmonella assay, covering tens of thousands of agents, data on even more agents probably exist in unpublished form, largely as proprietary studies by industry. The Salmonella assay is a model for the development of 21st century in vitro toxicology assays in terms of the establishment of standard procedures, ability to test various agents, transferability across laboratories, validation and testing, and structure-activity analysis. Conclusions: Similar to a stethoscope as a first-line, inexpensive tool in medicine, the Salmonella assay can serve a similar, indispensable role in the foreseeable future of 21st century toxicology