A New Approach to Environmental Valuation for New Zealand

New Zealand’s Resource Management Act is frequently criticised for the costs and delays it imposes on activities, but less attention is given to the consistency of values it applies to environmental effects through its decisions. The wide variety of parties who exercise decision roles under the act lack guidance on the economic value of the environment, and non-market valuation studies are too costly to be widely used and too few and varied to infer reliable generic values. Drawing on experience in estimating the public value of safety improvements, this article proposes an alternative approach that measures people’s aversion to the risk of environmental impacts of different scales and severity which could yield values sufficiently generic to be widely used, and outlines its uses both within and beyond the RMA applications

Adalimumab in Juvenile Idiopathic Arthritis–Associated Uveitis:5-Year Follow-up of the Bristol Participants of the SYCAMORE Trial

PURPOSE:To determine longer-term outcomes of participants enrolled from a single center in the SYCAMORE trial, a randomized placebo-controlled trial of adalimumab versus placebo in children with juvenile idiopathic arthritis-associated uveitis (JIA-U) uncontrolled on methotrexate. DESIGN:Retrospective interventional case series. METHODS:Medical records of all 28 SYCAMORE participants recruited at the Bristol Eye Hospital were reviewed at approximately 3-monthly intervals up to 5 years from the trial randomization date. Uveitis activity, treatment course, visual outcomes, ocular complications and adverse events were recorded. Data are presented using summary statistics. RESULTS:Following withdrawal of the investigational medicinal product (IMP), 25 of the 28 participants were started on adalimumab for active juvenile idiopathic arthritis-associated uveitis (JIA-U). Of the 12 participants in the active treatment arm of the SYCAMORE study, 11 (92%) were restarted on adalimumab after withdrawal of the IMP for active JIA-U (median time to flare 188 days (range 42-413)). Two participants stopped adalimumab for uncontrolled JIA-U. One participant had a reduction in vision to 0.3 due to cataract. Mean visual acuity for the remaining 27 participants was -0.04 (right eye) and -0.05 (left eye). CONCLUSIONS:Drug-induced remission of JIA-U did not persist when adalimumab was withdrawn after 1-2 years treatment. Adalimumab was well tolerated and visual acuity outcomes were excellent

Population Pharmacokinetic and Pharmacodynamic Modeling for Assessing Risk of Bisphosphonate-related Osteonecrosis of the Jaw

Objective: We hypothesized that patients with bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) accumulate higher levels of BP in bone than those without BRONJ. Study Design: Using the Pmetrics package and published data, we designed a population pharmacokinetic model of pamidronate concentration in plasma and bone and derived a toxic bone BP threshold of 0.2 mmol/L. With the model, and using patient individual BP duration and bone mineral content estimated from lean body weight, we calculated bone BP levels in 153 subjects. Results: Mean bone BP in 69 BRONJ cases was higher than in 84 controls (0.20 vs 0.10 mmol/L, P \u3c 0.001), consistent with the toxic bone threshold of 0.2 mmol/L. BRONJ was also associated with longer duration BP therapy (5.3 vs 2.7 years, P \u3c 0.001), older age (76 vs 70 years, P \u3c 0.001), and Asian race (49% vs 14%, P \u3c 0.001). Conclusions: Our model accurately discriminated BRONJ cases from controls among patients on BP therapy. © 2013 Elsevier Inc

A phase II trial protocol of Tocilizumab in anti-TNF refractory patients with JIA-associated uveitis (the APTITUDE trial).

BackgroundJuvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of intraocular inflammation (uveitis). In the initial stages of mild-moderate inflammation uveitis is asymptomatic. Most children with mild-moderate uveitis are managed on topical steroid drops with or without systemic methotrexate (MTX). When children with moderate-severe uveitis are refractory to MTX, monoclonal anti-tumour necrosis factor agents have been trialled, interim analysis data showed positive results. However, several children with severe recalcitrant disease or non-responsive to anti-tumour necrosis factor agents remain and are at greater risk of significant ocular complications and visual loss. Further evidence of alternative therapies is needed with evidence of a potential role of anti-interleukin-6 agents in the management of severe refractory uveitis.MethodsThe trial will be conducted following a two-stage Simon design. The trial will register at least 22 patients aged 2 to 18 years with active JIA-associated uveitis, who have taken MTX for at least 12 weeks and have failed an anti-TNF agent. It will take place in 7 centres across the UK. All participants will be treated for 6 months, with follow up of 9 months from registration. Participants will receive a stable dose of MTX and those weighing ≥30 kg will be dosed with 162 mg of Tocilizumab every 2 weeks and participants weighing DiscussionThis is a novel adaptive design study of subcutaneous IL-6 inhibition in anti-TNF refractory JIA associated uveitis which will be able to determine if further research should be conducted. This is the first trial to look at ophthalmology outcomes in the efficacy of Tocilizumab in uveitis.This is the first paediatric clinical trial to assess the clinical effectiveness and safety of tocilizumab with MTX in JIA associated uveitis.Trials registrationThe Trial is registered on the ISRCTN registry (ISRCTN95363507) on the 10/06/2015 and EU Clinical Trials Register on the 03/07/2015 (EudraCT Number: 2015-001323-23)

Using genetic algorithms to generate test sequences for complex timed systems

The generation of test data for state based specifications is a computationally expensive process. This problem is magnified if we consider that time con- straints have to be taken into account to govern the transitions of the studied system. The main goal of this paper is to introduce a complete methodology, sup- ported by tools, that addresses this issue by represent- ing the test data generation problem as an optimisa- tion problem. We use heuristics to generate test cases. In order to assess the suitability of our approach we consider two different case studies: a communication protocol and the scientific application BIPS3D. We give details concerning how the test case generation problem can be presented as a search problem and automated. Genetic algorithms (GAs) and random search are used to generate test data and evaluate the approach. GAs outperform random search and seem to scale well as the problem size increases. It is worth to mention that we use a very simple fitness function that can be eas- ily adapted to be used with other evolutionary search techniques

The social value of a QALY : raising the bar or barring the raise?

Background: Since the inception of the National Institute for Health and Clinical Excellence (NICE) in England, there have been questions about the empirical basis for the cost-per-QALY threshold used by NICE and whether QALYs gained by different beneficiaries of health care should be weighted equally. The Social Value of a QALY (SVQ) project, reported in this paper, was commissioned to address these two questions. The results of SVQ were released during a time of considerable debate about the NICE threshold, and authors with differing perspectives have drawn on the SVQ results to support their cases. As these discussions continue, and given the selective use of results by those involved, it is important, therefore, not only to present a summary overview of SVQ, but also for those who conducted the research to contribute to the debate as to its implications for NICE. Discussion: The issue of the threshold was addressed in two ways: first, by combining, via a set of models, the current UK Value of a Prevented Fatality (used in transport policy) with data on fatality age, life expectancy and age-related quality of life; and, second, via a survey designed to test the feasibility of combining respondents’ answers to willingness to pay and health state utility questions to arrive at values of a QALY. Modelling resulted in values of £10,000-£70,000 per QALY. Via survey research, most methods of aggregating the data resulted in values of a QALY of £18,000-£40,000, although others resulted in implausibly high values. An additional survey, addressing the issue of weighting QALYs, used two methods, one indicating that QALYs should not be weighted and the other that greater weight could be given to QALYs gained by some groups. Summary: Although we conducted only a feasibility study and a modelling exercise, neither present compelling evidence for moving the NICE threshold up or down. Some preliminary evidence would indicate it could be moved up for some types of QALY and down for others. While many members of the public appear to be open to the possibility of using somewhat different QALY weights for different groups of beneficiaries, we do not yet have any secure evidence base for introducing such a system

Tocilizumab in patients with anti-TNF refractory juvenile idiopathic arthritis-associated uveitis (APTITUDE): a multicentre, single-arm, phase 2 trial

Background:Uveitis associated with juvenile idiopathic arthritis is a cause of major ocular morbidity. A substantial proportion of children are refractory to systemic methotrexate and TNF inhibitors. Our aim was to study the safety and efficacy of tocilizumab in children with juvenile idiopathic arthritis-associated uveitis refractory to both methotrexate and TNF inhibitors. Methods:This multicentre, single-arm, phase 2 trial was done following a Simon's two-stage design at seven tertiary hospital sites in the UK. Patients aged 2-18 years with active juvenile idiopathic arthritis-associated uveitis were eligible. All patients had been on a stable dose of methotrexate for at least 12 weeks and had not responded to treatment with a TNF inhibitor. Patients weighing 30 kg or more were treated with 162 mg subcutaneous tocilizumab every 2 weeks for 24 weeks, and participants weighing less than 30 kg were treated with 162 mg every 3 weeks for 24 weeks. The primary outcome was treatment response defined as a two-step decrease, or decrease to zero, from baseline in the level of inflammation (anterior chamber cells) at week 12, per the standardisation of uveitis nomenclature criteria. A phase 3 trial would be justified if more than seven patients responded to treatment. An interim analysis was planned to assess whether the trial would be stopped for futility, with futility defined as two or fewer treatment responses among ten participants. Adverse events were collected up to 30 calendar days after treatment cessation. The primary analysis was done in the intention-to-treat population and the safety analysis was done in all patients who started the treatment. This trial is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN95363507) and EU Clinical Trials Register (EudraCT 2015-001323-23). Findings:22 participants were enrolled to the trial between Dec 3, 2015, and March 9, 2018, and 21 participants received treatment. One participant was found to be ineligible immediately after enrolment and was therefore withdrawn. Seven of 21 (median unbiased estimate of proportion 34% [95% CI 25-57]) responded to treatment (p=0·11). Safety results were consistent with the known safety profile of tocilizumab. Interpretation:The primary endpoint was not met, and thus the results do not support a phase 3 trial of tocilizumab in patients with juvenile idiopathic arthritis-associated uveitis. Importantly, data on the use of tocilizumab in clinical practice is now captured in national registries. Despite this trial not meeting the threshold required to justify a larger phase 3 trial, several patients responded to treatment; as such, tocilzumab might still be a therapeutic option in some children with uveitis refractory to anti-TNF drugs, given the absence of other treatment options. Funding:Versus Arthritis and the National Institute for Health Research Clinical Research Network: Children

Low Dose Organochlorine Pesticides and Polychlorinated Biphenyls Predict Obesity, Dyslipidemia, and Insulin Resistance among People Free of Diabetes

There is emerging evidence that background exposure to persistent organic pollutants (POPs) are important in the development of conditions predisposing to diabetes as well as of type 2 diabetes itself. We recently reported that low dose POPs predicted incident type 2 diabetes in a nested case-control study. The current study examined if low dose POPs predicted future adiposity, dyslipidemia, and insulin resistance among controls without diabetes in that study.The 90 controls were diabetes-free during 20 years follow-up. They were a stratified random sample, enriched with overweight and obese persons. POPs measured in 1987-88 (year 2) sera included 8 organochlorine (OC) pesticides, 22 polychlorinated biphenyls (PCBs), and 1 polybrominated biphenyl (PBB). Body mass index (BMI), triglycerides, HDL-cholesterol, LDL-cholesterol, and homeostasis model assessment value for insulin resistance (HOMA-IR) were study outcomes at 2005-06 (year 20). The evolution of study outcomes during 18 years by categories of serum concentrations of POPs at year 2 was evaluated by adjusting for the baseline values of outcomes plus potential confounders. Parallel to prediction of type 2 diabetes, many statistically significant associations of POPs with dysmetabolic conditions appeared at low dose, forming inverted U-shaped dose-response relations. Among OC pesticides, p,p'-DDE most consistently predicted higher BMI, triglycerides, and HOMA-IR and lower HDL-cholesterol at year 20 after adjusting for baseline values. Oxychlordane, trans-nonachlor, and hexachlorobenzene also significantly predicted higher triglycerides. Persistent PCBs with ≥7 chlorides predicted higher BMI, triglycerides, and HOMA-IR and lower HDL-cholesterol at year 20 with similar dose-response curves.Simultaneous exposure to various POPs in the general population may contribute to development of obesity, dyslipidemia, and insulin resistance, common precursors of type 2 diabetes and cardiovascular diseases. Although obesity is a primary cause of these metabolic abnormalities, POPs exposure may contribute to excess adiposity and other features of dysmetabolism