Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT

Abstract Background Children with juvenile idiopathic arthritis (JIA) are at risk of uveitis. The role of adalimumab (Humira®; AbbVie Inc., Ludwigshafen, Germany) in the management of uveitis in children needs to be determined. Objective To compare the efficacy, safety and cost-effectiveness of adalimumab in combination with methotrexate (MTX) versus placebo with MTX alone, with regard to controlling disease activity in refractory uveitis associated with JIA. Design This was a randomised (applying a ratio of 2 : 1 in favour of adalimumab), double-blind, placebo-controlled, multicentre parallel-group trial with an integrated economic evaluation. A central web-based system used computer-generated tables to allocate treatments. A cost–utility analysis based on visual acuity was conducted and a 10-year extrapolation by Markov modelling was also carried out. Setting The setting was tertiary care centres throughout the UK. Participants Patients aged 2–18 years inclusive, with persistently active JIA-associated uveitis (despite optimised MTX treatment for at least 12 weeks). Interventions All participants received a stable dose of MTX and either adalimumab (20 mg/0.8 ml for patients weighing < 30 kg or 40 mg/0.8 ml for patients weighing ≥ 30 kg by subcutaneous injection every 2 weeks based on body weight) or a placebo (0.8 ml as appropriate according to body weight by subcutaneous injection every 2 weeks) for up to 18 months. A follow-up appointment was arranged at 6 months. Main outcome measures Primary outcome – time to treatment failure [multicomponent score as defined by set criteria based on the Standardisation of Uveitis Nomenclature (SUN) criteria]. Economic outcome – incremental cost per quality-adjusted life-year (QALY) gained from the perspective of the NHS in England and Personal Social Services providers. Full details of secondary outcomes are provided in the study protocol. Results A total of 90 participants were randomised (adalimumab, n = 60; placebo, n = 30). There were 14 (23%) treatment failures in the adalimumab group and 17 (57%) in the placebo group. The analysis of the data from the double-blind phase of the trial showed that the hazard risk (HR) of treatment failure was significantly reduced, by 75%, for participants in the adalimumab group (HR 0.25, 95% confidence interval 0.12 to 0.51; p < 0.0001 from log-rank test). The cost-effectiveness of adalimumab plus MTX was £129,025 per QALY gained. Adalimumab-treated participants had a much higher incidence of adverse and serious adverse events. Conclusions Adalimumab in combination with MTX is safe and effective in the management of JIA-associated uveitis. However, the likelihood of cost-effectiveness is < 1% at the £30,000-per-QALY threshold. Future work A clinical trial is required to define the most effective time to stop therapy. Prognostic biomarkers of early and complete response should also be identified

Cost-effectiveness analysis of adalimumab for the treatment of uveitis associated with Juvenile Idiopathic Arthritis

Purpose To investigate the cost effectiveness of adalimumab in combination with methotrexate, compared with methotrexate alone, for the management of uveitis associated with juvenile idiopathic arthritis (JIA). Design A cost-utility analysis based on a clinical trial and decision analytic model. Participants Children and adolescents 2 to 18 years of age with persistently active uveitis associated with JIA, despite optimized methotrexate treatment for at least 12 weeks. Methods The SYCAMORE (Randomised controlled trial of the clinical effectiveness, SafetY and Cost effectiveness of Adalimumab in combination with MethOtRExate for the treatment of juvenile idiopathic arthritis associated uveitis) trial (identifier, ISRCTN10065623) of methotrexate (up to 25 mg weekly) with or without fortnightly administered adalimumab (20 or 40 mg, according to body weight) provided data on resource use (based on patient self-report and electronic records) and health utilities (from the Health Utilities Index questionnaire). Surgical event rates and long-term outcomes were based on data from a 10-year longitudinal cohort. A Markov model was used to extrapolate the effects of treatment based on visual impairment. Main Outcome Measures Medical costs to the National Health Service in the United Kingdom, utility of defined health states, quality-adjusted life-years (QALYs), and incremental cost per QALY. Results Adalimumab in combination with methotrexate resulted in additional costs of £39 316, with a 0.30 QALY gain compared with methotrexate alone, resulting in an incremental cost-effectiveness ratio of £129 025 per QALY gained. The probability of cost effectiveness at a threshold of £30 000 per QALY was less than 1%. Based on a threshold analysis, a price reduction of 84% would be necessary for adalimumab to be cost effective. Conclusions Adalimumab is clinically effective in uveitis associated with JIA; however, its cost effectiveness is not demonstrated compared with methotrexate alone in the United Kingdom setting

Linking world bank development indicators and outcomes of congenital heart surgery in low-income and middle-income countries: Retrospective analysis of quality improvement data

Objective Many low-income and middle-income countries (LMICs) struggle to provide the health services investment required for life-saving congenital heart disease (CHD) surgery. We explored associations between risk-adjusted CHD surgical mortality from 17 LMICs and global development indices to identify patterns that might inform investment strategies. Design Retrospective analysis: country-specific standardised mortality ratios were graphed against global development indices reflective of wealth and healthcare investment. Spearman correlation coefficients were calculated. Setting and participants The International Quality Improvement Collaborative (IQIC) keeps a volunteer registry of outcomes of CHD surgery programmes in low-resource settings. Inclusion in the IQIC is voluntary enrolment by hospital sites. Patients in the registry underwent congenital heart surgery. Sites that actively participated in IQIC in 2013, 2014 or 2015 and passed a 10% data audit were asked for permission to share data for this study. 31 sites in 17 countries are included. Outcome measures In-hospital mortality: standardised mortality ratios were calculated. Risk adjustment for in-hospital mortality uses the Risk Adjustment for Congenital Heart Surgery method, a model including surgical risk category, age group, prematurity, presence of a major non-cardiac structural anomaly and multiple congenital heart procedures during admission. Results The IQIC registry includes 24 917 congenital heart surgeries performed in children less than 18 years of age. The overall in-hospital mortality rate was 5.0%. Country-level congenital heart surgery standardised mortality ratios were negatively correlated with gross domestic product (GDP) per capita (r=-0.34, p=0.18), and health expenditure per capita (r=-0.23, p=0.37) and positively correlated with under-five mortality (r=0.60, p=0.01) and undernourishment (r=0.39, p=0.17). Countries with lower development had wider variation in mortality. GDP per capita is a driver of the association between some other measures and mortality. Conclusions Results display a moderate relationship among wealth, healthcare investment and malnutrition, with significant variation, including superior results in many countries with low GDP per capita. These findings provide context and optimism for investment in CHD procedures in low-resource settings. © 2019 BMJ Publishing Group Limited

The embodied becoming of autism and childhood: a storytelling methodology

In this article I explore a methodology of storytelling as a means of bringing together research around autism and childhood in a new way, as a site of the embodied becoming of autism and childhood. Through reflection on an ethnographic story of embodiment, the body is explored as a site of knowledge production that contests its dominantly storied subjectivation as a ‘disordered’ child. Storytelling is used to experiment with a line of flight from the autistic-child-research assemblage into new spaces of potential and possibility where the becomings of bodies within the collision of autism and childhood can be celebrated

Oxygen- and capacity-limited thermal tolerance: blurring ecology and physiology

No abstract available

Why California retailers stop selling tobacco products, and what their customers and employees think about it when they do: case studies

BACKGROUND: In California, some 40, 000 retailers sell tobacco products. Tobacco's ubiquitousness in retail settings normalizes use and cues smoking urges among former smokers and those attempting cessation. Thus, limiting the number of retailers is regarded as key to ending the tobacco epidemic. In the past decade, independent pharmacies and local grocery chains in California and elsewhere have voluntarily abandoned tobacco sales. No previous studies have examined the reasons for this emerging phenomenon. We sought to learn what motivated retailers to discontinue tobacco sales and what employees and customers thought about their decision. METHODS: We conducted case studies of seven California retailers (three grocery stores, four pharmacies) that had voluntarily ceased tobacco sales within the past 7 years. We interviewed owners, managers, and employees, conducted consumer focus groups, unobtrusively observed businesses and the surrounding environment, and examined any media coverage of each retailer's decision. We analyzed data using qualitative content analysis. RESULTS: For independent pharmacies, the only reason given for the decision to end tobacco sales was that tobacco caused disease and death. Grocers listed health among several factors, including regulatory pressures and wanting to be seen as "making a difference." Media coverage of stores' new policies was limited, and only three retailers alerted customers. Management reported few or no customer complaints and supportive or indifferent employees. Pharmacy employees were pleased to no longer be selling a deadly product. Grocery store management saw the decision to end tobacco sales as enhancing the stores' image and consistent with their inventory of healthy foods. Focus group participants (smokers and nonsmokers) were largely unaware that retailers had stopped selling tobacco; however, almost all supported the decision, viewing it as promoting public health. Many said knowing this made them more likely to shop at the store. Most thought that advertising the store's policy was essential to generate good public relations and tobacco norm changes. CONCLUSIONS: Voluntary retailer abandonment of tobacco sales both reflects and extends social norm changes that have problematized tobacco in California. Our findings suggest that such voluntary initiatives by retailers are welcomed by consumers and should be publicized, enhancing public health efforts

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery