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Malaria control is difficult where there is intense year-round transmission of multiple plasmodium species, such as in Papua New Guinea.Between April 2005 and July 2007, we conducted an open-label, randomized, parallel-group study of conventional chloroquine-sulfadoxine-pyrimethamine and artesunate-sulfadoxine-pyrimethamine, dihydroartemisinin-piperaquine, and artemether-lumefantrine in children in Papua New Guinea 0.5 to 5 years of age who had falciparum or vivax malaria. The primary end point was the rate of adequate clinical and parasitologic response at day 42 after the start of treatment with regard to Plasmodium falciparum, after correction for reinfections identified through polymerase-chain-reaction (PCR) genotyping of polymorphic loci in parasite DNA. Secondary end points included the rate of adequate clinical and parasitologic response at day 42 with regard to P. vivax without correction through PCR genotyping.Of 2802 febrile children screened, 482 with falciparum malaria and 195 with vivax malaria were included. The highest rate of adequate clinical and parasitologic response for P. falciparum was in the artemether-lumefantrine group (95.2%), as compared with 81.5% in the chloroquine-sulfadoxine-pyrimethamine group (P=0.003), 85.4% in the artesunate-sulfadoxine-pyrimethamine group (P=0.02), and 88.0% in the dihydroartemisinin-piperaquine group (P=0.06). The rate of adequate clinical and parasitologic response for P. vivax in the dihydroartemisinin-piperaquine group (69.4%) was more than twice that in each of the other three treatment groups. The in vitro chloroquine and piperaquine levels that inhibited growth of local P. falciparum isolates by 50% correlated significantly (P0.001). Rash occurred more often with artesunate-sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine than with chloroquine-sulfadoxine-pyrimethamine (P=0.004 for both comparisons).The most effective regimens were artemether-lumefantrine against P. falciparum and dihydroartemisinin-piperaquine against P. vivax. The relatively high rate of treatment failure with dihydroartemisinin-piperaquine against P. falciparum may reflect cross-resistance between chloroquine and piperaquine. (Australian New Zealand Clinical Trials Registry number, ACTRN12605000550606.)

BackgroundHome oxygen therapy (HOT) is commonly used for patients with severe chronic heart failure (CHF) who have intractable breathlessness. There is no trial evidence to support its use.ObjectivesTo detect whether or not there was a quality-of-life benefit from HOT given as long-term oxygen therapy (LTOT) for at least 15 hours per day in the home, including overnight hours, compared with best medical therapy (BMT) in patients with severely symptomatic CHF.DesignA pragmatic, two-arm, randomised controlled trial recruiting patients with severe CHF. It included a linked qualitative substudy to assess the views of patients using home oxygen, and a free-standing substudy to assess the haemodynamic effects of acute oxygen administration.SettingHeart failure outpatient clinics in hospital or the community, in a range of urban and rural settings.ParticipantsPatients had to have heart failure from any aetiology, New York Heart Association (NYHA) class III/IV symptoms, at least moderate left ventricular systolic dysfunction, and be receiving maximally tolerated medical management. Patients were excluded if they had had a cardiac resynchronisation therapy device implanted within the past 3 months, chronic obstructive pulmonary disease fulfilling the criteria for LTOT or malignant disease that would impair survival or were using a device or medication that would impede their ability to use LTOT.InterventionsPatients received BMT and were randomised (unblinded) to open-label LTOT, prescribed for 15 hours per day including overnight hours, or no oxygen therapy.Main outcome measuresThe primary end point was quality of life as measured by the Minnesota Living with Heart Failure (MLwHF) questionnaire score at 6 months. Secondary outcomes included assessing the effect of LTOT on patient symptoms and disease severity, and assessing its acceptability to patients and carers.ResultsBetween April 2012 and February 2014, 114 patients were randomised to receive either LTOT or BMT. The mean age was 72.3 years [standard deviation (SD) 11.3 years] and 70% were male. Ischaemic heart disease was the cause of heart failure in 84%; 95% were in NYHA class III; the mean left ventricular ejection fraction was 27.8%; and the median N-terminal pro-B-type natriuretic hormone was 2203 ng/l. The primary analysis used a covariance pattern mixed model which included patients only if they provided data for all baseline covariates adjusted for in the model and outcome data for at least one post-randomisation time point (n = 102: intervention,n = 51; control,n = 51). There was no difference in the MLwHF questionnaire score at 6 months between the two arms [at baseline the mean score was 54.0 (SD 18.4) for LTOT and 54.0 (SD 17.9) for BMT; at 6 months the mean score was 48.1 (SD 18.5) for LTOT and 49.0 (SD 20.2) for BMT; adjusted mean difference –0.10, 95% confidence interval (CI) –6.88 to 6.69;p = 0.98]. At 3 months, the adjusted mean MLwHF questionnaire score was lower in the LTOT group (–5.47, 95% CI –10.54 to –0.41;p = 0.03) and breathlessness scores improved, although the effect did not persist to 6 months. There was no effect of LTOT on any secondary measure. There was a greater number of deaths in the BMT arm (n = 12 vs.n = 6). Adherence was poor, with only 11% of patients reporting using the oxygen as prescribed.ConclusionsAlthough the study was significantly underpowered, HOT prescribed for 15 hours per day and subsequently used for a mean of 5.4 hours per day has no impact on quality of life as measured by the MLwHF questionnaire score at 6 months. Suggestions for future research include (1) a trial of patients with severe heart failure randomised to have emergency oxygen supply in the house, supplied by cylinders rather than an oxygen concentrator, powered to detect a reduction in admissions to hospital, and (2) a study of bed-bound patients with heart failure who are in the last few weeks of life, powered to detect changes in symptom severity.Trial registrationCurrent Controlled Trials ISRCTN60260702.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 19, No. 75. See the NIHR Journals Library website for further project information.

A simple extension of standard meta-analysis can provide quantitative estimates of the potential health benefits of further research and of implementing the findings of existing research, which can help inform research prioritisation and efforts to change clinical practice

Objectives To establish whether evidence about the effectiveness of a health care intervention is sufficient to justify the use of the intervention in practice and show how value of information (VOI) analysis can be used to place a value on the need for additional evidence and inform research prioritization decisions. Study Design and Setting Meta-analysis provides an estimate of the effect of an intervention with uncertainty. VOI analysis determines the adverse health consequences of not resolving this uncertainty. A case study examining the evidence before the high profile trial of Corticosteroid Randomisation After Significant Head injury (CRASH) shows the consequences on patient outcomes if this trial had not been successfully funded. Results The consequences of uncertainty before CRASH were high at 40 deaths and 1,067 years of full health per annum. VOI analysis indicates that CRASH was worthwhile and the UK National Health Service would have had to spend an additional £205 million elsewhere to generate health benefits similar to CRASH. Conclusions VOI analysis can be integrated with the results of meta-analysis to help inform whether a particular research proposal is potentially worthwhile and whether it should be prioritized over other research topics that could be commissioned with the same resources

This addendum paper presents additional material on an output feedback eigenstructure assignment approach derived in Clarke et al. (2003). There, a two-stage process is followed in which a subset of the desired eigenvectors is assigned in the first stage, followed by a dual set in the second stage. Depending upon the number of available degrees of freedom, and the manner in which they are distributed between the stages, it is possible that not all are used. A technique to recover these unused degrees of freedom in a final and independent stage is presented here. The technique, known as retro-assignment, is illustrated using an extension to the original numerical example.

This paper presents a new method of output feedback eigenstructure assignment. A new, reduced orthogonality condition is derived which is less restrictive on the design degrees of freedom than others in the literature. From this a novel, general formulation for the gain matrix is admitted which utilizes a two stage design process. In the first stage, a subset of desired eigenvectors is assigned, either left or right. In the second stage, a dual set is assigned which adheres to the necessary and sufficient conditions for output feedback eigenstructure assignment proved earlier in the paper. A numerical example is presented to illustrate the whole procedure.

A novel eigenstructure assignment method is presented which trades exact closed loop eigenvalue location against an improvement in the associated closed loop eigenvector match against membership of a desired set via either constrained or unconstrained optimizations. The polynomial approach removes the dependence of the cost functions on the closed loop eigenvector by describing the allowable desired eigenvector subspace as a function of the eigenvalue location. A fixed-wing aircraft example is used to demonstrates the benefit of eigenvalue trade-off over basic projection.

Existing work, to generate an eigenstructure suitable for achieving good short-term attitude command response in a generic single rotor helicopter, is extended here to provide eigenvectors appropriate to the (more complex) rate command case. The generated eigenstructure is, like the original, consistent with the physical relationships between the state variables. It achieves appropriate mode decoupling, and translates exactly into ideal transfer functions for use with a variety of control design methodologies. A simple numerical example is provided to show that the behaviour of a system with this eigenstructure displays the expected response.

Objectives: The Medical Outcomes Study HIV Health Survey (MOS-HIV) is frequently used in HIV clinical trials; however, scores generated from the MOS-HIV are not suited for cost-effectiveness analyses as they do not assign utility values to health states. Our objective was to estimate and externally validate several mapping algorithms to predict Health Utilities Index Mark 3 (HUI3) and EQ-5D-3L utility values from the MOS-HIV. Methods: We developed and validated mapping algorithms using data from two HIV clinical trials. Data from the first trial (n = 367) formed the estimation data set for the HUI3 (4,610 observations) and EQ-5D-3L (4,662 observations) mapping algorithms; data from the second trial (n = 168) formed the HUI3 (1,135 observations) and EQ-5D-3L (1,152 observations) external validation data set. We compared ordinary least squares (OLS) models of increasing complexity with the more flexible two-part, beta regression, and finite mixture models. We assessed model performance using mean absolute error (MAE) and mean squared error (MSE). Results: The OLS model that used MOS-HIV dimension scores along with squared terms gave the best HUI3 predictions (mean observed 0.84; mean predicted 0.80; MAE 0.0961); the finite mixture model gave the best EQ-5D-3L predictions (mean observed 0.90; mean predicted 0.88; MAE 0.0567). All models produced higher prediction errors at the lower end of the HUI3 and EQ-5D-3L score ranges (

Objective To model the social distribution of quality-adjusted life expectancy (QALE) in England by combining survey data on health-related quality of life with administrative data on mortality. Methods Health Survey for England data sets for 2010, 2011, and 2012 were pooled (n = 35,062) and used to model health-related quality of life as a function of sex, age, and socioeconomic status (SES). Office for National Statistics mortality rates were used to construct life tables for age-sex-SES groups. These quality-of-life and length-of-life estimates were then combined to predict QALE as a function of these characteristics. Missing data were imputed, and Monte-Carlo simulation was used to estimate standard errors. Sensitivity analysis was conducted to explore alternative regression models and measures of SES. Results Socioeconomic inequality in QALE at birth was estimated at 11.87 quality-adjusted life-years (QALYs), with a sex difference of 1 QALY. When the socioeconomic-sex subgroups are ranked by QALE, a differential of 10.97 QALYs is found between the most and least healthy quintile groups. This differential can be broken down into a life expectancy difference of 7.28 years and a quality-of-life adjustment of 3.69 years. Conclusions The methods proposed in this article refine simple binary quality-adjustment measures such as the widely used disability-free life expectancy, providing a more accurate picture of overall health inequality in society than has hitherto been available. The predictions also lend themselves well to the task of evaluating the health inequality impact of interventions in the context of cost-effectiveness analysis.

To describe perceived benefits and safety of community water fluoridation (CWF) and investigate factors associated with those perceptions of CWF among respondents to a proprietary survey in the United States.We obtained data from the 2009 HealthStyles survey, a convenience sample of 4,556 respondents. Pearson's chi-squared and logistic regression were used to determine the associations between certain socio-demographic factors and perceptions regarding the safety and health benefits of CWF.The majority of respondents (55.3 percent) strongly agreed/agreed that CWF was safe, while 31.5 percent were neutral, and 13.2 percent disagreed/strongly disagreed. Twenty-seven percent of respondents reported CWF had no health benefit, 57.3 percent reported some benefit, and 15.5 percent reported great benefit. Perceived CWF safety and benefit in the bivariate analyses were associated with gender, age, race/ethnicity, education, marital status, income, sealant knowledge, CWF knowledge, past year dental utilization, and perceived vaccine safety. Respondents with knowledge of CWF (47.9 percent) were more likely to agree that it was safe (69.8 percent) than those who reported no knowledge (41.3 percent). Among respondents who said childhood vaccines were not safe (4.0 percent), almost half disagreed that CWF was safe. Logistic regression results indicated that perceived CWF safety and benefits increased with CWF knowledge, perceived vaccine safety, and income.Although only a minority of the US population perceived CWF as unsafe or providing no benefit to health, perceptions regarding CWF varied by knowledge of CWF and socio-demographic factors. Oral health promotion activities should consider these differing perceptions of CWF among groups to tailor oral health messaging appropriately.

This article is an introduction to distributional cost-effectiveness analysis, a framework for incorporating health inequality impacts into the cost-effectiveness analysis of health sector programs. It starts by discussing why one might want to do this kind of analysis. It then provides a brief discussion of the methods and data requirements for extending cost-effectiveness analysis to model distributions of levels and changes in health within the general population, and to adjust these distributions according to different social value judgments of what constitutes fair and unfair sources of variation in health. Methods for comparing these health distributions are then described, focusing on the use of standard tools from the income inequality literature – in particular, the Atkinson and Kolm indices of relative and absolute inequality – to analyze tradeoffs between the twin policy objectives of improving total health and reducing unfair health inequality.

The concept of power is discussed in the broader health literature and the occupational therapy literature from three perspectives. These are the trait approaches to professionalization, the medical dominance perspective and the view of health care work places as organizations. The results of the review suggest that the power of the profession of occupational therapy is linked to a number of factors. These include its status as an occupation, the fact that the majority of its members are women and the extent to which therapists have knowledge and skills related to working with other disciplines in a changing political climate. While the review enables the type of knowledge and skills which would assist therapists to develop and exercise their power within the health sector to be suggested, the extent to which therapists actually possess the knowledge and skills is unknown due to a lack of research in the area.

Risk-based cleanup goals or preliminary remediation goals (PRGs) are established at hazardous waste sites when contaminant concentrations in air, soil, surface water, or groundwater exceed specified acceptable risk levels. When derived in accordance with the Environmental Protection Agency's risk assessment guidance, the PRG is intended to represent the average contaminant concentration within an exposure unit area that is left on the site following remediation. The PRG, however, frequently has been used inconsistently at Superfund sites with a number of remediation decisions using the PRG as a not-to-exceed concentration (NTEC). Such misapplications could result in overly conservative and unnecessarily costly remedial actions. The PRG should be applied in remedial actions in the same manner in which it was generated. Statistical methods, such as Bower's Confidence Response Goal, and mathematical methods such as "iterative removal of hot spots," are available to assist in the development of NTECs that ensure the average postremediation contaminant concentration is at or below the PRG. These NTECs can provide the risk manager with a more practical cleanup goal. In addition, an acute PRG can be developed to ensure that contaminant concentrations left on-site following remediation are not so high as to pose an acute or short-term health risk if excessive exposure to small areas of the site should occur. A case study demonstrates cost savings of five to ten times associated with the more scientifically sound use of the PRG as a postremediation site average, and development of a separate NTEC and acute PRG based on the methods referenced in this article.

The methods a mother selects to physically care for her young children may subject her to back strain or injury depending on the methods she selects. Little is known about what motivates mothers to select particular child-care methods and equipment. The aim of this qualitative study was to explore the choices mothers of young children make in this area and their experiences using the methods they select. Nine mothers completed a brief questionnaire and participated in a semi-structured interview. Analysis of the data revealed a number of motivating factors that were considered before making a final decision on what method to use. Rarely were issues related to posture and back care considered. Primarily, mothers chose methods based on what was best for the child, without consideration of their own needs. Consideration of the effect of a method on their back was given only when they experienced back strain. Further research is required to investigate the best methods for lifting and handling young children while providing maximum protection for the mothers' backs. Copyright © 2000 Whurr Publishers Ltd.

Exposure of children to lead in the environment was assessed at the Murray Smelter Superfund site using both a deterministic risk assessment approach, the Integrated Exposure Uptake Biokinetic (IEUBK) model, and a probabilistic approach, the Integrated Stochastic Exposure (ISE) model. When site-specific data on lead in environmental media were input as point estimates into the IEUBK model, unacceptable risks were predicted for children living within five of eight study zones. The predicted soil cleanup goal was 550 ppm. Concentration and exposure data were then input into the ISE model as probability distribution functions and a one-dimensional Monte Carlo analysis (ID MCA) was run to predict the expected distribution of exposures and blood lead values. Uncertainty surrounding these predictions was examined in a two-dimensional Monte Carlo analysis (2-D MCA). The ISE model predicted risks that were in the same rank order as those predicted by the IEUBK model, although the probability estimates of exceedin...

The integrated exposure uptake biokinetic (IEUBK) model, recommended for use by the U.S. Environmental Protection Agency at residential Superfund sites to predict potential risks to children from lead exposure and to establish lead remediation levels, requires an interindividual geometric standard deviation (GSDi) as an essential input parameter. The GSDi quantifies the variability of blood lead concentrations for children exposed to similar environmental concentrations of lead. Estimates of potential risks are directly related to the GSDi, and therefore the GSDi directly impacts the scope of remediation at Superfund sites. Site-specific GSDi can be calculated for sites where blood lead and environmental lead have been measured. This paper uses data from blood and environmental lead studies conducted at the Bingham Creek and Sandy, Utah, Superfund sites to calculate GSDi using regression modeling, box modeling, and structural equation modeling. GSDis were calculated using various methods for treating values below the analytical method detection and quantitation limits. Treatment of nonquantifiable blood lead concentrations affected the GSDi more than the statistical method used to calculate the GSDi. For any given treatment, the different statistical methods produced similar GSDis. Because of the uncertainties associated with data in the blood lead studies, we recommend that a range of GSDis be used when analyzing site-specific risks associated with exposure to environmental lead instead of a single estimate. Because the different statistical methods produce similar GSDis, we recommend a simple procedure to calculate site-specific GSDi from a scientifically sound blood and environmental lead study. Images Figure 1

The U.S. Environmental Protection Agency (EPA) recommends the use of the one-sided 95% upper confidence limit of the arithmetic mean based on either a normal or lognormal distribution for the contaminant (or exposure point) concentration term in the Superfund risk assessment process. When the data are not normal or lognormal this recommended approach may overestimate the exposure point concentration (EPC) and may lead to unecessary cleanup at a hazardous waste site. The EPA concentration term only seems to perform like alternative EPC methods when the data are well fit by a lognormal distribution. Several alternative methods for calculating the EPC are investigated and compared using soil data collected from three hazardous waste sites in Montana, Utah, and Colorado. For data sets that are well fit by a lognormal distribution, values for the Chebychev inequality or the EPA concentration term may be appropriate EPCs. For data sets where the soil concentration data are well fit by gamma distributions, Wong's method may be used for calculating EPCs. The studentized bootstrap-t and Hall's bootstrap-t transformation are recommended for EPC calculation when all distribution fits are poor. If a data set is well fit by a distribution, parametric bootstrap may provide a suitable EPC.

In this chapter we discuss the cost-effectiveness analysis (CEA) of public health interventions where there are combined, and potentially conflicting, objectives of increasing total population health and reducing unfair health inequalities in the population. Our focus is on identifying appropriate health inequality measures in this context to quantify the impacts of interventions on unfair health inequality and, where necessary, analyse equity-efficiency trade-offs between improving total population health and reducing unfair health inequality. We recognise that this requires a number of important social value judgements to be made, and so prefer measures that facilitate transparency about these social value judgements. We briefly summarise the literature on health inequality and health-related social welfare functions, and conclude that while valuable it is not entirely suitable for our purpose. We borrow instead from the wider literature on economic inequality, highlighting how this translates to a health setting, and identify appropriate measures for CEA. We conclude with a stylised example illustrating how we would apply a battery of dominance rules and social welfare indices to evaluate the health distributions associated with two hypothetical health interventions.

This paper presents a case study application of a new methodological framework for undertaking distributional cost-effectiveness analysis (DCEA) to combine the objectives of maximising health and minimising unfair variation in health when evaluating population health interventions. The NHS Bowel Cancer Screening Programme (BCSP) introduced in 2006 is expected to improve population health on average but also to worsen population health inequalities associated with deprivation and ethnicity – a classic case of intervention generated inequality. We demonstrate the DCEA framework by examining two redesign options for the BCSP: (1) the introduction of an enhanced targeted reminder aimed at increasing screening uptake in deprived and ethnically diverse neighbourhoods and (2) the introduction of a basic universal reminder aimed at increasing screening uptake across the whole population. Our analysis indicates that the universal reminder is the strategy that maximises population health while the targeted reminder is the screening strategy that minimises unfair variation in health. The framework is used to demonstrate how these two objectives can be traded off against each other, and how alternative social value judgements influence the assessment of which strategy is best, including judgements about which dimensions of health variation are considered unfair and judgements about societal levels of inequality aversion.

This paper presents an application of a new methodological framework for undertaking distributional cost-effectiveness analysis to combine the objectives of maximising health and minimising unfair variation in health when evaluating population health interventions. The National Health Service bowel cancer screening programme introduced in 2006 is expected to improve population health on average and to worsen population health inequalities associated with deprivation and ethnicity--a classic case of 'intervention-generated inequality'. We demonstrate the distributional cost-effectiveness analysis framework by examining two redesign options for the bowel cancer screening programme: (i) the introduction of an enhanced targeted reminder aimed at increasing screening uptake in deprived and ethnically diverse neighbourhoods and (ii) the introduction of a basic universal reminder aimed at increasing screening uptake across the whole population. Our analysis indicates that the universal reminder is the strategy that maximises population health, while the targeted reminder is the screening strategy that minimises unfair variation in health. The framework is used to demonstrate how these two objectives can be traded off against each other, and how alternative social value judgements influence the assessment of which strategy is best, including judgements about which dimensions of health variation are considered unfair and judgements about societal levels of inequality aversion.

This report summarizes the results of a study to develop an in vitro bioaccessibility (IVBA) extraction technique for estimating the relative bioavailability (RBA) of arsenic (As) in soil. The study was implemented in several steps. In step 1, key variables in the extraction protocol were identified. In step 2, 21 different extraction conditions were tested on 12 different soils with reliable RBA values measured in swine or monkeys to identify which yielded useful in vivo-in vitro correlations (IVIVC). In step 3, three extraction conditions were evaluated using 39 different test soils to make a final selection of the best IVIVC. In step 4, the within- and between-lab reproducibility of the extraction method was examined. The optimum IVIVC model for swine utilized a pH 1.5 IVBA extraction fluid, with an R (2) value of .723. For monkeys, the optimum IVIVC model was obtained using a pH 7 IVBA extraction fluid that contained phosphate, with an R (2) value of .755. Within-lab precision of IVBA results was typically less than 3%, with an average of 0.8% for all 4 labs. Between-lab variation in mean IVBA values was generally less than 7%, with an overall average of 3%. The principal advantages of this IVBA method compared to other in vitro methods described in the literature are that (1) the fluids and extraction conditions are simple, (2) the results have been calibrated against a larger data set than any other method, and (3) the method has been demonstrated to be reproducible both within and between labs.

The purpose of this research is to illustrate: i) the principles of what assessments are required when considering the need for additional evidence and the priority of proposed research; and ii) how these assessments might be informed by quantitative analysis based on standard methods of systematic review and meta-analysis. We briefly outline the principles of what type of assessments are needed when considering research prioritization and commissioning. These are more fully examined through the integration of the principles of value of information analysis with the type of meta-analysis commonly conducted in systematic review and its application to four topics or case studies. The case studies were selected to cover a number of contexts in which these assessments are likely to be required and include: where the primary endpoint in existing studies capture key aspects of outcome; where it can be linked to other important aspects of outcome; when different ‘weights’ might be used to reflect the relevance and quality of different studies and when more than two alternative interventions need to be compared. Throughout, we distinguish the value of additional evidence and the value of implementing the findings from existing research. We also show how the value of additional evidence and the need for further research depends on the clinical difference in key aspects of outcome that would need to be demonstrated before clinical practice ‘should’ or is likely to change. We also consider whether the expected health benefits of additional evidence are sufficient to regard a particular research proposal as potentially worthwhile and whether it should it be prioritized over other research topics that could have been commissioned with the same resources. We also set out the implications of this type of analysis for research design, including whether randomised design is likely to be needed, the most appropriate scale of future research and the sequence in which different types of study might be undertaken. The report demonstrates how making best use of the results of standard meta-analysis can directly inform the questions posed in research prioritisation and commissioning. In principle, this type of analysis could become part of the routine reporting of the findings of systematic review. In addition, it is sufficiently general to be relevant across a range of different types of health care systems, whether or not formal cost effectiveness analysis is explicitly used as part of the decision making process.

Objective To examine the full spectrum of psychiatric comorbidity in juvenile obsessive-compulsive disorder (OCD) in a naturalistic manner when no exclusionary criteria are used for sample selection. Method Consecutive referrals to a specialized pediatric OCD clinic were evaluated by means of structured diagnostic interviews and rating scales. No exclusionary criteria were used for sample selection. Findings were compared with those of previously published reports of juvenile OCD. Results Compared with previous studies, our sample of juveniles with OCD had high rates of comorbidity not only with tic, mood, and anxiety disorders but also with disruptive behavior disorders. Conclusions Our findings indicate that in the naturalistic setting, juvenile OCD is heavily comorbid with both internalizing and externalizing disorders. The presence of such a complex comorbid state has important clinical and research implications and stresses the relevance of limiting exclusionary criteria in studies of juvenile OCD.

Objective To investigate a new mechanism for identifying social disability in children with attention-deficit hyperactivity disorder (ADHD), employing psychometric methodology used in defining learning disabilities. Method Two groups of index children were examined: 140 children with ADHD (referred from both psychiatric and pediatric sources) and 120 non-ADHD comparison children. Subjects were defined as socially disabled if they had a value greater than 1.65 on a standardized discrepancy score between observed and expected scores on a measure of social functioning (with expected scores derived as a function of the child's estimated Full Scale IQ). Children identified as socially disabled were compared with non-socially disabled probands on psychopathology, familiality, cognitive functioning, school history, and treatment history. Results Using this psychometric approach, 22% of the ADHD probands qualified as socially disabled, whereas none of the comparison probands qualified ( p ≤ .001). Socially disabled ADHD probands were significantly more impaired than were non-socially disabled ADHD probands in global and specific measures of social functioning and patterns of psychiatric comorbidity. Conclusions The psychometrically defined construct of social disability may identify children with ADHD who are at very high risk for severe social dysfunction and whose course and prognosis may vary from those of other children with ADHD. This subgroup of children with ADHD may be at heightened risk for poor outcome, and their identification may facilitate the development of clinical interventions aimed at ameliorating their specific difficulties.

Objective To evaluate the scope of the available therapeutic armamentarium in attention-deficit hyperactivity disorder (ADHD). Method The literature of medication trials in ADHD was systematically reviewed, with attention to issues of psychiatric comorbidity, age, gender, and ethnic background. Results One hundred fifty-five controlled studies of 5,768 children, adolescents, and adults have documented the efficacy of stimulants in an estimated 70% of subjects. The literature clearly documents that stimulants not only improve abnormal behaviors of ADHD, but also self-esteem, cognition, and social and family function. However, response varied in different age groups and with certain comorbid conditions. In addition, there is an impressive body of literature documenting the efficacy of tricyclic antidepressants on ADHD in more than 1,000 subjects. Studies of alternative antidepressants, antipsychotics, antihypertensives, and other compounds were also reviewed. Conclusions The available literature indicates the important role of psychophar-macological agents in the reduction of the core symptoms of ADHD and associated impairments. More research is needed on alternative pharmacological treatments and to further evaluate established therapeutics beyond school-age Caucasian boys. In addition, more research is needed on the efficacy of treatment for comorbid ADHD, use of combined medications, and the combination of medication and psychosocial treatment.

A method is described for measuring the in vitro bioaccessibility (IVBA) of arsenic in soil or soil-like media, and using the measured IVBA value to estimate the relative bioavailability (RBA) in swine or monkeys using empiric regression models developed from 20 (swine) or 17 (monkey) calibration soils. The correlation coefficients for the models are high (0.85 for swine, 0.87 for monkey), and the precision of the method is high, both within and between laboratories. This method is the most thoroughly tested, calibrated, and validated IVBA approach for estimation of arsenic RBA that has been described to date.

Following a licence extension to include those aged 6-11 years, the National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of omalizumab (Novartis Pharmaceuticals UK) to submit evidence for the clinical and cost effectiveness of this drug for patients with severe persistent allergic asthma in this age bracket. NICE had previously considered the use of omalizumab in patients aged 12 years and over. The Centre for Reviews and Dissemination (CRD) and the Centre for Health Economics (CHE) at the University of York were commissioned as the Evidence Review Group (ERG) to critically appraise the evidence presented by the manufacturer. This article summarizes that review of the evidence, the deliberations of the NICE Appraisal Committee and the resulting NICE guidance. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The relevant patient population was patients aged 6-11 years of age with severe persistent allergic immunoglobulin E-mediated asthma whose condition remained uncontrolled despite best standard care with high-dose inhaled corticosteroids and a long-acting inhaled β2-agonist. The main clinical effectiveness data were derived from a pre-planned subgroup analysis of a single randomized controlled trial comparing omalizumab plus standard therapy against standard therapy alone. At a 52-week follow-up, the only outcome to show a statistically significant benefit of omalizumab compared with placebo was the number of exacerbations defined as 'clinically significant' &lsqb;CS&rsqb; (relative risk &lsqb;RR&rsqb; 0.504; 95% CI 0.350, 0.725; p < 0.001). At the ERG's request, the manufacturer provided analyses stratified by baseline exacerbation rate, which indicated the effect of omalizumab on CS exacerbations was statistically significant only for those children with ≥3 exacerbations as baseline. The ERG identified a number of issues relating to the clinical effectiveness results: it was unclear whether the pre-planned subgroup analysis had sufficient power; the definition of CS exacerbation was less severe than that used in UK clinical practice; and the method for imputing exacerbations for those who withdrew from treatment may have underestimated the exacerbation rate. The incremental cost-effectiveness ratio based on the manufacturer's results was considerably above the threshold range stated in the NICE Guide to the Methods of Technology Appraisal. The ERG identified numerous issues relating to the cost-effectiveness results, which included the following: the 10-year time horizon for treatment may exceed that in clinical practice; the assumption of constant exacerbation rates over a lifetime given that adolescence is expected to impact on the severity of asthma; and whether it is appropriate to use health-related quality-of-life data collected in adults for children. The ERG concluded that omalizumab appears to reduce CS exacerbations but there was no evidence of improvement in daily symptoms, CS severe (CSS) exacerbations or hospitalization rates. The main driver of cost effectiveness was the reduction in asthma-related mortality associated with a reduction in CSS exacerbations. As the number of CSS exacerbations avoided was low, as is asthma-related mortality in children, the potential small gain in QALYs associated with omalizumab was not sufficient to compensate for the high treatment cost even under the most favourable scenario analyses. The Appraisal Committee recommended that omalizumab should not be routinely provided for the treatment of severe persistent allergic asthma in children aged 6-11 years.

Pharmacokinetic differences between piperaquine (PQ) base and PQ tetraphosphate were investigated in 34 Papua New Guinean children aged 5 to 10 years treated for uncomplicated malaria with artemisinin-PQ (ART-PQ) base or dihydroartemisinin-PQ (DHA-PQ) tetraphosphate. Twelve children received ART-PQ base (two daily doses of 3 mg of ART and 18 mg of PQ base as granules/kg of body weight) as recommended by the manufacturer, with regular clinical assessment and blood sampling over 56 days. PQ concentrations in plasma samples collected from 22 children of similar ages with malaria in a previously published pharmacokinetic study of DHA-PQ tetraphosphate (three daily doses of 2.5 mg of ART and 20 mg of PQ tetraphosphate as tablets/kg of body weight) were available for comparison. The disposition of ART was also assessed in the 12 children who received ART-PQ base. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and ART was assayed using liquid chromatography-mass spectrometry. Multicompartment pharmacokinetic models for PQ and ART were developed using a population-based approach. ART-PQ base was well tolerated, and initial fever abatement and parasite clearance were prompt. There were no differences between the two treatments in the values for the PQ area under the concentration-time curve from time zero to infinity (AUC 0–∞ ), with medians of 49,451 ( n = 12) and 44,556 ( n = 22) μg · h/liter for ART-PQ base and DHA-PQ tetraphosphate, respectively. Recurrent parasitemia was associated with lower PQ exposure. Using a two-compartment ART model, the median AUC 0–∞ was 1,652 μg · h/liter. There was evidence of autoinduction of ART metabolism (relative bioavailability for the second dose, 0.27). These and previously published data suggest that a 3-day ART-PQ base regimen should be further evaluated, in line with World Health Organization recommendations for all artemisinin combination therapies.

The history of how American women readers have been studied is tied closely to the history of Women's Studies in America. This is true in several senses: one is that Women's Studies from the start concerned itself with identifying and describing the woman reader (and, later, women readers – an important distinction). The second is that the history of Women's Studies is, quite literally, largely a history of women – in this case, feminists – reading. After all, as Judith Fetterley declared in 1978, “At its best feminist criticism is a political act whose aim is not simply to interpret the world but to change it by changing the consciousness of those who read and their relation to what they read.” This essay has, then, a dual focus: describing some of the many ways in which women readers have been and are being studied and suggesting why certain kinds of studies appeared at different historical moments. Twentieth-century feminists were not, of course, the first to address the topic of the woman reader, a controversial matter dating back to Classical Greece. Indeed, every advance in the technologies of literacy brought with it protests against, and sometimes arguments for, women reading. The history of the novel in particular is deeply imbricated with advice for, fears about, warnings to educators, parents, girls themselves.

Artemisinin-naphthoquine (ART-NQ) is a fixed-dose coformulated antimalarial therapy recommended as a single-dose treatment and marketed in Papua New Guinea among other tropical countries. We conducted a tolerability, safety, and efficacy study of ART-NQ for Papua New Guinean children aged 5 to 12 years with uncomplicated malaria, comparing single-dose ART-NQ (15 and 6 mg/kg of body weight) given with water (group 1; n = 15), single-dose ART-NQ (22 and 9 mg/kg) given with milk (group 2; n = 17), or two daily doses of 22 and 9 mg/kg given with water (group 3; n = 16). Of the 48 children (45 with Plasmodium falciparum malaria, 2 with Plasmodium vivax malaria, and 1 with mixed-species malaria), 2 in group 2 did not attend all follow-up assessments. All regimens were well tolerated, with no serious adverse events. There were no clinically significant changes in pulse, blood pressure, rate-corrected electrocardiographic QT, routine biochemistry/hematology, or hearing after treatment. Fever clearance was prompt. Mean 50% parasite clearance times were 4, 4, and 5 h for groups 1, 2, and 3, respectively. One group 1 patient had PCR-confirmed P. falciparum recrudescence at day 23; four had PCR-confirmed P. falciparum reinfections on day 28 or 42; and three had P. vivax infections detected on day 42. The only recurrent parasitemia in groups 2 and 3 occurred in a group 2 child who developed a P. vivax infection on day 42. Day 14 gametocyte positivity levels were 20%, 27%, and 9% in groups 1, 2, and 3, respectively. The lower single ART-NQ dose was associated with relatively frequent recurrence of parasitemia, but the prolonged gametocytemia in all three groups has implications for the transmission of malaria.

© Queen’s Printer and Controller of HMSO 2012. This work was produced by Claxton et al. under the terms of a commissioning contract issued by the Secretary of State for Health. Background: The general issue of balancing the value of evidence about the performance of a technology and the value of access to a technology can be seen as central to a number of policy questions. Establishing the key principles of what assessments are needed, as well as how they should be made, will enable them to be addressed in an explicit and transparent manner. Objectives: The aims of this research are to (1) establish the key principles of what assessments are needed to inform an ‘only in research’ (OIR) or ‘approval with research’ (AWR) recommendation, (2) evaluate previous National Institute for Health and Clinical Evidence (NICE) guidance in which OIR or AWR recommendations were made or considered and (3) evaluate a range of alternative options to establish criteria, additional information and/or analysis that could be made available to inform the assessments needed. Data sources: All NICE draft and final guidance up to January 2010 was considered in the review of NICE technology appraisal guidance. Four case studies were used to evaluate the range of options of what information and analysis could be made available to inform the assessment required. These were based on a reanalysis of existing health technology appraisals for NICE or the Health Technology Assessment programme. Review methods: A critical review of policies, practice and literature was undertaken using traditional systematic searching based on initial search terms informed by key publications. An iterative approach was adopted using ‘pearl growing’ evaluated through capture–recapture methods. In addition, grey literature, policy documents and other sources, such as special interest groups and the expertise of the Advisory Group for the project, were used to contribute to this process. Results: A series of recommendations, or options, for NICE to consider were developed with the involvement of key stakeholders. These establish the key principles and associated criteria that might guide OIR and AWR recommendations and identify what, if any, additional information or analysis might be included in the technology appraisal process, including how such recommendations might be more likely to be implemented through publically funded and sponsored research. To meet these aims the research is broadly structured as follows. A critical review of policy, practice and literature in this area informs the development of a coherent conceptual framework to establish the key principles and the sequence of assessment and judgements required. This sequence of assessment and judgement is represented as an algorithm, which can also be summarised as a simple set of explicit criteria or a 7-point checklist of assessments. A review of previous NICE guidance in which OIR or AWR recommendations were either made or considered was undertaken to examine the extent to which the key principles are evident. The application of the checklist of assessment to a series of four case studies informs considerations of whether or not such assessments can be made based on existing information and analysis in current NICE appraisal and in what circumstances could additional information and/or analysis be useful. Finally, some of the implications that this more explicit assessment of OIR and AWR might have for policy (e.g. NICE guidance and drug pricing), the process of appraisal (e.g. greater involvement of research commissioners) and methods of appraisal (e.g. should additional information, evidence and analysis be required) are drawn together. At each stage this research has been informed by a diverse and international Advisory Group and the feedback from participants at two workshops involving a wide range of key stakeholders, which included members of NICE and its Advisory Committees (including lay members and other NICE programmes), patient advocates, manufacturers, and research and NHS commissioners, as well as relevant academics. Limitations: Further research is required to establish how these considerations could be integrated within a practical value-based pricing scheme. In addition, irrecoverable opportunity costs are commonly associated with many health technologies that offer future benefits following treatment. The significance of these types of irrecoverable costs is not widely recognised and further research to demonstrate their potential impact more generally is needed. Conclusions: The categories of guidance available to NICE have a wider application than is reflected in the review of previous guidance. Importantly, determining which category of guidance will be appropriate depends only partly on an assessment of expected costeffectiveness. As well as AWR for technologies expected to be cost effective and OIR for those not expected to be cost-effective, there are other important circumstances when OIR should be considered. In particular, for technologies expected to be cost-effective, OIR rather than approve may be appropriate when research is not possible with approval and OIR or even reject, rather than AWR or approve, may be appropriate even if research is possible with approval when there are significant irrecoverable costs. The National Institute for Health Research Health Technology Assessment programme

Background: The risk of recurrence following surgery in women with early breast cancer varies, depending upon prognostic factors. Adjuvant chemotherapy reduces this risk; however, increasingly effective regimens are associated with higher costs and toxicity profiles, making it likely that different regimens may be cost-effective for women with differing prognoses. To investigate this we performed a cost-effectiveness analysis of four treatment strategies: (1) no chemotherapy, (2) chemotherapy using cyclophosphamide, methotrexate, and fluorouracil (CMF) (a first generation regimen), (3) chemotherapy using Epirubicin-CMF (E-CMF) or fluorouracil, epirubicin, and cyclophosphamide (FEC60) (a second generation regimens), and (4) chemotherapy with FEC60 followed by docetaxel (FEC-D) (a third generation regimen). These adjuvant chemotherapy regimens were used in three large UK-led randomised controlled trials (RCTs). Methods: A Markov model was used to simulate the natural progression of early breast cancer and the impact of chemotherapy on modifying this process. The probability of a first recurrent event within the model was estimated for women with different prognostic risk profiles using a parametric regression-based survival model incorporating established prognostic factors. Other probabilities, treatment effects, costs and quality of life weights were estimated primarily using data from the three UK-led RCTs, a meta-analysis of all relevant RCTs, and other published literature. The model predicted the lifetime costs, quality adjusted life years (QALYs) and cost-effectiveness of the four strategies for women with differing prognoses. Sensitivity analyses investigated the impact of uncertain parameters and model assumptions. Findings: For women with an average to high risk of recurrence (based upon prognostic factors and any other adjuvant therapies received), FEC-D appeared most cost-effective assuming a threshold of £20,000 per QALY for the National Health Service (NHS). For younger low risk women, E-CMF/FEC60 tended to be the optimal strategy and, for some older low risk women, the model suggested a policy of no chemotherapy was cost-effective. For no patient group was CMF chemotherapy the preferred option. Sensitivity analyses demonstrated cost-effectiveness results to be particularly sensitive to the treatment effect estimate for FEC-D and the future price of docetaxel. Interpretation: To our knowledge, this analysis is the first cost-effectiveness comparison of no chemotherapy, and first, second, and third generation adjuvant chemotherapy regimens for early breast cancer patients with differing prognoses. The results demonstrate the potential for different treatment strategies to be cost-effective for different types of patients. These findings may prove useful for policy makers attempting to formulate cost-effective treatment guidelines in the field of early breast cancer. © 2011 Elsevier Ltd. All rights reserved.

The general issue of balancing the value of evidence about the performance of a technology and the value of access to a technology can be seen as central to a number of policy questions. Establishing the key principles of what assessments are needed, as well as how they should be made, will enable them to be addressed in an explicit and transparent manner. This report presents the key finding from MRC and NHIR funded research which aimed to: i) Establish the key principles of what assessments are needed to inform an only in research (OIR) or Approval with Research (AWR) recommendation. ii) Evaluate previous NICE guidance where OIR or AWR recommendations were made or considered. iii) Evaluate a range of alternative options to establish the criteria, additional information and/or analysis which could be made available to help the assessment needed to inform an OIR or AWR recommendation. iv) Provide a series of final recommendations, with the involvement of key stakeholders, establishing both the key principles and associated criteria that might guide OIR and AWR recommendations, identifying what, if any, additional information or analysis might be included in the Technology Appraisal process and how such recommendations might be more likely to be implemented through publicly funded and sponsored research. The key principles and the assessments and judgments required are discussed in Section 2. The sequence of assessment and judgment is represented as an algorithm, which can also be summarised as a simple set of explicit criteria or a seven point checklist of assessments. The application of the check list of assessment to a series of four case studies in Section 3 can inform considerations of whether such assessments can be made based on existing information and analysis in current NICE appraisal and in what circumstances could additional information and/or analysis be useful. In Section 4, some of the implications that this more explicit assessment of OIR and AWR might have for policy (e.g., NICE guidance and drug pricing), the process of appraisal (e.g., greater involvement of research commissioners) and methods of appraisal (e.g., should additional information, evidence and analysis be required) are drawn together.

Broad adoption of interventions that prove effective in randomized clinical trials or comparative effectiveness research may depend to a great extent on their costs and cost-effectiveness (CE). Many studies of behavioral health interventions for oral health promotion and disease prevention lack robust economic assessments of costs and CE.To describe methodologies employed to assess intervention costs, potential savings, net costs, CE, and the financial sustainability of behavioral health interventions to promote oral health.We provide an overview of terminology and strategies for conducting economic evaluations of behavioral interventions to improve oral health based on the recommendations of the Panel of Cost-Effectiveness in Health and Medicine. To illustrate these approaches, we summarize methodologies and findings from a limited number of published studies. The strategies include methods for assessing intervention costs, potential savings, net costs, CE, and financial sustainability from various perspectives (e.g., health-care provider, health system, health payer, employer, society). Statistical methods for estimating short-term and long-term economic outcomes and for examining the sensitivity of economic outcomes to cost parameters are described.Through the use of established protocols for evaluating costs and savings, it is possible to assess and compare intervention costs, net costs, CE, and financial sustainability. The addition of economic outcomes to outcomes reflecting effectiveness, appropriateness, acceptability, and organizational sustainability strengthens evaluations of oral health interventions and increases the potential that those found to be successful in research settings will be disseminated more broadly.

The effect of adherence, treatment failure, and comorbidities on the cost of HIV care is not well understood.To characterize the cost of HIV care including combination antiretroviral treatment (ART).Observational study of administrative data.Total 1896 randomly selected HIV-infected patients and 288 trial participants with multidrug-resistant HIV seen at the US Veterans Health Administration (VHA).Comorbidities, cost, pharmacy, and laboratory data.Many HIV-infected patients (24.5%) of the random sample did not receive ART. Outpatient pharmacy accounted for 62.8% of the costs of patients highly adherent with ART, 32.2% of the cost of those with lower adherence, and 6.2% of the cost of those not receiving ART. Compared with patients not receiving ART, high adherence was associated with lower hospital cost, but no greater total cost. Individuals with a low CD4 count (50 cells/mm) incurred 1.9 times the cost of patients with counts500. Most patients had medical, psychiatric, or substance abuse comorbidities. These conditions were associated with greater cost. Trial participants were less likely to have psychiatric and substance abuse comorbidities than the random sample of VHA patients with HIV.Patients receiving combination ART had higher medication costs but lower acute hospital cost. Poor control of HIV was associated with higher cost. The cost of psychiatric, substance abuse, rehabilitation, and long-term care and medications other than ART, often overlooked in HIV studies, was substantial.

Cost-effectiveness analysis (CEA) is intended to help collective purchasers of health care to determine which interventions to prioritize, by ranking them according to the cost of each unit of “health benefit” they produce. The primary focus of this article is on the social decision-making approach where the decision-maker's objective is assumed to be the maximization of health gains subject to a given budget constraint. This article begins with the rationale for presenting a full characterization and analysis of uncertainty within any CEA. An overview of methods that can be used to conduct a CEA that accounts for uncertainty is provided, including the means to present and interpret the results. The benefits and limitations of the methods for analyzing uncertainty are considered in the context of providing information to decision-makers. The article concludes by discussing the additional questions that arise when the need for further research to support those decisions is considered.

Background. The effect of antiretroviral therapy (ART) interruption or intensification on health-related quality of life (HRQoL) in advanced HIV patients is unknown. Objective. To assess the impact of temporary treatment interruption and intensification of ART on HRQoL. Design. A 2 x 2 factorial open label randomized controlled trial. Setting. Hospitals in the United States, Canada, and the United Kingdom. Patients. Multidrug resistant (MDR) HIV patients. Intervention. Patients were randomized to receive a 12-wk interruption or not, and ART intensification or standard ART. Measurements. The Health Utilities Index (HUI3), EQ-5D, standard gamble (SG), time tradeoff (TTO), visual analog scale (VAS), and the Medical Outcomes Study HIV Health Survey (MOS-HIV). Results. There were no significant differences in HRQoL among the four groups during follow-up; however, there was a temporary significant decline in HRQoL on some measures within the interruption group during interruption (HUI3 −0.05, P = 0.03; VAS −5.9, P = 0.002; physical health summary −2.9, P = 0.001; mental health summary −1.9, P = 0.02). Scores declined slightly overall during follow-up. Multivariate analysis showed significantly lower HRQoL associated with some clinical events. Limitations. The results may not apply to HIV patients who have not experienced multiple treatment failures or who have not developed MDR HIV. Conclusions. Temporary ART interruption and ART intensification provided neither superior nor inferior HRQoL compared with no interruption and standard ART. Among surviving patients, HRQoL scores declined only slightly over years of follow-up in this advanced HIV cohort; however, approximately one-third of patients died during the trial follow up. Lower HRQoL was associated with adverse clinical events.