Clofazimine for Treatment of Cryptosporidiosis in Human Immunodeficiency Virus Infected Adults: An Experimental Medicine, Randomized, Double-blind, Placebo-controlled Phase 2a Trial.

BACKGROUND: We evaluated the efficacy, pharmacokinetics (PK), and safety of clofazimine (CFZ) in patients living with human immunodeficiency virus (HIV) with cryptosporidiosis. METHODS: We performed a randomized, double-blind, placebo-controlled study. Primary outcomes in part A were reduction in Cryptosporidium shedding, safety, and PK. Primary analysis was according to protocol (ATP). Part B of the study compared CFZ PK in matched individuals living with HIV without cryptosporidiosis. RESULTS: Twenty part A and 10 part B participants completed the study ATP. Almost all part A participants had high viral loads and low CD4 counts, consistent with failure of antiretroviral (ARV) therapy. At study entry, the part A CFZ group had higher Cryptosporidium shedding, total stool weight, and more diarrheal episodes compared with the placebo group. Over the inpatient period, compared with those who received placebo, the CFZ group Cryptosporidium shedding increased by 2.17 log2 Cryptosporidium per gram stool (95% upper confidence limit, 3.82), total stool weight decreased by 45.3 g (P = .37), and number of diarrheal episodes increased by 2.32 (P = .87). The most frequent solicited adverse effects were diarrhea, abdominal pain, and malaise. One placebo and 3 CFZ participants died during the study. Plasma levels of CFZ in participants with cryptosporidiosis were 2-fold lower than in part B controls. CONCLUSIONS: Our findings do not support the efficacy of CFZ for the treatment of cryptosporidiosis in a severely immunocompromised HIV population. However, this trial demonstrates a pathway to assess the therapeutic potential of drugs for cryptosporidiosis treatment. Screening persons living with HIV for diarrhea, and especially Cryptosporidium infection, may identify those failing ARV therapy. CLINICAL TRIALS REGISTRATION: NCT03341767.

Costing the Morbidity and Mortality Consequences of Zoonoses Using Health-Adjusted Life Years.

Governments are routinely involved in the biosecurity of agricultural and food imports and exports. This involves controlling the complex ongoing threat of the broad range of zoonoses: endemic, exotic and newly emerging. Policy-related decision-making in these areas requires accurate information and predictions concerning the effects and potential impacts of zoonotic diseases. The aim of this article was to provide information concerning the development and use of utility-based tools, specifically disability-adjusted life years (DALYs), for measuring the burden on human disease (morbidity and mortality) as a consequence of zoonotic infections. Issues and challenges to their use are also considered. Non-monetary utility approaches that are reviewed in this paper form one of a number of tools that can be used to estimate the monetary and non-monetary 'cost' of morbidity- and mortality-related consequences. Other tools derive from cost-of-illness, willingness-to-pay and multicriteria approaches. Utility-based approaches are specifically designed to capture the pain, suffering and loss of functioning associated with diseases, zoonotic and otherwise. These effects are typically complicated to define, measure and subsequently 'cost'. Utility-based measures will not be able to capture all of the effects, especially those that extend beyond the health sector. These will more normally be captured in financial terms. Along with other uncommon diseases, the quality of the relevant epidemiological data may not be adequate to support the estimation of losses in utility as a result of zoonoses. Other issues in their use have been identified. New empirical studies have shown some success in addressing these issues. Other issues await further study. It is concluded that, bearing in mind all caveats, utility-based methods are important tools in assessing the magnitude of the impacts of zoonoses in human disease. They make an important contribution to decision-making and priority setting across all sectors. In doing so, they highlight the relative importance of the burden of zoonotic disease globally.

Feasibility and acceptability of web-based enhanced relapse prevention for bipolar disorder (ERPonline): trial protocol.

BACKGROUND: Relapse prevention interventions for Bipolar Disorder are effective but implementation in routine clinical services is poor. Web-based approaches offer a way to offer easily accessible access to evidence based interventions at low cost, and have been shown to be effective for other mood disorders. METHODS/DESIGN: This protocol describes the development and feasibility testing of the ERPonline web-based intervention using a single blind randomised controlled trial. Data will include the extent to which the site was used, detailed feedback from users about their experiences of the site, reported benefits and costs to mental health and wellbeing of users, and costs and savings to health services. We will gain an estimate of the likely effect size of ERPonline on a range of important outcomes including mood, functioning, quality of life and recovery. We will explore potential mechanisms of change, giving us a greater understanding of the underlying processes of change, and consequently how the site could be made more effective. We will be able to determine rates of recruitment and retention, and identify what factors could improve these rates. DISCUSSION: The findings will be used to improve the site in accordance with user needs, and inform the design of a large scale evaluation of the clinical and cost effectiveness of ERPonline. They will further contribute to the growing evidence base for web-based interventions designed to support people with mental health problems.

Employment, work hours and weight gain among middle-aged women.

OBJECTIVE: To investigate the influence of employment and work hours on weight gain and weight loss among middle-aged women. DESIGN: Quantile regression techniques were used to estimate the influence of employment and hours worked on percentage weight change over 2 years across the entire distribution of weight change in a cohort of middle-aged women. A range of controls was included in the models to isolate the effect of work status. SUBJECTS: A total of 9276 women aged 45-50 years at baseline who were present in both the 1996 and 1998 surveys of the Australian Longitudinal Study of Women's Health. The women were a representative sample of the Australian population. RESULTS: Being out of the labour force or unemployed was associated with lower weight gain and higher weight loss than being employed. The association was stronger at low to moderate levels of weight gain. Among employed women, working regular (35-40), long (41-48) or very long (49+) hours was associated with increasingly higher levels of weight gain compared with working part-time hours. The association was stronger for women with greater weight gain overall. The association between unemployment and weight change became insignificant when health status was controlled for. CONCLUSIONS: Employment was associated with more weight gain and less weight loss. Among the employed, working longer hours was associated with more weight gain, especially at the higher levels of weight gain where the health consequences are more serious. These findings suggest that as women work longer hours they are more likely to make lifestyle choices that are associated with weight gain.

Economic implications of obesity among people with atherothrombotic disease.

OBJECTIVE: The purpose of this study was to ascertain the impact of obesity on the cost of disease management in people with or at high risk of atherothrombotic disease from a governmental perspective using a bottom-up approach to cost estimation. In addition, the aim was also to explore the causes of any differences found. METHOD: The health-care costs of obesity were estimated from 2819 participants recruited into the nationwide Australian REACH Registry with established atherothrombotic disease or at least three risk factors for atherothrombosis. Enrollment was in 2004, through primary care general practices. Information was collected on the use of cardiovascular drugs, hospitalizations and ambulatory care services. 'Bottom-up' costing was undertaken by assigning unit costs to each health-care item, based on Australian Government-reimbursed figures 2006-2007. Linear-mixed models were used to estimate associations between direct medical costs and body mass index (BMI) categories. RESULTS: Annual pharmaceutical costs per person increased with increasing BMI category, even after adjusting for gender, age, living place, formal education, smoking status, hypertension and diabetes. Adjusted annual pharmaceutical costs of overweight and obese participants were higher ($7 (P=0.004) and $144 (<0.001), respectively) than those of the normal weight participants. This was due to participants in higher BMI categories receiving more pharmaceuticals than normal weight participants. There was no significant change across the BMI categories in annual ambulatory care costs and annual hospital costs. CONCLUSION: In these participants with or at high risk of atherothrombotic disease, annual pharmaceutical costs were greater in participants of higher BMI category, but there was not such a gradient in the annual hospital or ambulatory care costs. The greater cardiovascular pharmaceutical costs for participants of higher BMI categories remained even after adjusting for a range of demographic factors and comorbidities. Our results suggest that these costs are explained by the higher number of drugs used among people with atherothrombotic disease. Further investigation is needed to understand the reasons for this level of drug use.

The efficiency of the delivery of neonatal care in the UK.

BACKGROUND: A recent paper in Journal of Public Health Medicine (O'Neill et al., 2000; 22(1): 108-115) used regression modelling to determine the average costs of neonatal care services for a sample of 49 units in the United Kingdom in 1990-1991, and concluded that economies of scale were present in the sample as a whole. Although this form of modelling is useful, analysis of the efficiency of production for individual units is also important. METHODS: Data envelopment analysis (DEA) was used to analyse the data set published by O'Neil et al., to determine technical efficiency of neonatal units, measuring efficiency compared with a benchmark efficient frontier, and estimating economies of scale for each unit. Potential cost savings if units were to operate efficiently are estimated. RESULTS: There is evidence of substantial levels of technical inefficiency. Economies of scale varied between units, with increasing returns in the 36 inefficient units, and mainly constant returns in the 13 efficient units. This suggests that the presence of technical inefficiency was as important as scale inefficiencies. Total cost savings, if all units were operating efficiently, are estimated at l10.4 million, equivalent to 10 extra units producing 57,000 additional days of care. CONCLUSIONS: DEA is a technique of great potential value in analysing the efficiency of health care production. As well as inefficiencies in the production of neonatal care in the United Kingdom due to differences in the scale of production, there appears to have been considerable technical inefficiency, which was not due to differences in case mix. The potential cost savings from efficiency gains are large.

War of the Iguanas: conflicting molecular and morphological phylogenies and long-branch attraction in iguanid lizards.

Recent studies based on different types of data (i.e., morphology, molecules) have found strongly conflicting phylogenies for the genera of iguanid lizards but have been unable to explain the basis for this incongruence. We reanalyze published data from morphology and from the mitochondrial ND4, cytochrome b, 12S, and 16S genes to explore the sources of incongruence and resolve these conflicts. Much of the incongruence centers on the genus Cyclura, which is the sister taxon of Iguana, according to parsimony analyses of the morphology and the ribosomal genes, but is the sister taxon of all other Iguanini, according to the protein-coding genes. Maximum likelihood analyses show that there has been an increase in the rate of nucleotide substitution in Cyclura in the two protein-coding genes (ND4 and cytochrome b), although this increase is not as clear when parsimony is used to estimate branch lengths. Parametric simulations suggest that Cyclura may be misplaced by the protein-coding genes as a result of long-branch attraction; even when Cyclura and Iguana are sister taxa in a simulated phylogeny, Cyclura is still placed as the basal member of the Iguanini by parsimony analysis in 55% of the replicates. A similar long-branch attraction problem may also exist in the morphological data with regard to the placement of Sauromalus with the Galápagos iguanas (Amblyrhynchus and Conolophus). The results have many implications for the analysis of diverse data sets, the impact of long branches on parsimony and likelihood methods, and the use of certain protein-coding genes in phylogeny reconstruction.

Family and client perspectives on alternative residential settings for persons with severe mental illness.

OBJECTIVE: The housing preferences of persons with severe mental illness living in three types of community residences were examined, as were their perceptions of problems in these settings and the relationships between clients' and family members' housing preferences and perceptions of problems. METHODS: A closed-ended questionnaire was developed to gather demographic and diagnostic data and information about housing preferences and seven categories of service-related problems. It was completed by clients who lived in group settings with 24-hour on-site staff, in supported housing with on-site visits by staff, and in homes or apartments with no on-site professional services. Questionnaires were returned by 129 family members and 180 clients. RESULTS: Clients who lived in group settings were significantly more likely to be older, less educated, unemployed, and diagnosed as having schizophrenia than clients in other settings. Although a larger proportion of family members than clients preferred housing with more support, for both families and clients a statistically significant association was found between current and preferred residence. A strong and significant correlation was found between clients' and family members' perceptions of problems, which included stress on the family and clients' social isolation and relapse to illness. For clients who lived independently, a significantly greater proportion of both clients and families reported that social isolation was a problem. CONCLUSIONS: Although supported housing works well for some individuals, a continued need exists for an array of housing with varying levels of structure. The results suggest that clients and families identify the same problems as priorities.

The impact of the internal market on hospital efficiency, productivity and service quality.

In this paper we use non-parametric mathematical programming models to compute and decompose Malmquist indices of productivity and quality change, which are used to evaluate the reforms in the UK National Health Service in the early nineties. We focus on acute hospitals and we study them over the first five years of the reforms. The findings of the study indicate that there was a productivity slowdown in the first year after the reforms but productivity progress in the subsequent years and thus, overall there was a net gain in productivity over the entire period considered. Productivity trends were dominated by technical change rather than hospital relative efficiency changes, as hospitals were already largely relatively efficient at the time of the introduction of the reforms. In fact, over the last four years in the period studied there was small relative efficiency regress and this does not bear out the argument that the reforms would increase hospital efficiency. The productivity changes are similar when service quality is incorporated in the analysis but the magnitude of these changes diminishes. Quality of service followed different trends to productivity change and this may have been the price for the productivity gains achieved.

Efficiency measurement of health care: a review of non-parametric methods and applications.

There has been increasing interest in measuring the productive performance of health care services, since the mid-1980s. This paper reviews this literature and, in particular, the concept and measurement of efficiency and productivity. Concerning measurement, we focus on the use of Data Envelopment Analysis (DEA), a technique particularly appropriate when multiple outputs are produced from multiple inputs. Applications to hospitals and to the wider context of general health care are reviewed and the empirical evidence from both the USA and Europe (EU) is that public rather than private provision is more efficient.

Efficiency. Measured response.

An analysis of the activity of 75 acute hospitals over the period 1991-96 using data envelopment analysis shows that, while overall productivity increased, the efficiency of individual hospitals did not. A small decrease in the efficiency of individual hospitals was found in the last four years studied. An analysis of quality of care over the same period suggests that gains in volume of services may have been at the expense of quality of care. The results suggest that incentives for increasing hospital efficiency have a one-off impact rather than a sustained effect.

The efficiency of Scottish acute hospitals: an application of data envelopment analysis.

Measurement of the efficiency of health services would aid the promotion of a better allocation of health care resources. Economic analysis suggests a number of ways of defining and measuring efficiency. However, this rarely informs measures used in health service management. This paper looks at the potential for the use in the United Kingdom's National Health Service of the linear programming based method of data envelopment analysis (DEA). DEA is applied to data from 75 UK acute hospitals. The results demonstrate the capacity of DEA to produce a user-friendly array of results, based on sound theoretical underpinnings. These range from the measurement of relative efficiencies to quantified suggestions as to how hospitals may improve efficiency, by examining both their own efficiency and that of comparable units. Information is provided both about individual hospitals and the sample as a whole. DEA is also able to distinguish between hospitals demonstrating differing returns to scale. Our findings suggest that, although still very much under development, DEA is usable and, given the weakness of current means of measuring efficiency in the National Health Service, that DEA has a strong claim for further consideration.