Assessing the outputs, impact and value of investments in malaria research and development

Malaria is a major public health challenge, causing disease, disability and death in low and middle income countries. Over 3 billion people, almost half the world’s population, are at risk from the disease and more than 445,000 die each year, mainly in Sub-Saharan Africa, and mainly children. New technologies and innovations such as longer lasting bed nets and new drug therapies are making faster progress possible. Research is a critical component of this process. While there are several methodologies and frameworks to assess research impact, to date there have been no systematic global estimates on the rate of return or ‘payback’ from investment in malaria research. Such estimates could potentially be vital for justifying continuing expenditure on research in the face of increasing competing demands for the use of scarce research resources. The aim of this thesis is to contribute to the international evidence base by exploring methods and frameworks for assessing the impact of health research in the poorest countries, with a particular focus on malaria. This thesis highlights the importance of understanding what works in measuring research impact and a key methodological contribution is to show how various methods and techniques can be applied to the area of antimalarial medicines research. We reflect on the extent to which these novel applications can act as exemplars for further work, which could potentially consider the whole area of malaria research including vaccines and prevention technologies. It is hoped this work will help inform future approaches to monitoring and evaluation of the impact and value of all development interventions and programmesOpen Acces

Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial

Background Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus.Methods This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.Findings Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Interpretation Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the

Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 ] HEALTH ]F2 ]2009 ]223175). The CIMBA data management and data analysis were supported by Cancer Research.UK grants 12292/A11174 and C1287/A10118. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME ]ON Post ]GWAS Initiative (U19 ]CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The cBio portal is developed and maintained by the Computational Biology Center at Memorial Sloan ] Kettering Cancer Center. SH is supported by an NHMRC Program Grant to GCT. Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium, funding for which was provided by the Wellcome Trust under award 076113. The results published here are, in part, based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancerhttp://dx.doi.org/10.1038/ng.3185This is the Author Accepted Manuscript of 'Identification of six new susceptibility loci for invasive epithelial ovarian cancer' which was published in Nature Genetics 47, 164–171 (2015) © Nature Publishing Group - content may only be used for academic research

Household demand for insecticide-treated bednets in Tanzania and policy options for increasing uptake.

There has been considerable controversy about the most appropriate means of delivering insecticide-treated nets (ITNs) to prevent malaria. Household demand for ITNs is a key factor influencing the choice of delivery strategy, but evidence to date about price and income elasticities comes either from studies of hypothetical willingness to pay or small-scale policy experiments. This study estimates the price and income elasticities of demand for ITNs using nationally representative household survey data and actual consumer choices, in the context of a national scheme to provide vouchers for subsidized nets to pregnant women in Tanzania. Under this distribution system, the estimated price elasticity of demand for subsidized ITNs equals -0.12 and the income elasticity estimates range from zero to 0.47, depending on household socio-economic status. The model also shows a substantial decline in short-term ITN purchases for women whose household received a free ITN. These findings suggest that if the Tanzanian government continues to use a mixed public-private model to distribute ITNs, increasing the consumer subsidy alone will not dramatically improve ITN coverage. A concerted effort is required including an increase in the subsidy amount, attention to income growth for poor households, increases in women's and girls' education levels, and expansion of the retail ITN distribution network. Use of a catch-up campaign to distribute free ITNs would increase coverage but raises questions about the effect of households' long-term purchase decisions for ITNs

Income inequality and population health

A number of studies have suggested that inequalities in the distribution of income may be an important cause of variations in the average level of population health among rich industrial nations. However, what is missing from the debate so far is any systematic review of evidence about the relationship between different measures of income distribution and indicators of population health. This paper aims to bridge that gap. First, it summarizes the recent English language literature on this topic and illustrates the methodological problems that weaken the inferences that can be derived from it. Secondly, it presents new empirical estimates of the relationship between different measures of income distribution, infant mortality and life expectancy based on the most authoritative data published to date. In contrast to most earlier studies, we find very little support for the view that income inequality is associated with variations in average levels of national health in rich industrial countries. Some possible explanations for these differences are outlined

Income inequality and population health

A number of studies have suggested that inequalities in the distribution of income may be an important cause of variations in the average level of population health among rich industrial nations. However, what is missing from the debate so far is any systematic review of evidence about the relationship between different measures of income distribution and indicators of population health. This paper aims to bridge that gap. First, it summarizes the recent English language literature on this topic and illustrates the methodological problems that weaken the inferences that can be derived from it. Secondly, it presents new empirical estimates of the relationship between different measures of income distribution, infant mortality and life expectancy based on the most authoritative data published to date. In contrast to most earlier studies, we find very little support for the view that income inequality is associated with variations in average levels of national health in rich industrial countries. Some possible explanations for these differences are outlined.inequality income distribution life expectancy infant mortality OECD countries