The application of cost-effectiveness analysis to disease control programmes in developing countries, with special reference to malaria control in Nepal.

The aims of this research study are three-fold: 1. to explore the relevance of recent developments In the methodology of cost-effectiveness analysis to disease control programmes In developing countries and specifically to malaria control in Nepal; 2. to apply cost-effectiveness analysis to the malaria control programme in Nepal in terms both of (a) the cost-effectiveness of various malaria control strategies and (b) the cost-effectiveness of the malaria control programme as a whole, in order to refine a methodology capable of more general application to disease control programmes in developing countries; 3. to assess whether policy-relevant conclusions can be drawn from the application of cost-effectiveness analysis to the malaria control programme in Nepal. The thesis is structured as follows. After the first introductory chapter, Chapter 2 reviews the literature on the cost-effectiveness analysis of disease control programmes, considering first the methodology of cost-effectiveness analysis, then its application to disease control programmes in first developed and then developing countries, and finally its application to malaria control. Chapter 3 briefly describes the epidemiology of malaria and policies and strategies of control before considering the history of malaria control in Nepal, present malaria control strategies and economic characteristics of the control programme. In Chapter 4, objectives and methods are presented for the study of malaria control in Nepal with a description of the theoretical framework of the analysis followed by a description of the various sub-studies, comprising a cost analysis, an effectiveness analysis and two surveys of malaria patients. The findings are presented in three chapters. The first (Chapter 5) presents the results of an analysis of the recurrent expenditure of NMEO (Nepal Malaria Eradication Organization) districts. The second assesses the internal efficiency of the Nepalese malaria control programme, considering first vector control strategies and second case detection and treatment strategies. The following chapter (Chapter 7) presents results relating to the desirability of malaria control (as opposed to other Investments). These results are discussed in Chapter 8 in terms both of the application of the cost-effectiveness methodology and of the findings In Nepal. Chapter 9 then draws out the Implications of the findings for malaria control policies and strategies In Nepal. In Chapter 10, conclusions are drawn relating to the three alms of the research study Identified above and recommendations are given. Finally, Chapter 11 draws out the Implications of this study for further research

Ocean de-oxygenation, the global phosphorus cycle, and the possibility of human-caused large-scale ocean anoxia

The major biogeochemical cycles that keep the present-day Earth habitable are linked by a network of feedbacks, which has led to a broadly stable chemical composition of the oceans and atmosphere over hundreds of millions of years. This includes the processes that control both the atmospheric and oceanic concentrations of oxygen. However, one notable exception to the generally well-behaved dynamics of this system is the propensity for episodes of ocean anoxia to occur and to persist for 105–106 years, these ocean anoxic events (OAEs) being particularly associated with warm ‘greenhouse’ climates. A powerful mechanism responsible for past OAEs was an increase in phosphorus supply to the oceans, leading to higher ocean productivity and oxygen demand in subsurface water. This can be amplified by positive feedbacks on the nutrient content of the ocean, with low oxygen promoting further release of phosphorus from ocean sediments, leading to a potentially self-sustaining condition of deoxygenation. We use a simple model for phosphorus in the ocean to explore this feedback, and to evaluate the potential for humans to bring on global-scale anoxia by enhancing P supply to the oceans. While this is not an immediate global change concern, it is a future possibility on millennial and longer time scales, when considering both phosphate rock mining and increased chemical weathering due to climate change. Ocean deoxygenation, once begun, may be self-sustaining and eventually could result in long-lasting and unpleasant consequences for the Earth's biosphere

Composite 3D printing of biomimetic human teeth

Human teeth are mechanically robust through a complex structural composite organisation of materials and morphology. Efforts to replicate mechanical function in artificial teeth (typodont teeth), such as in dental training applications, attempt to replicate the structure and morphology of real teeth but lack tactile similarities during mechanical cutting of the teeth. In this study, biomimetic typodont teeth, with morphology derived from X-ray microtomography scans of extracted teeth, were 3D printed using an approach to develop novel composites. These composites with a range of glass, hydroxyapatite and porcelain reinforcements within a methacrylate-based photopolymer resin were compared to six commercial artificial typodont teeth. Mechanical performance of the extracted human teeth and 3D printed typodont teeth were evaluated using a haptic approach of measuring applied cutting forces. Results indicate 3D printed typodont teeth replicating enamel and dentine can be mechanically comparable to extracted human teeth despite the material compositions differing from the materials found in human teeth. A multiple parameter variable of material elastic modulus and hardness is shown to describe the haptic response when cutting through both human and biomimetic, highlighting a critical dependence between the ratio of material mechanical properties and not absolute material properties in determining tooth mechanical performance under the action of cutting forces

Addressing patient treatment preferences at trial recruitment.

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Chlorpyrifos- and chlorpyrifos oxon-induced neurite retraction in pre-differentiated N2a cells is associated with transient hyperphosphorylation of neurofilament heavy chain and ERK 1/2

Chlorpyrifos (CPF) and CPF-oxon (CPO) are known to inhibit neurite outgrowth but little is known about their ability to induce neurite retraction in differentiating neuronal cells. The aims of this study were to determine the ability of these compounds to destabilize neurites and to identify the key molecular events involved. N2a cells were induced to differentiate for 20 h before exposure to CPF or CPO for 2-8 h. Fixed cell monolayers labeled with carboxyfluorescein succinimidyl ester or immunofluorescently stained with antibodies to tubulin (B512) or phosphorylated neurofilament heavy chain (Ta51) showed time- and concentration-dependent reductions in numbers and length of axon-like processes compared to the control, respectively, retraction of neurites being observed within 2 h of exposure by live cell imaging. Neurofilament disruption was also observed in treated cells stained by indirect immunofluorescence with anti- phosphorylated neurofilament heavy chain (NFH) monoclonal antibody SMI34, while the microtubule network was unaffected. Western blotting analysis revealed transiently increased levels of reactivity of Ta51 after 2 h exposure and reduced levels of reactivity of the same antibody following 8 h treatment with both compounds, whereas reactivity with antibodies to anti-total NFH or anti-tubulin was not affected. The alteration in NFH phosphorylation at 2 h exposure was associated with increased activation of extracellular signal-regulated protein kinase ERK 1/2. However, increased levels of phosphatase activity were observed following 8 h exposure. These findings suggest for the first time that organophosphorothionate pesticide-induced neurite retraction in N2a cells is associated with transient increases in NFH phosphorylation and ERK1/2 activation

Inositol for the prevention of neural tube defects: a pilot randomised controlled trial

Although peri-conceptional folic acid (FA) supplementation can prevent a proportion of neural tube defects (NTD), there is increasing evidence that many NTD are FA non-responsive. The vitamin-like molecule inositol may offer a novel approach to preventing FA-non-responsive NTD. Inositol prevented NTD in a genetic mouse model, and was well tolerated by women in a small study of NTD recurrence. In the present study, we report the Prevention of Neural Tube Defects by Inositol (PONTI) pilot study designed to gain further experience of inositol usage in human pregnancy as a preliminary trial to a future large-scale controlled trial to evaluate efficacy of inositol in NTD prevention. Study subjects were UK women with a previous NTD pregnancy who planned to become pregnant again. Of 117 women who made contact, ninety-nine proved eligible and forty-seven agreed to be randomised (double-blind) to peri-conceptional supplementation with inositol plus FA or placebo plus FA. In total, thirty-three randomised pregnancies produced one NTD recurrence in the placebo plus FA group (n 19) and no recurrences in the inositol plus FA group (n 14). Of fifty-two women who declined randomisation, the peri-conceptional supplementation regimen and outcomes of twenty-two further pregnancies were documented. Two NTD recurred, both in women who took only FA in their next pregnancy. No adverse pregnancy events were associated with inositol supplementation. The findings of the PONTI pilot study encourage a large-scale controlled trial of inositol for NTD prevention, but indicate the need for a careful study design in view of the unwillingness of many high-risk women to be randomised

Rigorous 3D change determination in Antarctic Peninsula glaciers from stereo WorldView-2 and archival aerial imagery

This paper presents detailed elevation and volume analysis of 16 individual glaciers, grouped at four locations, spread across the Antarctic Peninsula (AP). The study makes use of newly available WorldView-2 satellite stereo imagery to exploit the previously untapped value of archival stereo aerial photography. High resolution photogrammetric digital elevation models (DEMs) are derived to determine three-dimensional glacier change over an unprecedented time span of six decades with an unparalleled mean areal coverage of 82 % per glacier. The use of an in-house robust surface matching algorithm ensured rigorous alignment of the DEMs to overcome inherent problems associated with processing archival photography, most notably the identification and correction of scale error in some datasets. The analysis provides insight into one of the most challenging and data-scarce areas on the planet by expanding the spatial extent north of the AP to include previously un-studied glaciers located in the South Shetland Islands. 81 % of glaciers studied showed considerable loss of volume over the period of record. The mean annual mass loss for all glaciers yielded 0.24 \ub1 0.08 m.w.e. per year, with a maximum mass loss of up to 62 m.w.e. and frontal retreat exceeding 2.2 km for Stadium Glacier, located furthest north on Elephant Island. Observed volumetric loss was broadly, though not always, correlated with frontal retreat. The combined mass balance of all 16 glaciers yielded -1.862 \ub1 0.006 Gt, which corresponds to -0.005 mm sea level equivalent (SLE) over the 57 year observation period

Long Term Planetary Habitability and the Carbonate-Silicate Cycle

The potential habitability of an exoplanet is traditionally assessed by determining whether its orbit falls within the circumstellar “habitable zone” of its star, defined as the distance at which water could be liquid on the surface of a planet (Kopparapu et al.,2013). Traditionally, these limits are determined by radiative-convective climate models, which are used to predict surface temperatures at user-specified levels of greenhouse gases. This approach ignores the vital question of the (bio)geochemical plausibility of the proposed chemical abundances. Carbon dioxide is the most important greenhouse gas in Earth's atmosphere in terms of regulating planetary temperature, with the long-term concentration controlled by the balance between volcanic outgassing and the sequestration of CO2 via chemical weathering and sedimentation, as modulated by ocean chemistry, circulation, and biological (microbial) productivity. We developed a model that incorporates key aspects of Earth's short- and long-term biogeochemical carbon cycle to explore the potential changes in the CO2 greenhouse due to variance in planet size and stellar insolation. We find that proposed changes in global topography, tectonics, and the hydrological cycle on larger planets result in proportionally greater surface temperatures for a given incident flux. For planets between 0.5 and 2 R⊕, the effect of these changes results in average global surface temperature deviations of up to 20 K, which suggests that these relationships must be considered in future studies of planetary habitability