Modeling the public health impact of malaria vaccines for developers and policymakers

Efforts to develop malaria vaccines show promise. Mathematical model-based estimates of the potential demand, public health impact, and cost and financing requirements can be used to inform investment and adoption decisions by vaccine developers and policymakers on the use of malaria vaccines as complements to existing interventions. However, the complexity of such models may make their outputs inaccessible to non-modeling specialists. This paper describes a Malaria Vaccine Model (MVM) developed to address the specific needs of developers and policymakers, who need to access sophisticated modeling results and to test various scenarios in a user-friendly interface. The model's functionality is demonstrated through a hypothetical vaccine.; The MVM has three modules: supply and demand forecast; public health impact; and implementation cost and financing requirements. These modules include pre-entered reference data and also allow for user-defined inputs. The model includes an integrated sensitivity analysis function. Model functionality was demonstrated by estimating the public health impact of a hypothetical pre-erythrocytic malaria vaccine with 85% efficacy against uncomplicated disease and a vaccine efficacy decay rate of four years, based on internationally-established targets. Demand for this hypothetical vaccine was estimated based on historical vaccine implementation rates for routine infant immunization in 40 African countries over a 10-year period. Assumed purchase price was $5 per dose and injection equipment and delivery costs were$0.40 per dose.; The model projects the number of doses needed, uncomplicated and severe cases averted, deaths and disability-adjusted life years (DALYs) averted, and cost to avert each. In the demonstration scenario, based on a projected demand of 532 million doses, the MVM estimated that 150 million uncomplicated cases of malaria and 1.1 million deaths would be averted over 10 years. This is equivalent to 943 uncomplicate cases and 7 deaths averted per 1,000 vaccinees. In discounted 2011 US dollars, this represents $11 per uncomplicated case averted and$1,482 per death averted. If vaccine efficacy were reduced to 75%, the estimated uncomplicated cases and deaths averted over 10 years would decrease by 14% and 19%, respectively.; The MVM can provide valuable information to assist decision-making by vaccine developers and policymakers, information which will be refined and strengthened as field studies progress allowing further validation of modeling assumptions

Flow system modeling with applications to fuel cell systems

Fuel cell systems have garnered much attention recently as a possible source of clean, efficient energy. These systems are presently being designed in various arrangements to combine the use of fuel cells with other efficient power producing devices such as gas turbines, producing a system which is more efficient than either the fuel cell or gas turbine alone. The accurate modeling of these types of systems is an important contribution to the increasing development of such technologies. Of particular interest is the transient behavior of these systems, including the flow and thermal behavior of the air and fuel used. The contribution of this work is the development of a numerical, one-dimensional, variable-area duct model to predict the transient flow and thermal behavior of gasses moving through the system. Additional transient models for plenum, tee, and elbow components are created, and these parts are connected with the duct model to perform simulations of simple flow systems. Some thermal and flow characteristics of these systems are analyzed and discussed. As a verification of the models created, a portion of an actual fuel cell system is modeled and the results are compared with experimental data

Improved particle size control for the dispersion polymerization of methyl methacrylate in supercritical carbon dioxide

Dispersion polymerization is a well-established method of producing polymer particles that are easily handled and processed. With careful choice of reaction conditions this technique can yield well defined, spherical particles for a wide range of applications. The use of supercritical carbon dioxide (scCO2) as a reaction medium offers a route to performing these syntheses without excessive use of volatile organic solvents and minimizes work-up and disposal steps. However a significant drawback has been the fact that up till now the control of particle size and morphology from CO2 have been limited. This study presents control of particle size and morphology over an unprecedented range for a single stabilizer in scCO2 by coordinating a few simple parameters to tailor the conditions toward different sizes. Further, this study introduces the novel approach in scCO2 of using delayed monomer addition which allows considerable reduction of the batch-to-batch variability as well as reduced agglomeration between particles

MICROBIAL INTERACTIONS IN AN ANTARCTIC DESERT: RESPONSES TO ENVIRONMENTAL CHANGE AND TOOLS FOR LIFE DETECTION

Cryosphere microorganisms can provide fundamental insights into individual and community response to a changing climate, and how we may detect past or present life on other planets. The polar desert of the McMurdo Dry Valleys (MDV), the largest ice-free region in Antarctica, supports microbially-dominated ecosystems that experience extremes of temperature, salinity, nutrient availability, and solar radiation. A changing Antarctic climate leads to alteration of these natural gradients, thus, studying how organisms respond to changing stressors can inform predictions of future impacts to ecosystems. This dissertation elucidates how MDV microorganisms interact with their environment through culture-based and multi-omics techniques performed on both environmental materials and bacterial isolates. We describe the ecophysiology of a red pigmented strain of Massilia frigida (strain DJPM01) isolated from a microbial mat. Through genomic analyses, adaptations to cold and saline environments, and biosynthesis genes for the pigment prodigiosin were identified. The synthesis of prodigiosin was confirmed using mass spectrometry, and breakdown of this pigment was observed when DJPM01 cultures were incubated under ultraviolet light, a relevant stressor for polar bacteria. To investigate the impact of salinity on whole communities and individual species, we leveraged samples from a natural salinity gradient in MDV soils that forms from permafrost melt. Environmental soil DNA was sequenced to examine differences in community structure and potential correlations with salinity. We then identified changes in transcription and metabolite production in a potentially novel Gillisia sp., isolated from this soil gradient, under elevated salt concentrations. A Shewanella sp. BF02_Schw, isolated from a Mars analog feature known as Blood Falls, was used to describe biosignatures produced during iron reduction, a plausible metabolic strategy for life on early Earth and Mars. Employing instrumentation relevant to both in situ and sample return Mars missions, we identified mineral and molecular biosignatures produced under high iron concentration and confirmed the biogenicity of these signatures via transcriptomics. Collectively, this dissertation describes specific ways that MDV microorganisms interact with their environment that provide insight into the impact of climatic change on Antarctic communities and inform strategies for the detection of life on other planets

Community action: value or instrument? An ethics and planning critical review

The community concept has maintained a constant and growing interest in urban studies and many related fields. The origin of this continuing interest seems to derive from the importance of the concept of community within diverse forms of political language and interpretations within different planning practices. In this contribution, through the analysis of different ethical and planning theories, we want to provide an update framework on community action. According to this objective, the argumentation will proceed through a literature review on four ethics theories and three key aspects related to spatial planning, as well as matching this theoretical analysis with exemplifying practices. The final objective is to provide an original analysis on drivers and outcomesof different forms of community, raising general issues that refer to spatial planning, social organization and regulation

Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease

Background Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann–Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. Methods We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. Results With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P = 0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P = 0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). Conclusions Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease.National Human Genome Research Institute (U.S.) (Grant 5U54HG003067-11

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery

Lassa Fever in Post-Conflict Sierra Leone

Background: Lassa fever (LF), an often-fatal hemorrhagic disease caused by Lassa virus (LASV), is a major public health threat in West Africa. When the violent civil conflict in Sierra Leone (1991 to 2002) ended, an international consortium assisted in restoration of the LF program at Kenema Government Hospital (KGH) in an area with the world's highest incidence of the disease. Methodology/Principal Findings Clinical and laboratory records of patients presenting to the KGH Lassa Ward in the post-conflict period were organized electronically. Recombinant antigen-based LF immunoassays were used to assess LASV antigenemia and LASV-specific antibodies in patients who met criteria for suspected LF. KGH has been reestablished as a center for LF treatment and research, with over 500 suspected cases now presenting yearly. Higher case fatality rates (CFRs) in LF patients were observed compared to studies conducted prior to the civil conflict. Different criteria for defining LF stages and differences in sensitivity of assays likely account for these differences. The highest incidence of LF in Sierra Leone was observed during the dry season. LF cases were observed in ten of Sierra Leone's thirteen districts, with numerous cases from outside the traditional endemic zone. Deaths in patients presenting with LASV antigenemia were skewed towards individuals less than 29 years of age. Women self-reporting as pregnant were significantly overrepresented among LASV antigenemic patients. The CFR of ribavirin-treated patients presenting early in acute infection was lower than in untreated subjects. Conclusions/Significance: Lassa fever remains a major public health threat in Sierra Leone. Outreach activities should expand because LF may be more widespread in Sierra Leone than previously recognized. Enhanced case finding to ensure rapid diagnosis and treatment is imperative to reduce mortality. Even with ribavirin treatment, there was a high rate of fatalities underscoring the need to develop more effective and/or supplemental treatments for LF

A Gene Expression Fingerprint of C. Elegans Embryonic Motor Neurons

Differential gene expression specifies the highly diverse cell types that constitute the nervous system. With its sequenced genome and simple, well-defined neuroanatomy, the nematode C. elegans is a useful model system in which to correlate gene expression with neuron identity. The UNC-4 transcription factor is expressed in thirteen embryonic motor neurons where it specifies axonal morphology and synaptic function. These cells can be marked with an unc-4::GFP reporter transgene. Here we describe a powerful strategy, Micro-Array Profiling of C. elegans cells (MAPCeL), and confirm that this approach provides a comprehensive gene expression profile of unc-4::GFP motor neurons in vivo.