The global pipeline of new medicines for the control and elimination of malaria

ABSTRACT: Over the past decade, there has been a transformation in the portfolio of medicines to combat malaria. New fixed-dose artemisinin combination therapy is available, with four different types having received approval from Stringent Regulatory Authorities or the World Health Organization (WHO). However, there is still scope for improvement. The Malaria Eradication Research agenda identified several gaps in the current portfolio. Simpler regimens, such as a single-dose cure are needed, compared with the current three-day treatment. In addition, new medicines that prevent transmission and also relapse are needed, but with better safety profiles than current medicines. There is also a big opportunity for new medicines to prevent reinfection and to provide chemoprotection. This study reviews the global portfolio of new medicines in development against malaria, as of the summer of 2012. Cell-based phenotypic screening, and 'fast followers' of clinically validated classes, mean that there are now many new classes of molecules starting in clinical development, especially for the blood stages of malaria. There remain significant gaps for medicines blocking transmission, preventing relapse, and long-duration molecules for chemoprotection. The nascent pipeline of new medicines is significantly stronger than five years ago. However, there are still risks ahead in clinical development and sustainable funding of clinical studies is vital if this early promise is going to be delivered.     

Effects of local extinction of the plains vizcacha (Lagostomus maximus) on vegetation patterns in semi-arid scrub

We studied spatial and temporal effects of local extinction of the plains vizcacha (Lagostomus maximus) on plant communities following widespread, natural extinctions of vizcachas in semi-arid scrub of Argentina. Spatial patterns in vegetation were examined along transects extending outward from active and extinct vizcacha burrow systems. Responses of vegetation to removal of vizcachas were assessed experimentally with exclosures and by documenting vegetation dynamics for 6 years following extinctions. Transect data demonstrated clear spatial patterns in plant cover, particularly an increase in perennial grasses, outward from active vizcacha burrows. These patterns were consistent with predictions based on foraging theory and studies that document grasses as the preferred food of vizcachas. Removal of vizcachas, experimentally and with extinctions, resulted in an immediate increase in perennial and annual forbs indicating that intense herbivory can depress forb cover, as well as grasses. After a 1-year lag following cessation of herbivory, cover of grasses increased. Forbs declined as grasses increased. The long-term effect of extinction of vizcachas was a conversion of colony sites from open patches dominated by forbs to dense bunch grass characteristic of the matrix. Major changes in vegetation occurred within 2–3 years after extinction, resulting in a large pulse of landscape change. However, some species of grasses were uncommon until 5–6 years after the vizcacha extinction. With extinction and colonization, vizcachas generate a dynamic mosaic of patches on the landscape and create temporal, as well as spatial, heterogeneity in semi-arid scrub.     

Effects of treatment-induced mortality and tumor-induced mortality on tests for carcinogenicity in small samples

Statistical tests of carcinogenicity are shown to have varying degrees of robustness to the effects of mortality. Mortality induced by two different mechanisms is studied--mortality due to the tumor of interest, and mortality due to treatment independent of the tumor. The two most commonly used tests, the life-table test and the Cochran-Armitage linear trend test, are seen to be highly sensitive to increases in treatment lethality using small-sample simulations. Increases in tumor lethality are seen to affect the performance of commonly used prevalence tests such as logistic regression. A simple survival-adjusted quantal response test appears to be the most robust of all the procedures considered.     

Interannual population dynamics of the green spruce aphid Elatobium abietinum (Walker) in France

The hypothesis that similar processes govern interannual dynamics of green spruce aphid in the UK and France, is generally supported by the application of a general discrete model. A simple model based on relatively few parameters was able to closely characterise interannual population dynamics from completely independent aerial and arboreal samples of aphids. Long-term field population estimates of the green spruce aphid Elatobium abietinum (Walker) in France have provided the opportunity to select and evaluate the generality of a model, which was developed in the UK to explain the year-to-year variations in peak abundance of the aphid. The objective was to observe the influence of the local climates and disturbing climate factors on the population densities of the insect in two regions of France. The model uses climate variables and aphid population data from regular samples in the two regions that were investigated. A general discrete model was used to predict aphid population densities. The model performed well in tracking the interannual patterns of population but was less likely to predict absolute population density. To improve predictions, further account would need to be taken of additional site-specific climate variables and the strength of overcompensating density dependence. Nevertheless, it is clear that broadly similar processes are at work in the population dynamics of this insect across its biogeographical range.     

Effects of 1-methyl cyclohexane carboxylic acid (CCA) on cellular energetics in neuroblastoma cells

The level of cellular energetics has been estimated in neuroblastoma cells under different culture conditions. The cellular accumulation of isomerase-2-deoxy [¹⁴C]D-glucose-6-phosphate was taken as reflecting glucose utilization. A considerably higher amount of radioactivity — 2.5 to 4 times — is found in CCA treated cells, as compared to other types of cultures, corresponding to a higher rate of deoxyglucose penetration and utilization.     

Geographical Variation in Ribotype Profiles of Escherichia coli Isolates from Humans, Swine, Poultry, Beef, and Dairy Cattle in Florida

Waters impacted by fecal pollution can exact high risks to human health and can result in financial losses due to closures of water systems used for recreation and for harvesting seafood. Identifying the sources of fecal pollution in water is paramount in assessing the potential human health risks involved as well as in assessing necessary remedial action. Recently, various researchers have used the ribotyping method to identify sources of bacterial indicators (Escherichia coli and enterococci) in environmental waters. While these studies have identified genotypic differences between human- and animal-derived indicators that are capable of differentiating organisms isolated from humans and various animal hosts, most have focused on organisms collected from a confined geographic area and have not addressed the question of whether these ribotype profiles are watershed specific or if they can be applied universally to organisms from other geographic locations. In this study, E. coli isolates were obtained from humans, beef cattle, dairy cattle, swine, and poultry from locations in northern, central, and southern Florida and were subjected to ribotyping analysis. The intent was to determine (i) if ribotype profiles are capable of discriminating the source of E. coli at the host species level and (ii) if the resulting fingerprints are uniform over an extended geographic area or if they can be applied only to a specific watershed. Our research indicated that, using a single restriction enzyme (HindIII), the ribotyping procedure is not capable of differentiating E. coli isolates from the different animal species sampled in this study. Results indicate, however, that this procedure can still be used effectively to differentiate E. coli as being either human or animal derived when applied to organisms isolated from a large geographic region.     

Ancestral acquisitions,gene flow and multiple evolutionary trajectories of the type three secretion system and effectors in Xanthomonas plant pathogens

Deciphering the evolutionary history and transmission patterns of virulence determinants is necessary to understand the emergence of novel pathogens. The main virulence determinant of most pathogenic proteobacteria is the type three secretion system (T3SS). The Xanthomonas genus includes bacteria responsible for numerous epidemics in agroecosystems worldwide and represents a major threat to plant health. The main virulence factor of Xanthomonas is the Hrp2 family T3SS; however, this system is not conserved in all strains and it has not been previously determined whether the distribution of T3SS in this bacterial genus has resulted from losses or independent acquisitions. Based on comparative genomics of 82 genome sequences representing the diversity of the genus, we have inferred three ancestral acquisitions of the Hrp2 cluster during Xanthomonas evolution followed by subsequent losses in some commensal strains and re‐acquisition in some species. While mutation was the main force driving polymorphism at the gene level, interspecies homologous recombination of large fragments expanding through several genes shaped Hrp2 cluster polymorphism. Horizontal gene transfer of the entire Hrp2 cluster also occurred. A reduced core effectome composed of xopF1, xopM, avrBs2 and xopR was identified that may allow commensal strains overcoming plant basal immunity. In contrast, stepwise accumulation of numerous type 3 effector genes was shown in successful pathogens responsible for epidemics. Our data suggest that capacity to intimately interact with plants through T3SS would be an ancestral trait of xanthomonads. Since its acquisition, T3SS has experienced a highly dynamic evolutionary history characterized by intense gene flux between species that may reflect its role in host adaptation.     

A Dutch guideline for the treatment of scoliosis in neuromuscular disorders

Background

Children with neuromuscular disorders with a progressive muscle weakness such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy frequently develop a progressive scoliosis. A severe scoliosis compromises respiratory function and makes sitting more difficult. Spinal surgery is considered the primary treatment option for correcting severe scoliosis in neuromuscular disorders. Surgery in this population requires a multidisciplinary approach, careful planning, dedicated surgical procedures, and specialized after care.

Methods

The guideline is based on scientific evidence and expert opinions. A multidisciplinary working group representing experts from all relevant specialties performed the research. A literature search was conducted to collect scientific evidence in answer to specific questions posed by the working group. Literature was classified according to the level of evidence.

Results

For most aspects of the treatment scientific evidence is scarce and only low level cohort studies were found. Nevertheless, a high degree of consensus was reached about the management of patients with scoliosis in neuromuscular disorders. This was translated into a set of recommendations, which are now officially accepted as a general guideline in the Netherlands.

Conclusion

In order to optimize the treatment for scoliosis in neuromuscular disorders a Dutch guideline has been composed. This evidence-based, multidisciplinary guideline addresses conservative treatment, the preoperative, perioperative, and postoperative care of scoliosis in neuromuscular disorders.     

Association between phosphorus and suspended solids in an Everglades treatment wetland dominated by submersed aquatic vegetation

Restoration of the Everglades requires reduction of total phosphorus (TP) in the influent run-off from the Everglades agricultural area (EAA). The Everglades nutrient removal project tested phosphorus (P) - removal efficiencies of several treatment wetland cells. The best TP reduction has occurred within the submersed aquatic vegetation (SAV) - dominated treatment Cell 4. A significant proportion of the P reduction in Cell 4 over several years has been in the form of particulate P (PP). This study was conducted to (i) determine and compare the components of suspended solids in the Cell 4 influent and effluent waters, and (ii) investigate associations between PP and individual particulate components. Identification and quantification of components were accomplished using X-ray diffraction, thermogravimetry, scanning electron microscopy, and energy dispersive X-ray elemental analysis. The dominant particulate components in the Cell 4 water column are organic matter (OM), biogenic Si (predominantly diatom frustules), and calcite. Concentrations of PP, suspended solids, and particulate OM were greater at the Cell 4 inflow than at the outflow; consistent differences between particulate calcite in the influent vs. the effluent were not found. PP was positively correlated with particulate OM, but was not correlated with calcite. Data suggest that particulate OM, including microbial cells, plays an important role in P transport from the EAA. Possibly, a shift from planktonic to periphytic microbial distribution contributes to PP reduction. The importance of planktonic organisms as vectors of P in Everglades water warrants further study.