Genetically engineered parasites: the solution to designing an effective malaria vaccine?

Genetic engineering provides an ingenious method of attenuating Plasmodium falciparum parasites for next generation vaccines. A novel approach stimulates new optimism in the struggle to eliminate the burden of malaria

Intracortical Microstimulation Maps of Motor, Somatosensory, and Posterior Parietal Cortex in Tree Shrews (Tupaia Belangeri) Reveal Complex Movement Representations

Long-train intracortical microstimulation (LT-ICMS) is a popular method for studying the organization of motor and posterior parietal cortex (PPC) in mammals. In primates, LT-ICMS evokes both multi-joint and multiple body-part movements in primary motor, premotor, and posterior parietal cortex. In rodents LT-ICMS evokes complex movements of a single limb in motor cortex. Unfortunately, very little is known about motor/PPC organization in other mammals. Tree shrews are closely related to both primates and rodents and could provide insights into the evolution of complex movement domains in primates. The present study investigated the extent of cortex in which movements could be evoked with ICMS and the characteristics of movements elicited using both short-train (ST) and LT ICMS in tree shrews. We demonstrate that LT-ICMS and ST-ICMS maps are similar, with the movements elicited with ST-ICMS being truncated versions of those elicited with LT-ICMS. In addition, LT-ICMS evoked complex movements within motor cortex similar to those in rodents. More complex movements involving multiple body parts such as the hand and mouth were also elicited in motor cortex and PPC, as in primates. Our results suggest that complex movement networks present in PPC and motor cortex were present in mammals prior to the emergence of primates

Differences in research funding for women scientists: a systematic comparison of UK investments in global infectious disease research during 1997–2010

Objectives: There has not previously been a systematic comparison of awards for research funding in infectious diseases by sex. We investigated funding awards to UK institutions for all infectious disease research from 1997 to 2010, across disease categories and along the research and development continuum. Design: Systematic comparison. Methods: Data were obtained from several sources for awards from the period 1997 to 2010 and each study assigned to—disease categories; type of science (preclinical, phases I–III trials, product development, implementation research); categories of funding organisation. Fold differences and statistical analysis were used to compare total investment, study numbers, mean grant and median grant between men and women. Results: 6052 studies were included in the final analysis, comprising 4357 grants (72%) awarded to men and 1695 grants (28%) awarded to women, totalling £2.274 billion. Of this, men received £1.786 billion (78.5%) and women £488 million (21.5%). The median value of award was greater for men (£179 389; IQR £59 146–£371 977) than women (£125 556; IQR £30 982–£261 834). Awards were greater for male principal investigators (PIs) across all infectious disease systems, excepting neurological infections and sexually transmitted infections. The proportion of total funding awarded to women ranged from 14.3% in 1998 to 26.8% in 2009 (mean 21.4%), and was lowest for preclinical research at 18.2% (£285.5 million of £1.573 billion) and highest for operational research at 30.9% (£151.4 million of £489.7 million). Conclusions: There are consistent differences in funding received by men and women PIs: women have fewer funded studies and receive less funding in absolute and in relative terms; the median funding awarded to women is lower across most infectious disease areas, by funder, and type of science. These differences remain broadly unchanged over the 14-year study period

Funding Infectious Disease Research: A Systematic Analysis of UK Research Investments by Funders 1997–2010

Background: Research investments are essential to address the burden of disease, however allocation of limited resources is poorly documented. We systematically reviewed the investments awarded by funding organisations to UK institutions and their global partners for infectious disease research. Methodology/Principal Findings Public and philanthropic investments for the period 1997 to 2010 were included. We categorised studies by infectious disease, cross-cutting theme, and by research and development value chain, reflecting the type of science. We identified 6165 funded studies, with a total research investment of UK £2.6 billion. Public organisations provided £1.4 billion (54.0%) of investments compared with £1.1 billion (42.4%) by philanthropic organisations. Global health studies represented an investment of £928 million (35.7%). The Wellcome Trust was the leading investor with £688 million (26.5%), closely followed by the UK Medical Research Council (MRC) with £673 million (25.9%). Funding over time was volatile, ranging from ∼£40 million to ∼£160 million per year for philanthropic organisations and ∼£30 million to ∼£230 million for public funders. Conclusions/Significance: Infectious disease research funding requires global coordination and strategic long-term vision. Our analysis demonstrates the diversity and inconsistent patterns in investment, with volatility in annual funding amounts and limited investment for product development and clinical trials

Investments in respiratory infectious disease research 1997–2010: a systematic analysis of UK funding

Objectives: Respiratory infections are responsible for a large global burden of disease. We assessed the public and philanthropic investments awarded to UK institutions for respiratory infectious disease research to identify areas of underinvestment. We aimed to identify projects and categorise them by pathogen, disease and position along the research and development value chain. Setting: The UK. Participants: Institutions that host and carry out infectious disease research. Primary and secondary outcome measures The total amount spent and number of studies with a focus on several different respiratory pathogens or diseases, and to correlate these against the global burden of disease; also the total amount spent and number of studies relating to the type of science, the predominant funder in each category and the mean and median award size. Results: We identified 6165 infectious disease studies with a total investment of £2·6 billion. Respiratory research received £419 million (16.1%) across 1192 (19.3%) studies. The Wellcome Trust provided greatest investment (£135.2 million; 32.3%). Tuberculosis received £155 million (37.1%), influenza £80 million (19.1%) and pneumonia £27.8 million (6.6%). Despite high burden, there was relatively little investment in vaccine-preventable diseases including diphtheria (£0.1 million, 0.03%), measles (£5.0 million, 1.2%) and drug-resistant tuberculosis. There were 802 preclinical studies (67.3%) receiving £273 million (65.2%), while implementation research received £81 million (19.3%) across 274 studies (23%). There were comparatively few phase I–IV trials or product development studies. Global health research received £68.3 million (16.3%). Relative investment was strongly correlated with 2010 disease burden. Conclusions: The UK predominantly funds preclinical science. Tuberculosis is the most studied respiratory disease. The high global burden of pneumonia-related disease warrants greater investment than it has historically received. Other priority areas include antimicrobial resistance (particularly within tuberculosis), economics and proactive investments for emerging infectious threats

Systematic analysis of funding awarded for antimicrobial resistance research to institutions in the UK, 1997–2010

Objectives: To assess the level of research funding awarded to UK institutions specifically for antimicrobial resistance-related research and how closely the topics funded relate to the clinical and public health burden of resistance. Methods: Databases and web sites were systematically searched for information on how infectious disease research studies were funded for the period 1997–2010. Studies specifically related to antimicrobial resistance, including bacteriology, virology, mycology and parasitology research, were identified and categorized in terms of funding by pathogen and disease and by a research and development value chain describing the type of science. Results: The overall dataset included 6165 studies receiving a total investment of £2.6 billion, of which £102 million was directed towards antimicrobial resistance research (5.5% of total studies, 3.9% of total spend). Of 337 resistance-related projects, 175 studies focused on bacteriology (40.2% of total resistance-related spending), 42 focused on antiviral resistance (17.2% of funding) and 51 focused on parasitology (27.4% of funding). Mean annual funding ranged from £1.9 million in 1997 to £22.1 million in 2009. Conclusions: Despite the fact that the emergence of antimicrobial resistance threatens our future ability to treat many infections, the proportion of the UK infection-research spend targeting this important area is small. There are encouraging signs of increased investment in this area, but it is important that this is sustained and targeted at areas of projected greatest burden. Two areas of particular concern requiring more investment are tuberculosis and multidrug-resistant Gram-negative bacteria

'A bite before bed': exposure to malaria vectors outside the times of net use in the highlands of western Kenya.

BACKGROUND: The human population in the highlands of Nyanza Province, western Kenya, is subject to sporadic epidemics of Plasmodium falciparum. Indoor residual spraying (IRS) and long-lasting insecticide treated nets (LLINs) are used widely in this area. These interventions are most effective when Anopheles rest and feed indoors and when biting occurs at times when individuals use LLINs. It is therefore important to test the current assumption of vector feeding preferences, and late night feeding times, in order to estimate the extent to which LLINs protect the inhabitants from vector bites. METHODS: Mosquito collections were made for six consecutive nights each month between June 2011 and May 2012. CDC light-traps were set next to occupied LLINs inside and outside randomly selected houses and emptied hourly. The net usage of residents, their hours of house entry and exit and times of sleeping were recorded and the individual hourly exposure to vectors indoors and outdoors was calculated. Using these data, the true protective efficacy of nets (P*), for this population was estimated, and compared between genders, age groups and from month to month. RESULTS: Primary vector species (Anopheles funestus s.l. and Anopheles arabiensis) were more likely to feed indoors but the secondary vector Anopheles coustani demonstrated exophagic behaviour (p < 0.05). A rise in vector biting activity was recorded at 19:30 outdoors and 18:30 indoors. Individuals using LLINs experienced a moderate reduction in their overall exposure to malaria vectors from 1.3 to 0.47 bites per night. The P* for the population over the study period was calculated as 51% and varied significantly with age and season (p < 0.01). CONCLUSIONS: In the present study, LLINs offered the local population partial protection against malaria vector bites. It is likely that P* would be estimated to be greater if the overall suppression of the local vector population due to widespread community net use could be taken into account. However, the overlap of early biting habit of vectors and human activity in this region indicates that additional methods of vector control are required to limit transmission. Regular surveillance of both vector behaviour and domestic human-behaviour patterns would assist the planning of future control interventions in this region

The need to promote behaviour change at the cultural level: one factor explaining the limited impact of the MEMA kwa Vijana adolescent sexual health intervention in rural Tanzania. A process evaluation

Background - Few of the many behavioral sexual health interventions in Africa have been rigorously evaluated. Where biological outcomes have been measured, improvements have rarely been found. One of the most rigorous trials was of the multi-component MEMA kwa Vijana adolescent sexual health programme, which showed improvements in knowledge and reported attitudes and behaviour, but none in biological outcomes. This paper attempts to explain these outcomes by reviewing the process evaluation findings, particularly in terms of contextual factors. Methods - A large-scale, primarily qualitative process evaluation based mainly on participant observation identified the principal contextual barriers and facilitators of behavioural change. Results - The contextual barriers involved four interrelated socio-structural factors: culture (i.e. shared practices and systems of belief), economic circumstances, social status, and gender. At an individual level they appeared to operate through the constructs of the theories underlying MEMA kwa Vijana - Social Cognitive Theory and the Theory of Reasoned Action – but the intervention was unable to substantially modify these individual-level constructs, apart from knowledge. Conclusion - The process evaluation suggests that one important reason for this failure is that the intervention did not operate sufficiently at a structural level, particularly in regard to culture. Recently most structural interventions have focused on gender or/and economics. Complementing these with a cultural approach could address the belief systems that justify and perpetuate gender and economic inequalities, as well as other barriers to behaviour change

Sexual Phenotype Differences in zic2 mRNA Abundance in the Preoptic Area of a Protogynous Teleost, Thalassoma bifasciatum

The highly conserved members of the zic family of zinc-finger transcription factors are primarily known for their roles in embryonic signaling pathways and regulation of cellular proliferation and differentiation. This study describes sexual phenotype differences in abundances of zic2 mRNA in the preoptic area of the hypothalamus, a region strongly implicated in sexual behavior and function, in an adult teleost, Thalassoma bifasciatum. The bluehead wrasse (Thalassoma bifasciatum) is a valuable model for studying neuroendocrine processes because it displays two discrete male phenotypes, initial phase (IP) males and territorial, terminal phase (TP) males, and undergoes socially-controlled protogynous sex change. Previously generated microarray-based comparisons suggested that zic2 was upregulated in the brains of terminal phase males relative to initial phase males. To further explore this difference, we cloned a 727 bp sequence for neural zic2 from field-collected animals. Riboprobe-based in situ hybridization was employed to localize zic2 signal in adult bluehead brains and assess the relative abundance of brain zic2 mRNA across sexual phenotypes. We found zic2 mRNA expression was extremely abundant in the granular cells of the cerebellum and widespread in other brain regions including in the thalamus, hypothalamus, habenula, torus semicircularis, torus longitudinalis, medial longitudinal fascicle and telencephalic areas. Quantitative autoradiography and phosphorimaging showed zic2 mRNA hybridization signal in the preoptic area of the hypothalamus was significantly higher in terminal phase males relative to both initial phase males and females, and silver grain analysis confirmed this relationship between phenotypes. No significant difference in abundance was found in zic2 signal across phenotypes in the habenula, a brain region not implicated in the control of sexual behavior, or cerebellum