Addressing the challenge of neonatal mortality.

Reducing neonatal mortality remains a challenge with an estimated 3.0 million neonatal deaths in 2011, three-quarters of these in sub-Saharan Africa and Southern Asia. The leading causes of neonatal death globally are complications of preterm birth, intrapartum-related causes and infections. While post-neonatal, under-5 deaths fell by 47% between 1990 and 2011, neonatal deaths only fell by 32% and they now account for 43% of all under-5 child deaths. This article reviews the progress in reducing neonatal deaths in high-burden countries and presents an overview of known effective interventions to reduce neonatal mortality and the challenges faced in implementing these in high-burden settings. Effective action is possible to reduce neonatal mortality, but innovative approaches to implementation will be required if these preventable deaths are to be avoided

Causal mediation analysis with multiple mediators.

In diverse fields of empirical research-including many in the biological sciences-attempts are made to decompose the effect of an exposure on an outcome into its effects via a number of different pathways. For example, we may wish to separate the effect of heavy alcohol consumption on systolic blood pressure (SBP) into effects via body mass index (BMI), via gamma-glutamyl transpeptidase (GGT), and via other pathways. Much progress has been made, mainly due to contributions from the field of causal inference, in understanding the precise nature of statistical estimands that capture such intuitive effects, the assumptions under which they can be identified, and statistical methods for doing so. These contributions have focused almost entirely on settings with a single mediator, or a set of mediators considered en bloc; in many applications, however, researchers attempt a much more ambitious decomposition into numerous path-specific effects through many mediators. In this article, we give counterfactual definitions of such path-specific estimands in settings with multiple mediators, when earlier mediators may affect later ones, showing that there are many ways in which decomposition can be done. We discuss the strong assumptions under which the effects are identified, suggesting a sensitivity analysis approach when a particular subset of the assumptions cannot be justified. These ideas are illustrated using data on alcohol consumption, SBP, BMI, and GGT from the Izhevsk Family Study. We aim to bridge the gap from "single mediator theory" to "multiple mediator practice," highlighting the ambitious nature of this endeavor and giving practical suggestions on how to proceed

Harnessing the power of genomics and immunoinformatics to produce improved vaccines

The role of cellular immunity as a mediator of protection against disease is gaining recognition, particularly with regard to the many pathogens for which we presently lack effective vaccines. As a result, there is an ever-increasing need to understand the T-cell populations induced by vaccination and, therefore, T-cell epitopes responsible for triggering their activation. Although the characterization and harnessing of cellular immunity for vaccine development is an active area of research interest, the field still needs to rigorously define T-cell epitope specificities, above all, on a genomic level. New immunoinformatic epitope mapping tools now make it possible to identify pathogen epitopes and perform comparisons against human and microbial genomic data sets. Such information will help to determine whether adaptive immune responses elicited by a vaccine are both pathogen-specific and protective, but not crossreactive against host or host-associated sequences that could jeopardize self-tolerance and/or human microbiome–host homeostasis. Here, we discuss advances in genomics and vaccine design and their relevance to the development of safer, more effective vaccines

Is the teaching of skeletal image-interpretation at undergraduate level effective in preparing students for practice?

Poster presentatio

Three-dimensional structure of human basic fibroblast growth factor, a structural homolog of interleukin 1β

The three-dimensional structure of the 146-residue form of human basic fibroblast growth factor (bFGF), expressed as a recombinant protein in yeast, has been determined by x-ray crystallography to a resolution of 1.8 Å. bFGF is composed entirely of β-sheet structure, comprising a three-fold repeat of a four-stranded antiparallel β-meander. The topology of bFGF is identical to that of interleukin 1β, showing that although the two proteins share only 10% sequence identity, bFGF, interleukin 1, and their homologs comprise a family of structurally related mitogenic factors. Analysis of the three-dimensional structure in light of functional studies of bFGF suggests that the receptor binding site and the positively charged heparin binding site correspond to adjacent but separate loci on the β-barrel

Investment case for eliminating mother-to-child transmission of syphilis: promoting better maternal and child health and stronger health systems

Mother-to-child transmission (MTCT) of syphilis (commonly referred to as “congenital syphilis”) is relatively simple to eliminate and it is inexpensive to detect and treat, making it a possible “easy win” in terms of cost, feasibility and speed of scale-up. Investing in screening and treatment for syphilis in pregnant women ranks as one of the most cost-effective antenatal interventions. Screening all pregnant women, using simple and low-cost technologies, is feasible, even in low-resource settings. Syphilis is easily cured with penicillin, and MTCT of syphilis is easily prevented when pregnant mothers with syphilis infection are identified early and treated promptly. Penicillin is off patent, widely available, on the World Health Organization (WHO) list of essential medicines and, above all, inexpensive

Tregitope: Immunomodulation Powerhouse

IVIG is frequently used in the ‘pre-conditioning’ regimens for higher risk transplants; its effects are attributed in part to induction of Tregs. We have identified regulatory T cell (Treg) epitopes, now known as Tregitopes, in IgG, the main component of intravenous immunoglobulin therapy (IVIg). Tregitopes provide one explanation for the expansion and activation of Treg cells following IVIg treatment. Tregitopes are peptides that exhibit high affinity binding to multiple human HLA Class II DR; they are conserved across IgG isotypes and mammalian species. In vitro and in vivo, for human PBMC and in animal models, Tregitopes activate Tregs. Studies to delineate the mechanism of action have shown that Tregitopes’ effects are very similar to IVIg in vitro. Here we demonstrate that Tregitopes induce Tregs to produce IL-10, leading to modulation of dendritic cell phenotype (down-regulation of Class II, CD80 and CD86 and up-regulation of ILT3), and describe the effects of Tregitopes in the ABM-TCR-transgenic skin transplantation model. The discovery of Tregitopes in IgG and other autologous proteins may contribute to improved understanding of the mechanism of action of IVIg and lead to the application of these powerful immunomodulators to improve transplantation success and suppress autoimmune disease, in the future

Insecticide-treated curtains reduce the prevalence and intensity of malaria infection in Burkina Faso

A large, randomized controlled trial to investigate the impact of insecticide-treated curtains (ITC) on child mortality was conducted in an area of seasonal, holoendemic malaria in Burkina Faso. 158 communities totalling some 90,000 people were censused and grouped into 16 geographical clusters, 8 of which were randomly selected to receive ITC in June-July 1994, just prior to the rainy season. In September-October 1995, at the peak period of malaria transmission, a cross-sectional survey was conducted in 84 of the villages. A random sample of 905 children aged 6-59 months was identified and visited. 763 children (84%) were present at the time of the visit and recruited into the study. Mothers were asked about fever in the past 24 h, the child's temperature was taken, and a sample of blood collected to identify and quantify malaria infections and to measure haemoglobin (Hb) levels. Children protected by ITC were less likely to be infected with Plasmodium falciparum (risk ratio = 0.92; 95% CI 0.86, 0.98) or P. malariae (risk ratio = 0.42, 95% CI 0.19, 0.95). The mean intensity of P. falciparum infections was lower among children protected by ITC (899 vs. 1583 trophozoites/microliter; P < 0.001), while the mean Hb level was 0.4 g/dl higher (P < 0.001). While we found no evidence that ITC had an impact on the prevalence of malaria-associated fever episodes, the confidence intervals around our estimates of the impact of ITC on malaria morbidity were wide. We conclude that widespread implementation of ITC in this area of high malaria transmission led to a modest reduction in the prevalence of malaria infection and to a more substantial reduction in the intensity of these infections which caused increased Hb levels. We were unable to demonstrate any impact of ITC on malaria morbidity, but the wide confidence intervals around our point estimates do not preclude the possibility of a substantial impact

T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation

Protein therapeutics hold a prominent and rapidly expanding place among medicinal products. Purified blood products, recombinant cytokines, growth factors, enzyme replacement factors, monoclonal antibodies, fusion proteins, and chimeric fusion proteins are all examples of therapeutic proteins that have been developed in the past few decades and approved for use in the treatment of human disease. Despite early belief that the fully human nature of these proteins would represent a significant advantage, adverse effects associated with immune responses to some biologic therapies have become a topic of some concern. As a result, drug developers are devising strategies to assess immune responses to protein therapeutics during both the preclinical and the clinical phases of development. While there are many factors that contribute to protein immunogenicity, T cell- (thymus-) dependent (Td) responses appear to play a critical role in the development of antibody responses to biologic therapeutics. A range of methodologies to predict and measure Td immune responses to protein drugs has been developed. This review will focus on the Td contribution to immunogenicity, summarizing current approaches for the prediction and measurement of T cell-dependent immune responses to protein biologics, discussing the advantages and limitations of these technologies, and suggesting a practical approach for assessing and mitigating Td immunogenicity