Impact of user fees on maternal health service utilization and related health outcomes: a systematic review.

OBJECTIVE: To assess the evidence of the impact of user fees on maternal health service utilization and related health outcomes in low- and middle-income countries, as well as their impact on inequalities in these outcomes. METHODS: Studies were identified by modifying a search strategy from a related systematic review. Primary studies of any design were included if they reported the effect of fee changes on maternal health service utilization, related health outcomes and inequalities in these outcomes. For each study, data were systematically extracted and a quality assessment conducted. Due to the heterogeneity of study methods, results were examined narratively. FINDINGS: Twenty studies were included. Designs and analytic approaches comprised: two interrupted time series, eight repeated cross-sectional, nine before-and-after without comparison groups and one before-and-after in three groups. Overall, the quality of studies was poor. Few studies addressed potential sources of bias, such as secular trends over time, and even basic tests of statistical significance were often not reported. Consistency in the direction of effects provided some evidence of an increase in facility delivery in particular after fees were removed, as well as possible increases in the number of managed delivery complications. There was little evidence of the effect on health outcomes or inequality in accessing care and, where available, the direction of effect varied. CONCLUSION: Despite the global momentum to abolish user fees for maternal and child health services, robust evidence quantifying impact remains scant. Improved methods for evaluating and reporting on these interventions are recommended, including better descriptions of the interventions and context, looking at a range of outcome measures, and adopting robust analytical methods that allow for adjustment of underlying and seasonal trends, reporting immediate as well as longer-term (e.g. at 6 months and 1 year) effects and using comparison groups where possible

Ball positioning in robotic billiards: a nonprehensile manipulation-based solution

The development and testing of a robotic system to play billiards is described in this paper. The last two decades have seen a number of developments in creating robots to play billiards. Although the designed systems have uccessfully incorporated the kinematics required for gameplay, a system level approach needed for accurate shot- making has not been realized. The current work considers the different aspects, like machine vision, dynamics, robot design and computational intelligence, and proposes, for the first time, a method based on robotic non-prehensile manipulation. High-speed video tracking is employed to determine the parameters of balls dynamics. Furthermore, three-dimensional impact models, involving ball spin and friction, are developed for different collisions. A three degree of freedom manipulator is designed and fabricated to execute shots. The design enables the manipulator to position the cue on the ball accurately and strike with controlled speeds. The manipulator is controlled from a PC via a microcontroller board. For a given table scenario, optimization is used to search the inverse dynamics space to find best parameters for the robotic shot maker. Experimental results show that a 90% potting accuracy and a 100–200 mm post-shot cue ball positioning accuracy has been achieved by the autonomous system

Transportability of tertiary qualifications and CPD: A continuing challenge for the global health workforce

Background: In workforces that are traditionally mobile and have long lead times for new supply, such as health, effective global indicators of tertiary education are increasingly essential. Difficulties with transportability of qualifications and cross-accreditation are now recognised as key barriers to meeting the rapidly shifting international demands for health care providers. The plethora of mixed education and service arrangements poses challenges for employers and regulators, let alone patients; in determining equivalence of training and competency between individuals, institutions and geographical locations. Discussion: This paper outlines the shortfall of the current indicators in assisting the process of global certification and competency recognition in the health care workforce. Using Organisation for Economic Cooperation and Development (OECD) data we highlight how International standardisation in the tertiary education sector is problematic for the global health workforce. Through a series of case studies, we then describe a model which enables institutions to compare themselves internally and with others internationally using bespoke or prioritised parameters rather than standards. Summary: The mobility of the global health workforce means that transportability of qualifications is an increasing area of concern. Valid qualifications based on workplace learning and assessment requires at least some variables to be benchmarked in order to judge performance. © 2012 Saltman et al.; licensee BioMed Central Ltd

Diverse specificities, phenotypes, and antiviral activities of cytomegalovirus-specific CD8+ T cells.

UNLABELLED: CD8(+) T cells specific for pp65, IE1, and IE2 are present at high frequencies in human cytomegalovirus (HCMV)-seropositive individuals, and these have been shown to have phenotypes associated with terminal differentiation, as well as both cytokine and proliferative dysfunctions, especially in the elderly. However, more recently, T cell responses to many other HCMV proteins have been described, but little is known about their phenotypes and functions. Consequently, in this study, we chose to determine the diversity of HCMV-specific CD8(+) T cell responses to the products of 11 HCMV open reading frames (ORFs) in a cohort of donors aged 20 to 80 years old as well as the ability of the T cells to secrete gamma interferon (IFN-γ). Finally, we also tested their functional antiviral capacity using a novel viral dissemination assay. We identified substantial CD8(+) T cell responses by IFN-γ enzyme-linked immunospot (ELISPOT) assays to all 11 of these HCMV proteins, and across the cohort, individuals displayed a range of responses, from tightly focused to highly diverse, which were stable over time. CD8(+) T cell responses to the HCMV ORFs were highly differentiated and predominantly CD45RA(+), CD57(+), and CD28(-), across the cohort. These highly differentiated cells had the ability to inhibit viral spread even following direct ex vivo isolation. Taken together, our data argue that HCMV-specific CD8(+) T cells have effective antiviral activity irrespective of the viral protein recognized across the whole cohort and despite viral immune evasion. IMPORTANCE: Human cytomegalovirus (HCMV) is normally carried without clinical symptoms and is widely prevalent in the population; however, it often causes severe clinical disease in individuals with compromised immune responses. HCMV is never cleared after primary infection but persists in the host for life. In HCMV carriers, the immune response to HCMV includes large numbers of virus-specific immune cells, and the virus has evolved many mechanisms to evade the immune response. While this immune response seems to protect healthy people from subsequent disease, the virus is never eliminated. It has been suggested that this continuous surveillance by the immune system may have deleterious effects in later life. The study presented in this paper examined immune responses from a cohort of donors and shows that these immune cells are effective at controlling the virus and can overcome the virus' lytic cycle immune evasion mechanisms.This work was funded by British Medical Research Council Grant G0701279 and supported by the NIHR Cambridge BRC Cell Phenotyping hub.This is the accepted manuscript version. The final published version is available from ASM at http://jvi.asm.org/content/early/2014/07/03/JVI.01477-14.abstract

Modeling of arylamide helix mimetics in the p53 peptide binding site of hDM2 suggests parallel and anti-parallel conformations are both stable.

The design of novel α-helix mimetic inhibitors of protein-protein interactions is of interest to pharmaceuticals and chemical genetics researchers as these inhibitors provide a chemical scaffold presenting side chains in the same geometry as an α-helix. This conformational arrangement allows the design of high affinity inhibitors mimicking known peptide sequences binding specific protein substrates. We show that GAFF and AutoDock potentials do not properly capture the conformational preferences of α-helix mimetics based on arylamide oligomers and identify alternate parameters matching solution NMR data and suitable for molecular dynamics simulation of arylamide compounds. Results from both docking and molecular dynamics simulations are consistent with the arylamides binding in the p53 peptide binding pocket. Simulations of arylamides in the p53 binding pocket of hDM2 are consistent with binding, exhibiting similar structural dynamics in the pocket as simulations of known hDM2 binders Nutlin-2 and a benzodiazepinedione compound. Arylamide conformations converge towards the same region of the binding pocket on the 20 ns time scale, and most, though not all dihedrals in the binding pocket are well sampled on this timescale. We show that there are two putative classes of binding modes for arylamide compounds supported equally by the modeling evidence. In the first, the arylamide compound lies parallel to the observed p53 helix. In the second class, not previously identified or proposed, the arylamide compound lies anti-parallel to the p53 helix

Quantitative elemental mapping of granulite-facies monazite: Textural insights and implications for petrochronology

Texturally complex monazite grains contained in two granulite-facies pelitic migmatites from southern Baffin Island, Arctic Canada, were mapped by laser ablation-inductively coupled plasma-mass spectrometry (using spot sizes < 5 µm) to quantitatively determine the spatial variation in trace element chemistry (with up to 1883 analyses per grain). The maps highlight the chemical complexity of monazite grains that have experienced multiple episodes of growth, resorption and chemical modification by dissolution-precipitation during high-grade metamorphism. Following detailed chemical characterisation of monazite compositional zones, a related U-Pb dataset is re-interpreted, allowing petrologically-significant ages to be extracted from a continuum of concordant data. Synthesis of these data with pseudosection modelling of prograde and peak conditions allows for the temporal evolution of monazite trace element chemistry to be placed in the context of the evolving P-T conditions and major phase assemblage. This approach enables a critical evaluation of three commonly used petrochronological indicators: linking Y to garnet abundance, the Eu anomaly to feldspar content, and Th/U to anatectic processes. Europium anomalies and Th/U behave in a relatively systematic fashion, suggesting that they are reliable petrochronological witnesses. However, Y systematics are variable, both within domains interpreted to have grown in a single event, between grains interpreted to be part of the same age population, and between samples that experienced similar metamorphic conditions and mineral assemblages. These observations caution against generalised petrological interpretations on the basis of Y content, as it suggests Y concentrations in monazite are controlled by domainal equilibria. The results reveal a ~45 Myr interval between prograde metamorphism and retrograde melt crystallisation in the study area, emphasising the long-lived nature of heat flow in high-grade metamorphic terranes. Such long timescales of metamorphism would be assisted by the growth, retention and dominance of high-Th suprasolidus monazite, as observed in this study, contributing to the radiogenic heating budget of mid- to lower-crustal environments. Careful characterisation of monazite grains suggests that continuum-style U-Pb datasets can be decoded to provide insights into the duration of metamorphic processes.Natural Sciences and Engineering Research Council Visiting Fellowship Isaac Newton Trust Research Grant (RG74916

Transient activation of human cytomegalovirus lytic gene expression during latency allows cytotoxic T cell killing of latently infected cells.

Human cytomegalovirus (HCMV) latency in the myeloid lineage is maintained by repressive histone modifications around the major immediate early promoter (MIEP), which results in inhibition of the lytic viral life cycle. We now show that pharmacological inhibition of histone deacetylases (HDACs) relieves this repression of the MIEP and induces transient expression of the viral lytic immediate early (IE) antigens but, importantly, not full virus reactivation. In turn, these latently infected cells now become targets for IE-specific cytotoxic T cells (CTLs) which are present at high frequency in all normal healthy HCMV positive carriers but would normally be unable to target latent (lytic antigen-negative) cells. This approach of transiently inducing viral lytic gene expression by HDAC inhibition, in otherwise latently infected cells, offers a window of opportunity to target and purge the latent myeloid cell reservoir by making these normally immunologically undetectable cells visible to pre-existing host immune responses to viral lytic antigens.This work was funded by a British Medical Research programme grant, grant number G0701279 and Wellcome Research Grant, grant number RG68483. This research was supported by the Cambridge NIHR BRC Cell Phenotyping Hub.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/srep2467

Different DNA End Configurations Dictate Which NHEJ Components Are Most Important for Joining Efficiency

The nonhomologous DNA end-joining (NHEJ) pathway is a key mechanism for repairing dsDNA breaks that occur often in eukaryotic cells. In the simplest model, these breaks are first recognized by Ku, which then interacts with other NHEJ proteins to improve their affinity at DNA ends. These include DNA-PK$_{cs}$ and Artemis for trimming the DNA ends; DNA polymerase μ and λ to add nucleotides; and the DNA ligase IV complex to ligate the ends with the additional factors, XRCC4 (X-ray repair cross-complementing protein 4), XLF (XRCC4-like factor/Cernunos), and PAXX (paralog of XRCC4 and XLF). $\textit{In vivo}$ studies have demonstrated the degrees of importance of these NHEJ proteins in the mechanism of repair of dsDNA breaks, but interpretations can be confounded by other cellular processes. $\textit{In vitro}$ studies with NHEJ proteins have been performed to evaluate the nucleolytic resection, polymerization, and ligation steps, but a complete system has been elusive. Here we have developed a NHEJ reconstitution system that includes the nuclease, polymerase, and ligase components to evaluate relative NHEJ efficiency and analyze ligated junctional sequences for various types of DNA ends, including blunt, 5' overhangs, and 3' overhangs. We find that different dsDNA end structures have differential dependence on these enzymatic components. The dependence of some end joining on only Ku and XRCC4·DNA ligase IV allows us to formulate a physical model that incorporates nuclease and polymerase components as needed.National Institutes of Health, Cancer Research UK Program Grant IDs: C6/A11224, C6946/A14492), Wellcome Trust (Grant IDs: WT092096, WT093167

Leishmania-specific surface antigens show sub-genus sequence variation and immune recognition.

A family of hydrophilic acylated surface (HASP) proteins, containing extensive and variant amino acid repeats, is expressed at the plasma membrane in infective extracellular (metacyclic) and intracellular (amastigote) stages of Old World Leishmania species. While HASPs are antigenic in the host and can induce protective immune responses, the biological functions of these Leishmania-specific proteins remain unresolved. Previous genome analysis has suggested that parasites of the sub-genus Leishmania (Viannia) have lost HASP genes from their genomes