Distance to care, care seeking and child mortality in rural Burkina Faso: findings from a population-based cross-sectional survey.

OBJECTIVE: Although distance has been identified as an important barrier to care, evidence for an effect of distance to care on child mortality is inconsistent. We investigated the association of distance to care with self-reported care seeking behaviours, neonatal and post-neonatal under-five child mortality in rural areas of Burkina Faso. METHODS: We performed a cross-sectional survey in 14 rural areas from November 2014 to March 2015. About 100 000 women were interviewed on their pregnancy history and about 5000 mothers were interviewed on their care seeking behaviours. Euclidean distances to the closest facility were calculated. Mixed-effects logistic and Poisson regressions were used respectively to compute odds ratios for care seeking behaviours and rate ratios for child mortality during the 5 years prior to the survey. RESULTS: Thirty per cent of the children lived more than 7 km from a facility. After controlling for confounding factors, there was a strong evidence of a decreasing trend in care seeking with increasing distance to care (P ≤ 0.005). There was evidence for an increasing trend in early neonatal mortality with increasing distance to care (P = 0.028), but not for late neonatal mortality (P = 0.479) and post-neonatal under-five child mortality (P = 0.488). In their first week of life, neonates living 7 km or more from a facility had an 18% higher mortality rate than neonates living within 2 km of a facility (RR = 1.18; 95%CI 1.00, 1.39; P = 0.056). In the late neonatal period, despite the lack of evidence for an association of mortality with distance, it is noteworthy that rate ratios were consistent with a trend and similar to or larger than estimates in early neonatal mortality. In this period, neonates living 7 km or more from a facility had an 18% higher mortality rate than neonates living within 2 km of a facility (RR = 1.18; 95%CI 0.92, 1.52; P = 0.202). Thus, the lack of evidence may reflect lower power due to fewer deaths rather than a weaker association. CONCLUSION: While better geographic access to care is strongly associated with increased care seeking in rural Burkina Faso, the impact on child mortality appears to be marginal. This suggests that, in addition to improving access to services, attention needs to be paid to quality of those services.

Enhanced Laser-Driven Ion Acceleration by Superponderomotive Electrons Generated from Near-Critical-Density Plasma.

We report on the experimental studies of laser driven ion acceleration from a double-layer target where a near-critical density target with a few-micron thickness is coated in front of a nanometer-thin diamondlike carbon foil. A significant enhancement of proton maximum energies from 12 to ∼30 MeV is observed when a relativistic laser pulse impinges on the double-layer target under linear polarization. We attributed the enhanced acceleration to superponderomotive electrons that were simultaneously measured in the experiments with energies far beyond the free-electron ponderomotive limit. Our interpretation is supported by two-dimensional simulation results.

Temporal Structure of Attosecond Pulses from Laser-Driven Coherent Synchrotron Emission.

The microscopic dynamics of laser-driven coherent synchrotron emission transmitted through thin foils are investigated using particle-in-cell simulations. For normal incidence interactions, we identify the formation of two distinct electron nanobunches from which emission takes place each half-cycle of the driving laser pulse. These emissions are separated temporally by 130 as and are dominant in different frequency ranges, which is a direct consequence of the distinct characteristics of each electron nanobunch. This may be exploited through spectral filtering to isolate these emissions, generating electromagnetic pulses of duration ∼70 as.

Noncollinear Polarization Gating of Attosecond Pulse Trains in the Relativistic Regime.

High order harmonics generated at relativistic intensities have long been recognized as a route to the most powerful extreme ultraviolet pulses. Reliably generating isolated attosecond pulses requires gating to only a single dominant optical cycle, but techniques developed for lower power lasers have not been readily transferable. We present a novel method to temporally gate attosecond pulse trains by combining noncollinear and polarization gating. This scheme uses a split beam configuration which allows pulse gating to be implemented at the high beam fluence typical of multi-TW to PW class laser systems. Scalings for the gate width demonstrate that isolated attosecond pulses are possible even for modest pulse durations achievable for existing and planned future ultrashort high-power laser systems. Experimental results demonstrating the spectral effects of temporal gating on harmonic spectra generated by a relativistic laser plasma interaction are shown.

Ion Acceleration Using Relativistic Pulse Shaping in Near-Critical-Density Plasmas.

Ultraintense laser pulses with a few-cycle rising edge are ideally suited to accelerating ions from ultrathin foils, and achieving such pulses in practice represents a formidable challenge. We show that such pulses can be obtained using sufficiently strong and well-controlled relativistic nonlinearities in spatially well-defined near-critical-density plasmas. The resulting ultraintense pulses with an extremely steep rising edge give rise to significantly enhanced carbon ion energies consistent with a transition to radiation pressure acceleration.

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.

Bright subcycle extreme ultraviolet bursts from a single dense relativistic electron sheet.

Double-foil targets separated by a low density plasma and irradiated by a petawatt-class laser are shown to be a copious source of coherent broadband radiation. Simulations show that a dense sheet of relativistic electrons is formed during the interaction of the laser with the tenuous plasma between the two foils. The coherent motion of the electron sheet as it transits the second foil results in strong broadband emission in the extreme ultraviolet, consistent with our experimental observations.

Dependence of laser-driven coherent synchrotron emission efficiency on pulse ellipticity and implications for polarization gating.

The polarization dependence of laser-driven coherent synchrotron emission transmitted through thin foils is investigated experimentally. The harmonic generation process is seen to be almost completely suppressed for circular polarization opening up the possibility of producing isolated attosecond pulses via polarization gating. Particle-in-cell simulations suggest that current laser pulses are capable of generating isolated attosecond pulses with high pulse energies.

Beaming of high-order harmonics generated from laser-plasma interactions.

Beam divergences of high-order extreme ultraviolet harmonics from intense laser interactions with steep plasma density gradients are studied through experiment and Fourier analysis of the harmonic spatial phase. We show that while emission due to the relativistically oscillating mirror mechanism can be explained by ponderomotive surface denting, in agreement with previous results, the divergence of the emission due to the coherent wake emission mechanism requires a combination of the dent phase and an intrinsic emission phase. The temporal dependence of the divergences for both mechanisms is highlighted while it is also shown that the coherent wake emission divergence can be small in circumstances where the phase terms compensate each other.

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.

Methods for dealing with time-dependent confounding.

Longitudinal studies, where data are repeatedly collected on subjects over a period, are common in medical research. When estimating the effect of a time-varying treatment or exposure on an outcome of interest measured at a later time, standard methods fail to give consistent estimators in the presence of time-varying confounders if those confounders are themselves affected by the treatment. Robins and colleagues have proposed several alternative methods that, provided certain assumptions hold, avoid the problems associated with standard approaches. They include the g-computation formula, inverse probability weighted estimation of marginal structural models and g-estimation of structural nested models. In this tutorial, we give a description of each of these methods, exploring the links and differences between them and the reasons for choosing one over the others in different settings.

Variant CJD infection in the spleen of a neurologically asymptomatic UK adult patient with haemophilia.

SUMMARY: All UK patients with bleeding disorders treated with any UK-sourced pooled factor concentrates between 1980 and 2001 have been informed that they may be at an increased risk of infection with variant Creutzfeldt-Jakob disease (vCJD). We describe a study to detect disease-associated, protease-resistant prion protein (PrP(res)) in 17 neurologically aymptomatic patients with haemophilia considered to be at increased risk of vCJD. Materials from 11 autopsy and seven biopsy cases were analysed for PrP(res). The tissues available from each case were variable, ranging from a single biopsy sample to a wide range of autopsy tissues. A single specimen from the spleen of one autopsy case gave a strong positive result on repeated testing for PrP(res) by Western blot analysis. This tissue came from a 73-year-old male patient with no history of neurological disease, who was heterozygous (methionine/valine) at codon 129 in the prion protein gene. He had received over 9000 units of factor VIII concentrate prepared from plasma pools known to include donations from a vCJD-infected donor, and some 400,000 units not known to include donations from vCJD-infected donors. He had also received 14 units of red blood cells and had undergone several surgical and invasive endoscopic procedures. Estimates of the relative risks of exposure through diet, surgery, endoscopy, blood transfusion and receipt of UK-sourced plasma products suggest that by far the most likely route of infection in this patient was receipt of UK plasma products.

Electron trajectories associated with laser-driven coherent synchrotron emission at the front surface of overdense plasmas.

We present an in-depth analysis of an ultrafast electron trajectory type that produces attosecond electromagnetic pulses in both the reflected and forward directions during normal incidence, relativistic laser-plasma interactions. Our particle-in-cell simulation results show that for a target which is opaque to the frequency of the driving laser pulse the emission trajectory is synchrotronlike but differs significantly from the previously identified figure-eight type which produces bright attosecond bursts exclusively in the reflected direction. The origin and characteristics of this trajectory type are explained in terms of the driving electromagnetic fields, the opacity of the plasma, and the conservation of canonical momentum.

Predictability of the UK variant Creutzfeldt-Jakob disease epidemic.

Back-calculation analysis of the variant Creutzfeldt-Jakob disease epidemic in the United Kingdom is used to estimate the number of infected individuals and future disease incidence. The model assumes a hazard of infection proportional to the incidence of bovine spongiform encephalopathy in the United Kingdom and accounts for precautionary control measures and very wide ranges of incubation periods. The model indicates that current case data are compatible with numbers of infections ranging from a few hundred to several millions. In the latter case, the model suggests that the mean incubation period must be well beyond the human life-span, resulting in disease epidemics of at most several thousand cases.

Humoral and cell-mediated immunity to MSP3 peptides in adults immunized with MSP3 in malaria endemic area, Burkina Faso.

We performed a single-blind, randomized phase 1 trial of the long synthetic peptide (LSP) of merozoite surface protein-3 (MSP3) in adults living in Burkina Faso. Thirty eligible volunteers were randomized to receive either the MSP3-LSP candidate vaccine or tetanus toxoid vaccine as a control. A dose of each vaccine was administered on days 0, 28 and 112 and the vaccine was formulated with aluminium hydroxide. Humoral immune responses were assessed by ELISA at days 0, 28, 56, 112, 140, 252 and 365 and cell-mediated immune responses by lymphoproliferation assay and by ELISA on days 0, 56 and 140. IgG responses to four peptides of MSP3 were similar in both vaccine groups. Higher IgG concentrations were recorded after the beginning of malaria high transmission season in both vaccine groups. The lymphocyte proliferation and the production of IFN-gamma in response to stimulation with the four overlapping peptides increased following vaccination in the MSP3-LSP vaccine group, but did not change appreciably in the control group. In contrast to natural infection, MSP3-LSP did not boost humoral responses to the four overlapping peptides of MSP3 to any detectable degree in our semi-immune adult. MSP3-LSP may be more immunogenic in young children with little or no acquired immunity.

Mass deworming for soil-transmitted helminths and schistosomiasis among pregnant women: A systematic review and individual participant data meta-analysis.

The objective of the review is to use individual participant data (IPD) meta-analysis to explore the effect of mass deworming during pregnancy. We developed a search strategy and searched the databases till March 2018. We included individually randomised controlled trials; cluster randomised controlled trials and quasi randomised studies providing preventive or therapeutic deworming drugs for soil transmitted helminthiases and schistosomiasis during pregnancy. All IPD were assessed for completeness, compared to published reports and entered into a common data spreadsheet. Out of the seven trials elgible for IPD, we received data from three trials; out of 8,515 potential IPD participants; data were captured for 5,957 participants. Findings from this IPD suggest that mass deworming during pregnancy reduces maternal anaemia by 23% (Risk ratio [RR]: 0.77, 95% confidence intreval [CI]: 0.73-0.81; three trials; 5,216 participants; moderate quality evidence). We did not find any evidence of an effect of mass deworming during pregnancy on any of the other outcomes. There was no evidence of effect modification; however these findings should be interpreted with caution due to small sample sizes. The quality of evidence was rated as moderate for our findings. Our analyses suggest that mass deworming during pregnancy is associated with reducing anaemia with no evidence of impact on any other maternal or pregnancy outcomes. Our analyses were limited by the availability of data for the impact by subgroups and effect modification. There is also a need to support and promote open data for future IPDs.

Do antibody responses to malaria vaccine candidates influenced by the level of malaria transmission protect from malaria?

OBJECTIVES: To examine whether the humoural response to malaria vaccine candidate antigens, Plasmodium falciparum [circumsporozoite repetitive sequence (NANP)(5) GLURP fragments (R0 and R2) and MSP3] varies with the level of malaria transmission and to determine whether the antibodies (IgG) present at the beginning of the malaria transmission season protect against clinical malaria. METHODS: Cross-sectional surveys were conducted to measure antibody response before, at the peak and at the end of the transmission season in children aged 6 months to 10 years in two villages with different levels of malaria transmission. A cohort study was performed to estimate the incidence of clinical malaria. RESULTS: Antibodies to these antigens showed different seasonal patterns. IgG concentrations to any of the four antigens were higher in the village with high entomological inoculation rate. Multivariate analysis of combined data from the two villages indicated that children who were classified as responders to the selected antigens were at lower risk of clinical malaria than children classified as non-responders [(NANP)(5) (incidence rate ratio (IRR) = 0.65, 95% CI: 0.46-0.92; P = 0.016), R0 (IRR = 0.69, 95% CI: 0.48-0.97; P = 0.032), R2 (IRR = 0.73, 95% CI: 0.50-1.06; P = 0.09), MSP3 (IRR = 0.52, 95% CI: 0.32-0.85; P = 0.009)]. Fitting a model with all four antibody responses showed that MSP3 looked the best malaria vaccine candidate (IRR = 0.63; 95% CI: 0.38-1.05; P = 0.08). CONCLUSION: Antibody levels to the four antigens are affected by the intensity of malaria transmission and associated with protection against clinical malaria. It is worthwhile investing in the development of these antigens as potential malaria vaccine candidates.

Estimating the birth prevalence and pregnancy outcomes of congenital malformations worldwide.

Congenital anomaly registries have two main surveillance aims: firstly to define baseline epidemiology of important congenital anomalies to facilitate programme, policy and resource planning, and secondly to identify clusters of cases and any other epidemiological changes that could give early warning of environmental or infectious hazards. However, setting up a sustainable registry and surveillance system is resource-intensive requiring national infrastructure for recording all cases and diagnostic facilities to identify those malformations that that are not externally visible. Consequently, not all countries have yet established robust surveillance systems. For these countries, methods are needed to generate estimates of prevalence of these disorders which can act as a starting point for assessing disease burden and service implications. Here, we describe how registry data from high-income settings can be used for generating reference rates that can be used as provisional estimates for countries with little or no observational data on non-syndromic congenital malformations.

Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion.

BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a novel human prion disease caused by infection with the agent of bovine spongiform encephalopathy (BSE). Epidemiological evidence does not suggest that sporadic CJD is transmitted from person to person via blood transfusion, but this evidence may not apply to vCJD. We aimed to identify whether vCJD is transmissible through blood transfusion. METHODS: The national CJD surveillance unit reported all cases of probable or definite vCJD to the UK blood services, which searched for donation records at blood centres and hospitals. Information on named recipients and donors was provided to the surveillance unit to establish if any matches existed between recipients or donors and the database of cases of vCJD. Recipients were also flagged at the UK Office of National Statistics to establish date and cause of death. FINDINGS: 48 individuals were identified as having received a labile blood component from a total of 15 donors who later became vCJD cases and appeared on the surveillance unit's register. One of these recipients was identified as developing symptoms of vCJD 6.5 years after receiving a transfusion of red cells donated by an individual 3.5 years before the donor developed symptoms of vCJD. INTERPRETATION: Our findings raise the possibility that this infection was transfusion transmitted. Infection in the recipient could have been due to past dietary exposure to the BSE agent. However, the age of the patient was well beyond that of most vCJD cases, and the chance of observing a case of vCJD in a recipient in the absence of transfusion transmitted infection is about 1 in 15000 to 1 in 30000.

The epidemiology of variant Creutzfeldt-Jakob disease.

Variant Creutzfeldt-Jakob disease (vCJD) was identified as a new disease in 1996. It was linked to infection with the bovine spongiform encephalopathy (BSE) agent although the epidemiological evidence for this was not strong, but later strain typing studies confirmed the association. The disease has affected predominantly young adults whose dietary and other characteristics are unexceptional compared to control groups, other than that all patients to date have been methoinine homozygous at codon 129 of the prion protein gene and the incidence has been about two times higher in the North of the UK. The number of cases in the 7 years after first identification of the disease has been considerably lower than initially feared, given the likely widespread exposure of the UK population to the BSE agent through contaminated beef products. Predictions of the possible future course of the epidemic have many associated uncertainties, but current mathematical models suggest that more than a few thousand cases is unlikely. Such modelling is limited by the absence of a test for infection with the vCJD agent. The development of a test that could be used on easily accessible tissue to detect infection early in the incubation period would not only advance understanding of the epidemiology of infection with the agent but would also aid the implementation of control measures to prevent potential iatrogenic spread.