Indoor residual spraying with a non-pyrethroid insecticide reduces the reservoir of <i>Plasmodium falciparum</i> in a high-transmission area in northern Ghana

High-malaria burden countries in sub-Saharan Africa are shifting from malaria control towards elimination. Hence, there is need to gain a contemporary understanding of how indoor residual spraying (IRS) with non-pyrethroid insecticides when combined with long-lasting insecticidal nets (LLINs) impregnated with pyrethroid insecticides, contribute to the efforts of National Malaria Control Programmes to interrupt transmission and reduce the reservoir of Plasmodium falciparum infections across all ages. Using an interrupted time-series study design, four age-stratified malariometric surveys, each of ~2,000 participants, were undertaken pre- and post-IRS in Bongo District, Ghana. Following the application of three-rounds of IRS, P. falciparum transmission intensity declined, as measured by a >90% reduction in the monthly entomological inoculation rate. This decline was accompanied by reductions in parasitological parameters, with participants of all ages being significantly less likely to harbor P. falciparum infections at the end of the wet season post-IRS (aOR = 0.22 [95% CI: 0.19–0.26], p-value < 0.001). In addition, multiplicity of infection (MOIvar) was measured using a parasite fingerprinting tool, designed to capture within-host genome diversity. At the end of the wet season post-IRS, the prevalence of multi-genome infections declined from 75.6% to 54.1%. This study demonstrates that in areas characterized by high seasonal malaria transmission, IRS in combination with LLINs can significantly reduce the reservoir of P. falciparum infection. Nonetheless despite this success, 41.6% of the population, especially older children and adolescents, still harboured multi-genome infections. Given the persistence of this diverse reservoir across all ages, these data highlight the importance of sustaining vector control in combination with targeted chemotherapy to move high-transmission settings towards pre-elimination. This study also points to the benefits of molecular surveillance to ensure that incremental achievements are not lost and that the goals advocated for in the WHO’s High Burden to High Impact strategy are realized

Frequency-Dependent Competition Between Strains Imparts Persistence to Perturbations in a Model of <i>Plasmodium falciparum</i> Malaria Transmission

In high-transmission endemic regions, local populations of Plasmodium falciparum exhibit vast diversity of the var genes encoding its major surface antigen, with each parasite comprising multiple copies from this diverse gene pool. This strategy to evade the immune system through large combinatorial antigenic diversity is common to other hyperdiverse pathogens. It underlies a series of fundamental epidemiological characteristics, including large reservoirs of transmission from high prevalence of asymptomatics and long-lasting infections. Previous theory has shown that negative frequency-dependent selection (NFDS) mediated by the acquisition of specific immunity by hosts structures the diversity of var gene repertoires, or strains, in a pattern of limiting similarity that is both non-random and non-neutral. A combination of stochastic agent-based models and network analyses has enabled the development and testing of theory in these complex adaptive systems, where assembly of local parasite diversity occurs under frequency-dependent selection and large pools of variation. We show here the application of these approaches to theory comparing the response of the malaria transmission system to intervention when strain diversity is assembled under (competition-based) selection vs. a form of neutrality, where immunity depends only on the number but not the genetic identity of previous infections. The transmission system is considerably more persistent under NFDS, exhibiting a lower extinction probability despite comparable prevalence during intervention. We explain this pattern on the basis of the structure of strain diversity, in particular the more pronounced fraction of highly dissimilar parasites. For simulations that survive intervention, prevalence under specific immunity is lower than under neutrality, because the recovery of diversity is considerably slower than that of prevalence and decreased var gene diversity reduces parasite transmission. A Principal Component Analysis of network features describing parasite similarity reveals that despite lower overall diversity, NFDS is quickly restored after intervention constraining strain structure and maintaining patterns of limiting similarity important to parasite persistence. Given the described enhanced persistence under perturbation, intervention efforts will likely require longer times than the usual practice to eliminate P. falciparum populations. We discuss implications of our findings and potential analogies for ecological communities with non-neutral assembly processes involving frequency-dependence

Community case management of childhood illnesses: policy and implementation in Countdown to 2015 countries

OBJECTIVE: To explore the policies for, and implementation of, the community case management (CCM) of childhood illnesses in the 68 countries that were prioritized by the "Countdown to 2015" initiative in 2008. METHODS: In 2009-2010, community approaches concerning CCM policy and implementation, the roles of community health workers (CHWs) and the availability of medicines for the treatment of malaria, diarrhoea, pneumonia and neonatal infections were investigated by sending questionnaires to implementers and policy-makers and through telephone discussions with appropriate researchers and experts. FINDINGS: Of the 59 countries that responded, 81%, 75%, 54% and 14% had a policy for the CCM of diarrhoea, malaria, pneumonia and neonatal infections, respectively. Only three (6%) of the 53 malaria-endemic countries providing responses had policies for all four of these conditions, although 17 (32%) had CCM policies for malaria, diarrhoea and pneumonia. Some CCM of childhood illnesses was being implemented - more commonly for diarrhoea and malaria than for pneumonia or neonatal infections - in 88% of the countries providing responses. According to the responses received, CHWs administered the recommended treatments for diarrhoea, malaria or pneumonia in 34% (17/50), 100% (41/41) and 100% (34/34) of the countries implementing CCM of these conditions, respectively. Common programme concerns were drug supplies, quality of care and CHW incentives, training and supervision. CONCLUSION: Despite progress, further efforts are needed towards policy reform and the expansion of CCM programmes. Ensuring the availability of recommended medicines and operational research, to assure quality, remain priorities

Competition for hosts modulates vast antigenic diversity to generate persistent strain structure in <i>Plasmodium falciparum</i>

In their competition for hosts, parasites with antigens that are novel to the host immune system will be at a competitive advantage. The resulting frequency-dependent selection can structure parasite populations into strains of limited genetic overlap. For the causative agent of malaria, Plasmodium falciparum, the high recombination rates and associated vast diversity of its highly antigenic and multicopy var genes preclude such clear clustering in endemic regions. This undermines the definition of strains as specific, temporally persisting gene variant combinations. We use temporal multilayer networks to analyze the genetic similarity of parasites in both simulated data and in an extensively and longitudinally sampled population in Ghana. When viewed over time, populations are structured into modules (i.e., groups) of parasite genomes whose var gene combinations are more similar within than between the modules and whose persistence is much longer than that of the individual genomes that compose them. Comparison to neutral models that retain parasite population dynamics but lack competition reveals that the selection imposed by host immunity promotes the persistence of these modules. The modular structure is, in turn, associated with a slower acquisition of immunity by individual hosts. Modules thus represent dynamically generated niches in host immune space, which can be interpreted as strains. Negative frequency-dependent selection therefore shapes the organization of the var diversity into parasite genomes, leaving a persistence signature over ecological time scales. Multilayer networks extend the scope of phylodynamics analyses by allowing quantification of temporal genetic structure in organisms that generate variation via recombination or other non-bifurcating processes. A strain structure similar to the one described here should apply to other pathogens with large antigenic spaces that evolve via recombination. For malaria, the temporal modular structure should enable the formulation of tractable epidemiological models that account for parasite antigenic diversity and its influence on intervention outcomes

Neutral vs. non-neutral genetic footprints of Plasmodium falciparum multiclonal infections.

At a time when effective tools for monitoring malaria control and eradication efforts are crucial, the increasing availability of molecular data motivates their application to epidemiology. The multiplicity of infection (MOI), defined as the number of genetically distinct parasite strains co-infecting a host, is one key epidemiological parameter for evaluating malaria interventions. Estimating MOI remains a challenge for high-transmission settings where individuals typically carry multiple co-occurring infections. Several quantitative approaches have been developed to estimate MOI, including two cost-effective ones relying on molecular data: i) THE REAL McCOIL method is based on putatively neutral single nucleotide polymorphism loci, and ii) the varcoding method is a fingerprinting approach that relies on the diversity and limited repertoire overlap of the var multigene family encoding the major Plasmodium falciparum blood-stage antigen PfEMP1 and is therefore under selection. In this study, we assess the robustness of the MOI estimates generated with these two approaches by simulating P. falciparum malaria dynamics under three transmission conditions using an extension of a previously developed stochastic agent-based model. We demonstrate that these approaches are complementary and best considered across distinct transmission intensities. While varcoding can underestimate MOI, it allows robust estimation, especially under high transmission where repertoire overlap is extremely limited from frequency-dependent selection. In contrast, THE REAL McCOIL often considerably overestimates MOI, but still provides reasonable estimates for low and moderate transmission. Regardless of transmission intensity, results for THE REAL McCOIL indicate that an inaccurate tail at high MOI values is generated, and that at high transmission, an apparently reasonable estimated MOI distribution can arise from some degree of compensation between overestimation and underestimation. As many countries pursue malaria elimination targets, defining the most suitable approach to estimate MOI based on sample size and local transmission intensity is highly recommended for monitoring the impact of intervention programs

Optical Properties of the Group-IVB Refractory Metal Compounds

We have calculated ab initio the direct interband electric dipole transitions of the carbides, nitrides and oxides of Ti, Zr and Hf in the rocksalt structure using the full-potential linear muffin-tin orbital method. The dipole matrix elements are calculated explicitly. Our results are in extraordinaryly good agreement with experiment. The optical spectra are analysed and we explain the origin of the different structures in the spectra in terms of the calculated electronic structure. We also discuss the trends in the optical properties as the metal and non-metal atom types are changes and how these trends relate to general concepts such as band filling, nuclear charge, and bandwith.JRC.E-Institute for Transuranium Elements (Karlsruhe

Initial number of SNPs and accuracy of the multiplicity of infection (MOI) estimates determined with THE REAL McCOIL approach.

The accuracy of MOI estimates is defined as the differences between estimated and true MOI per host. While null values highlight accurate MOI estimates (indicated by a dashed black horizontal line), the positive and negative values highlight over- and under-estimation, respectively. The dark and light green colors indicate respectively MOI estimations made without and with a measurement model (Fig 2). For each category, the horizontal central solid line represents the median, the diamond represents the mean, the box represents the interquartile range (IQR) from the 25th to 75th centiles, the whiskers indicate the most extreme data point which is no more than 1.5 times the interquartile range from the box, and the dots show the outliers, i.e. the points beyond the whiskers. A) Accuracy of MOI estimates per true MOI. B) Accuracy of MOI estimates per transmission intensity (S1 and S2 Tables). (EPS)</p

Pearson correlation coefficients between the inaccuracy of the minor allele frequency (MAF) per locus estimated with THE REAL McCOIL approach (defined as the absolute differences between estimated and true MAF per locus), and the locus properties.

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Reliability of the multiplicity of infection (MOI) estimations when intervention changed the recent transmission intensities.

Only one combination of parameters (i.e. run) per transmission intensity (i.e. run 12, 36, and 60 for the low-, moderate-, and high transmission intensities, respectively) is illustrated. For each category, the horizontal central solid line represents the median, the diamond represents the mean, the box represents the interquartile range (IQR) from the 25th to 75th centiles, the whiskers indicate the most extreme data point which is no more than 1.5 times the interquartile range from the box, and the dots show the outliers, i.e. the points beyond the whiskers. The upper, middle, and lower row panels correspond to simulations under low-, moderate-, and high-transmission settings, respectively (S1 and S2 Tables). A) Accuracy of MOI estimates, defined as the difference between estimated and true MOI per host. While null values highlight accurate MOI estimates (indicated by a dashed black horizontal line), the positive and negative values highlight over- and under-estimation, respectively. Estimates with the neutral SNP-based approach (THE REAL McCOIL) are indicated in green, and those with the var gene-based approach (varcoding) are indicated in blue. The dark and light green or blue colors indicate respectively MOI estimations made without and with a measurement model (Fig 2). The column panels show differences for specific true MOI values. B) Population distribution of the estimated and true MOI per host from the simulated “true” values and those estimated with the methods indicated by the colors similar to panel A. (EPS)</p