Antimalarial Drug Quality in the Most Severely Malarious Parts of Africa – A Six Country Study

A range of antimalarial drugs were procured from private pharmacies in urban and peri-urban areas in the major cities of six African countries, situated in the part of that continent and the world that is most highly endemic for malaria. Semi-quantitative thin-layer chromatography (TLC) and dissolution testing were used to measure active pharmaceutical ingredient content against internationally acceptable standards. 35% of all samples tested failed either or both tests, and were substandard. Further, 33% of treatments collected were artemisinin monotherapies, most of which (78%) were manufactured in disobservance of an appeal by the World Health Organisation (WHO) to withdraw these clinically inappropriate medicines from the market. The high persistence of substandard drugs and clinically inappropriate artemisinin monotherapies in the private sector risks patient safety and, through drug resistance, places the future of malaria treatment at risk globally

A systematic review of changing malaria disease burden in sub-Saharan Africa since 2000: comparing model predictions and empirical observations.

BACKGROUND: The most widely used measures of declining burden of malaria across sub-Saharan Africa are predictions from geospatial models. These models apply spatiotemporal autocorrelations and covariates to parasite prevalence data and then use a function of parasite prevalence to predict clinical malaria incidence. We attempted to assess whether trends in malaria cases, based on local surveillance, were similar to those captured by Malaria Atlas Project (MAP) incidence surfaces. METHODS: We undertook a systematic review (PROSPERO International Prospective Register of Systematic Reviews; ID = CRD42019116834) to identify empirical data on clinical malaria in Africa since 2000, where reports covered at least 5 continuous years. The trends in empirical data were then compared with the trends of time-space matched clinical malaria incidence from MAP using the Spearman rank correlation. The correlations (rho) between changes in empirically observed and modelled estimates of clinical malaria were displayed by forest plots and examined by meta-regression. RESULTS: Sixty-seven articles met our inclusion criteria representing 124 sites from 24 African countries. The single most important factor explaining the correlation between empirical observations and modelled predictions was the slope of empirically observed data over time (rho = - 0.989; 95% CI - 0.998, - 0.939; p < 0.001), i.e. steeper declines were associated with a stronger correlation between empirical observations and modelled predictions. Factors such as quality of study, reported measure of malaria and endemicity were only slightly predictive of such correlations. CONCLUSIONS: In many locations, both local surveillance data and modelled estimates showed declines in malaria burden and hence similar trends. However, there was a weak association between individual surveillance datasets and the modelled predictions where stalling in progress or resurgence of malaria burden was empirically observed. Surveillance data were patchy, indicating a need for improved surveillance to strengthen both empiric reporting and modelled predictions

Warm Molecular Hydrogen Emission in Normal Edge-On Galaxies NGC 4565 and NGC 5907

We have observed warm molecular hydrogen in two nearby edge-on disk galaxies, NGC 4565 and NGC 5907, using the Spitzer high-resolution infrared spectrograph. The 0-0 S(0) 28.2 micron and 0-0 S(1) 17.0 micron pure rotational lines were detected out to 10 kpc from the center of each galaxy on both sides of the major axis, and in NGC 4565 the S(0) line was detected at r = 15 kpc on one side. This location lies beyond a steep drop in the radio continuum emission from cosmic rays in the disk. Despite indications that star formation activity decreases with radius, the H2 excitation temperature and the ratio of the H2 line and the far-IR luminosity surface densities, Sigma_L(H2}/Sigma_L(TIR}, change very little as a function of radius, even into the diffuse outer region of the disk of NGC 4565. This suggests that the source of excitation of the H2 operates over a large range of radii, and is broadly independent of the strength and relative location of UV emission from young stars. Although excitation in photodissociation regions is the most common explanation for the widespread H2 emission, cosmic ray heating or shocks cannot be ruled out. The inferred mass surface densities of warm molecular hydrogen in both edge-on galaxies differ substantially, being 4(-60) M_solar/pc^2 and 3(-50) M_solar/pc^2 at r = 10 kpc for NGC 4565 and NGC 5907, respectively. The higher values represent very unlikely point-source upper limits. The point source case is not supported by the observed emission distribution in the spectral slits. These mass surface densities cannot support the observed rotation velocities in excess of 200 km/s. Therefore, warm molecular hydrogen cannot account for dark matter in these disk galaxies, contrary to what was implied by a previous ISO study of the nearby edge-on galaxy NGC 891.Comment: Accepted for publication in the Astronomical Journal (20 pages, 17 figures, 7 tables

Water-soluble substituted chitosan derivatives as technology platform for inhalation delivery of siRNA

Despite research efforts full potential of siRNA-based therapeutics has not yet been fully realized due to a need for suitable, effective delivery formulations. Here, we examine a potential of a new class of water-soluble chitosans as siRNA platform for pulmonary delivery. The system is based on piperazine-substituted chitosans, a material designed to integrate established, safe application of chitosan for mucosal administration with novel properties: the piperazine-substituted chitosans are freely water-soluble at physiological pH, possess low cytotoxicity (no significant reduction in cell viability up to 0.1 mg/ml), and provide efficient incorporation of siRNA into sub-300 nm colloidal complexes (at relatively low polymer/siRNA ratio of 5:1). In vitro, the complexes achieved silencing of a model gene at a level of 40–80%, when tested in a panel of lung epithelial cells. Considering the formulation ‘developability’, there were no significant changes in the complexes’ size and integrity on aerosolisation by microsprayer (PenCenturyTM) device. Following intratracheal aerolisation, the complexes deposited throughout the lung, although relatively inhomogeneously, as judged from IVIS imaging of the isolated mouse lung (visualizing DY647-siRNA). In vivo data illustrate absence of adverse effects on repeated administration of complexes and significant tumor reduction in atopical lung cancer model in mice. Altogether, the data illustrates potential of substituted chitosan derivatives to be utilized as a safe system for inhalation delivery of siRNA

The impact of intermittent presumptive treatment for malaria in pregnancy on hospital birth outcomes on the Kenyan coast

Background Intermittent preventive treatment (IPTp) to pregnant women with sulfadoxine–pyrimethamine (SP) is widely implemented for the prevention of malaria in pregnancy and adverse birth outcomes. The efficacy of SP is declining and there are concerns that IPTp may have reduced impact in areas of high resistance. Here we sought to determine the protection afforded by SP as part of IPTp against birth outcomes in an area with high levels of SP resistance on the Kenyan coast. Methods A secondary analysis of surveillance data on deliveries at the Kilifi County hospital between 2015 and 2021 was undertaken in an area of low malaria transmission and high parasite mutations associated with SP resistance. A multivariable logistic regression model was developed to estimate the effect of SP doses on the risk of low birthweight (LBW) deliveries and stillbirths. Results Among 27,786 deliveries, three or more doses of IPTp-SP were associated with a 27% reduction in the risk of LBW (adjusted odds ratio (aOR): 0.73; 95% CI: 0.64, 0.83; p &amp;lt; 0.001) compared to no-dose. A dose-response association was observed with increasing doses of SP from the second trimester linked to increasing protection against LBW deliveries. Three or more doses of IPTp-SP were also associated with a 21% reduction in stillbirth deliveries (aOR: 0.79; 95% CI: 0.65, 0.97; p= 0.044) compared to women who did not take any dose of IPTp-SP. Conclusions The continued, significant association of SP on LBW deliveries suggests that the intervention may have a non-malaria impact on pregnancy outcomes

Acute seizures attributable to falciparum malaria in an endemic area on the Kenyan coast

Falciparum malaria is an important cause of acute symptomatic seizures in children admitted to hospitals in sub-Saharan Africa, and these seizures are associated with neurological disabilities and epilepsy. However, it is difficult to determine the proportion of seizures attributable to malaria in endemic areas since a significant proportion of asymptomatic children have malaria parasitaemia. We studied children aged 0–13 years who had been admitted with a history of seizures to a rural Kenyan hospital between 2002 and 2008. We examined the changes in the incidence of seizures with the reduction of malaria. Logistic regression was used to model malaria-attributable fractions for seizures (the proportion of seizures caused by malaria) to determine if the observed decrease in acute symptomatic seizures was a measure of seizures that are attributable to malaria. The overall incidence of acute symptomatic seizures over the period was 651/100 000/year (95% confidence interval 632–670) and it was 400/100 000/year (95% confidence interval 385–415) for acute complex symptomatic seizures (convulsive status epilepticus, repetitive or focal) and 163/100 000/year (95% confidence interval 154–173) for febrile seizures. From 2002 to 2008, the incidence of all acute symptomatic seizures decreased by 809/100 000/year (69.2%) with 93.1% of this decrease in malaria-associated seizures. The decrease in the incidence of acute complex symptomatic seizures during the period was 111/100 000/year (57.2%) for convulsive status epilepticus, 440/100 000/year (73.7%) for repetitive seizures and 153/100 000/year (80.5%) for focal seizures. The adjusted malaria-attributable fractions for seizures with parasitaemia were 92.9% (95% confidence interval 90.4–95.1%) for all acute symptomatic seizures, 92.9% (95% confidence interval 89.4–95.5%) for convulsive status epilepticus, 93.6% (95% confidence interval 90.9–95.9%) for repetitive seizures and 91.8% (95% confidence interval 85.6–95.5%) for focal seizures. The adjusted malaria-attributable fractions for seizures in children above 6 months of age decreased with age. The observed decrease in all acute symptomatic seizures (809/100 000/year) was similar to the predicted decline (794/100 000/year) estimated by malaria-attributable fractions at the beginning of the study. In endemic areas, falciparum malaria is the most common cause of seizures and the risk for seizures in malaria decreases with age. The reduction in malaria has decreased the burden of seizures that are attributable to malaria and this could lead to reduced neurological disabilities and epilepsy in the area

Peripheral blood monocyte-to-lymphocyte ratio at study enrollment predicts efficacy of the RTS,S malaria vaccine: analysis of pooled phase II clinical trial data.

BACKGROUND: RTS,S is the most advanced candidate malaria vaccine but it is only partially protective and the causes of inter-individual variation in efficacy are poorly understood. Here, we investigated whether peripheral blood monocyte-to-lymphocyte ratios (ML ratio), previously shown to correlate with clinical malaria risk, could account for differences in RTS,S efficacy among phase II trial participants in Africa. METHODS: Of 11 geographical sites where RTS,S has been evaluated, pre-vaccination ML ratios were only available for trial participants in Kilifi, Kenya (N = 421) and Lambarene, Gabon (N = 189). Using time to first clinical malaria episode as the primary endpoint we evaluated the effect of accounting for ML ratio on RTS,S vaccine efficacy against clinical malaria by Cox regression modeling. RESULTS: The unadjusted efficacy of RTS,S in this combined dataset was 47% (95% confidence interval (CI) 26% to 62%, P <0.001). However, RTS,S efficacy decreased with increasing ML ratio, ranging from 67% (95% CI 64% to 70%) at an ML ratio of 0.1 to 5% (95% CI -3% to 13%) at an ML ratio of 0.6. The statistical interaction between RTS,S vaccination and ML ratio was still evident after adjustment for covariates associated with clinical malaria risk in this dataset. CONCLUSION: The results suggest that stratification of study participants by ML ratio, easily measured from full differential blood counts before vaccination, might help identify children who are highly protected and those that are refractory to protection with the RTS,S vaccine. Identifying causes of low vaccine efficacy among individuals with high ML ratio could inform strategies to improve overall RTS,S vaccine efficacy. TRIAL REGISTRATION: ClinicalTrials.Gov numbers NCT00380393 and NCT00436007

Age, Spatial, and Temporal Variations in Hospital Admissions with Malaria in Kilifi County, Kenya: A 25-Year Longitudinal Observational Study

Background Encouraging progress has been seen with reductions in Plasmodium falciparum malaria transmission in some parts of Africa. Reduced transmission might lead to increasing susceptibility to malaria among older children, which has implications for ongoing control strategies. Methods and findings We conducted a longitudinal observational study of children admitted to Kilifi County Hospital in Kenya and linked to data on residence and Insecticide Treated Net (ITN) ownership. This included data from 69,104 children admitted to Kilifi County Hospital aged from 3 months to 13 years between 1st January 1990 and 31st December 2014. The variation in malaria slide positivity among admissions was examined in logistic regression models using the predictors; location of residence, calendar time, child’s age, ITN use and Enhanced Vegetation Index (a proxy for soil moisture). The proportion of malaria slide positive admissions declined from 0.56 with 95% confidence interval (95%CI) 0.54 to 0.58 in 1998 to 0.07 95%CI 0.06 to 0.08 in 2009, but then increased again through to 0.24 95%CI 0.22 to 0.25 in 2014. Older children accounted for most of the increase after 2009 (0.035 95%CI (0.030 to 0.040) among young children compared to 0.22 95%CI 0.21 to 0.23 in older children). There was a non-linear relationship between malaria risk and prevalence of ITN use within a 2km radius of an admitted child’s residence such that the predicted malaria positive fraction varied from ~0.4 to <0.1 as the prevalence of ITN use varied from 20% to 80%. In this observational analysis we were unable to determine the cause of the decline in malaria between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use. Conclusion Following a period of reduced transmission a cohort of older children emerged who have increased susceptibility to malaria. Further reductions in malaria transmission are needed to mitigate against the increasing burden among older children and universal ITN coverage is a promising strategy to achieve this

Fraction of all hospital admissions and deaths attributable to malnutrition among children in rural Kenya235

Background: Malnutrition is common in the developing world and associated with disease and mortality. Because malnutrition frequently occurs among children in the community as well as those with acute illness, and because anthropometric indicators of nutritional status are continuous variables that preclude a single definition of malnutrition, malnutrition-attributable fractions of admissions and deaths cannot be calculated by simply enumerating individual children