Evaluation of seasonal malaria chemoprevention in two areas of intense seasonal malaria transmission: Secondary analysis of a household-randomised, placebo-controlled trial in Houndé District, Burkina Faso and Bougouni District, Mali.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is now widely deployed in the Sahel, including several countries that are major contributors to the global burden of malaria. Consequently, it is important to understand whether SMC continues to provide a high level of protection and how SMC might be improved. SMC was evaluated using data from a large, household-randomised trial in Houndé, Burkina Faso and Bougouni, Mali. METHODS AND FINDINGS: The parent trial evaluated monthly SMC plus either azithromycin (AZ) or placebo, administered as directly observed therapy 4 times per year between August and November (2014-2016). In July 2014, 19,578 children aged 3-59 months were randomised by household to study group. Children who remained within the age range 3-59 months in August each year, plus children born into study households or who moved into the study area, received study drugs in 2015 and 2016. These analyses focus on the approximately 10,000 children (5,000 per country) under observation each year in the SMC plus placebo group. Despite high coverage and high adherence to SMC, the incidence of hospitalisations or deaths due to malaria and uncomplicated clinical malaria remained high in the study areas (overall incidence rates 12.5 [95% confidence interval (CI): 11.2, 14.1] and 871.1 [95% CI: 852.3, 890.6] cases per 1,000 person-years, respectively) and peaked in July each year, before SMC delivery began in August. The incidence rate ratio comparing SMC within the past 28 days with SMC more than 35 days ago-adjusted for age, country, and household clustering-was 0.13 (95% CI: 0.08, 0.20), P < 0.001 for malaria hospitalisations and deaths from malaria and 0.21 (95% CI 0.20, 0.23), P < 0.001 for uncomplicated malaria, indicating protective efficacy of 87.4% (95% CI: 79.6%, 92.2%) and 78.3% (95% CI: 76.8%, 79.6%), respectively. The prevalence of malaria parasitaemia at weekly surveys during the rainy season and at the end of the transmission season was several times higher in children who missed the SMC course preceding the survey contact, and the smallest prevalence ratio observed was 2.98 (95% CI: 1.95, 4.54), P < 0.001. The frequency of molecular markers of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) resistance did not increase markedly over the study period either amongst study children or amongst school-age children resident in the study areas. After 3 years of SMC deployment, the day 28 PCR-unadjusted adequate clinical and parasitological response rate of the SP + AQ regimen in children with asymptomatic malaria was 98.3% (95% CI: 88.6%, 99.8%) in Burkina Faso and 96.1% (95% CI: 91.5%, 98.2%) in Mali. Key limitations of this study are the potential overdiagnosis of uncomplicated malaria by rapid diagnostic tests and the potential for residual confounding from factors related to adherence to the monthly SMC schedule. CONCLUSION: Despite strong evidence that SMC is providing a high level of protection, the burden of malaria remains substantial in the 2 study areas. These results emphasise the need for continuing support of SMC programmes. A fifth monthly SMC course is needed to adequately cover the whole transmission season in the study areas and in settings with similar epidemiology. TRIAL REGISTRATION: The AZ-SMC trial in which these data were collected was registered at clinicaltrials.gov: NCT02211729

Effect of Adding Azithromycin to Seasonal Malaria Chemoprevention.

BACKGROUND: Mass administration of azithromycin for trachoma control led to a sustained reduction in all-cause mortality among Ethiopian children. Whether the addition of azithromycin to the monthly sulfadoxine-pyrimethamine plus amodiaquine used for seasonal malaria chemoprevention could reduce mortality and morbidity among African children was unclear. METHODS: We randomly assigned children 3 to 59 months of age, according to household, to receive either azithromycin or placebo, together with sulfadoxine-pyrimethamine plus amodiaquine, during the annual malaria-transmission season in Burkina Faso and Mali. The drug combinations were administered in four 3-day cycles, at monthly intervals, for three successive seasons. The primary end point was death or hospital admission for at least 24 hours that was not due to trauma or elective surgery. Data were recorded by means of active and passive surveillance. RESULTS: In July 2014, a total of 19,578 children were randomly assigned to receive seasonal malaria chemoprevention plus either azithromycin (9735 children) or placebo (9843 children); each year, children who reached 5 years of age exited the trial and new children were enrolled. In the intention-to-treat analysis, the overall number of deaths and hospital admissions during three malaria-transmission seasons was 250 in the azithromycin group and 238 in the placebo group (events per 1000 child-years at risk, 24.8 vs. 23.5; incidence rate ratio, 1.1; 95% confidence interval [CI], 0.88 to 1.3). Results were similar in the per-protocol analysis. The following events occurred less frequently with azithromycin than with placebo: gastrointestinal infections (1647 vs. 1985 episodes; incidence rate ratio, 0.85; 95% CI, 0.79 to 0.91), upper respiratory tract infections (4893 vs. 5763 episodes; incidence rate ratio, 0.85; 95% CI, 0.81 to 0.90), and nonmalarial febrile illnesses (1122 vs. 1424 episodes; incidence rate ratio, 0.79; 95% CI, 0.73 to 0.87). The prevalence of malaria parasitemia and incidence of adverse events were similar in the two groups. CONCLUSIONS: Among children in Burkina Faso and Mali, the addition of azithromycin to the antimalarial agents used for seasonal malaria chemoprevention did not result in a lower incidence of death or hospital admission that was not due to trauma or surgery than antimalarial agents plus placebo, although a lower disease burden was noted with azithromycin than with placebo. (Funded by the Joint Global Health Trials scheme; ClinicalTrials.gov number, NCT02211729.)

Nutritional status in young children prior to the malaria transmission season in Burkina Faso and Mali, and its impact on the incidence of clinical malaria.

BACKGROUND: Malaria and malnutrition remain major problems in Sahel countries, especially in young children. The direct effect of malnutrition on malaria remains poorly understood, and may have important implications for malaria control. In this study, nutritional status and the association between malnutrition and subsequent incidence of symptomatic malaria were examined in children in Burkina Faso and Mali who received either azithromycin or placebo, alongside seasonal malaria chemoprevention. METHODS: Mid-upper arm circumference (MUAC) was measured in all 20,185 children who attended a screening visit prior to the malaria transmission season in 2015. Prior to the 2016 malaria season, weight, height and MUAC were measured among 4149 randomly selected children. Height-for-age, weight-for-age, weight-for-height, and MUAC-for-age were calculated as indicators of nutritional status. Malaria incidence was measured during the following rainy seasons. Multivariable random effects Poisson models were created for each nutritional indicator to study the effect of malnutrition on clinical malaria incidence for each country. RESULTS: In both 2015 and 2016, nutritional status prior to the malaria season was poor. The most prevalent form of malnutrition in Burkina Faso was being underweight (30.5%; 95% CI 28.6-32.6), whereas in Mali stunting was most prevalent (27.5%; 95% CI 25.6-29.5). In 2016, clinical malaria incidence was 675 per 1000 person-years (95% CI 613-744) in Burkina Faso, and 1245 per 1000 person-years (95% CI 1152-1347) in Mali. There was some evidence that severe stunting was associated with lower incidence of malaria in Mali (RR 0.81; 95% CI 0.64-1.02; p = 0.08), but this association was not seen in Burkina Faso. Being moderately underweight tended to be associated with higher incidence of clinical malaria in Burkina Faso (RR 1.27; 95% CI 0.98-1.64; p = 0.07), while this was the case in Mali for moderate wasting (RR 1.27; 95% CI 0.98-1.64; p = 0.07). However, these associations were not observed in severely affected children, nor consistent between countries. MUAC-for-age was not associated with malaria risk. CONCLUSIONS: Both malnutrition and malaria were common in the study areas, high despite high coverage of seasonal malaria chemoprevention and long-lasting insecticidal nets. However, no strong or consistent evidence was found for an association between any of the nutritional indicators and the subsequent incidence of clinical malaria

Persistent Submicroscopic Plasmodium falciparum Parasitemia 72 Hours after Treatment with Artemether-Lumefantrine Predicts 42-Day Treatment Failure in Mali and Burkina Faso.

A recent randomized controlled trial, the WANECAM (West African Network for Clinical Trials of Antimalarial Drugs) trial, conducted at seven centers in West Africa, found that artemether-lumefantrine, artesunate-amodiaquine, pyronaridine-artesunate, and dihydroartemisinin-piperaquine all displayed good efficacy. However, artemether-lumefantrine was associated with a shorter interval between clinical episodes than the other regimens. In a further comparison of these therapies, we identified cases of persisting submicroscopic parasitemia by quantitative PCR (qPCR) at 72 h posttreatment among WANECAM participants from 5 sites in Mali and Burkina Faso, and we compared treatment outcomes for this group to those with complete parasite clearance by 72 h. Among 552 evaluable patients, 17.7% had qPCR-detectable parasitemia at 72 h during their first treatment episode. This proportion varied among sites, reflecting differences in malaria transmission intensity, but did not differ among pooled drug treatment groups. However, patients who received artemether-lumefantrine and were qPCR positive at 72 h were significantly more likely to have microscopically detectable recurrent Plasmodium falciparum parasitemia by day 42 than those receiving other regimens and experienced, on average, a shorter interval before the next clinical episode. Haplotypes of pfcrt and pfmdr1 were also evaluated in persisting parasites. These data identify a possible threat to the parasitological efficacy of artemether-lumefantrine in West Africa, over a decade since it was first introduced on a large scale

Haematological consequences of acute uncomplicated falciparum malaria: a WorldWide Antimalarial Resistance Network pooled analysis of individual patient data

Background: Plasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia. Methods: Individual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall ≥ 25% at day 3 and day 7. Results: A total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0–19.7 g/dL) in Africa, 11.6 g/dL (range 5.0–20.0 g/dL) in Asia and 12.3 g/dL (range 6.9–17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to ≥ 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39–3.05], p < 0.001). Conclusions: In patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery

Surveillance moleculaire de la resistance de Plasmodium falciparum a l'artemisinine a Bobo-Dioulasso: evaluation de la frequence des alleles du gene k13-propeller

No Abstract

Accumulation during fruit development of components of interest in seed of Chia (Salvia hispanica L.) cultivar Oruro (c) released in France star

This study aimed to examine the accumulation of oil, fatty acids, sterols and tocopherols contents and compositions during fruit development on the new cultivar of Chia Oruro (Panam Cie, France) cultivated in France. This cultivar is the first released genotype in Europe and for cultivation in Europe. The experiment was conducted in 2017, in south-western France at the Regional centre for organic agriculture, at Auch (near Toulouse, South-West of France). Four samplings were made at 17, 24, 27 and 35 days after flowering (DAF). These dates of sampling correspond to stages 7-8 (fruit development and maturity) of BBCH scale. Oil content, fatty acid composition and sterols and tocopherols contents and profiles were determined. The highest levels of oil and tocopherols were reached at 27 DAF. In contrast, phytosterols content was highest at 17 DAF (726.2 mg/100 g of oil) and decreased after this date. beta-sitosterol was the main sterol in chia seed (63.4 to 89.1% of total sterols, depending of stage of fruit development). gamma-tocopherol represented more than 92% of the total tocopherols present in the seed. High levels of polyunsaturated fatty acids (74.4 to 80% of total fatty acids) were observed in our study confirming those already reported in this species. High levels of saturated and monounsaturated fatty acids were reported at earlier stages and decreased gradually during fruit development. Polyunsaturated fatty acids followed an opposite trend. Their level was lowest at 17 DAF (74.4%) and increased gradually to reach their higher level at 35 DAF (80%). These results suggested clearly the interest to harvest and use of seed before entire maturity of the grain.Cette étude a examiné l’accumulation de l’huile, des acides gras, des stérols et des tocophérols durant le développement du fruit du nouveau cultivar de Chia Oruro (Panam Cie, France) cultivé en France. Ce cultivar est le premier génotype sélectionné en Europe et pour l’Europe. L’expérimentation a été réalisée en 2017, dans le sud-ouest de la France, au Centre régional d’expérimentation en agriculture biologique, à Auch (près de Toulouse, dans le sud-ouest de la France). Quatre prélèvements ont été effectués 17, 24, 27 et 35 jours après la floraison (DAF). Ces dates d’échantillonnage correspondent aux stades 7–8 (développement du fruit et maturité) de l’échelle BBCH. La teneur en huile, la composition en acides gras et les teneurs et profils en stérols et en tocophérols ont été déterminés. Les teneurs les plus élevées d’huile et de tocophérols ont été atteintes à 27DAF. Au contraire, la teneur en phytostérols était la plus élevée à 17DAF (726,2 mg/100 g d’huile) et a diminué après cette date. Le b-sitostérol a été le principal stérol contenu dans les graines de chia (63,4 to 89,1% des stérols totaux et en fonction du stade de développement du fruit). Le g-tocophérol représente plus de 92% du total des tocophérols présents dans la graine. Des teneurs élevées d’acides gras polyinsaturés (74,4 à 80% des acides gras totaux) ont été observées dans notre étude, ce qui confirme celles déjà signalées chez cette espèce. Des teneurs plus élevées d’acides gras saturés et mono-insaturés ont été observées aux stades précoces du développement du fruit et ont diminué progressivement au cours de la maturation. Les acides gras polyinsaturés ont suivi une tendance opposée. Leur niveau était le plus bas à 17DAF (74,4 %) et a augmenté progressivement pour atteindre leur niveau supérieur à 35DAF (80 %). Ces résultats suggèrent clairement l’intérêt de récolter et d’utiliser les graines avant leur maturité complète

Выкарыстанне кадэтамі Дзяржаўнай думы ў барацьбе за ўладу (лета 1915 г. — люты 1917 г.)

This study aimed to examine the accumulation of oil, fatty acids, sterols and tocopherols contents and compositions during fruit development on the new cultivar of Chia Oruro (Panam Cie, France) cultivated in France. This cultivar is the first released genotype in Europe and for cultivation in Europe. The experiment was conducted in 2017, in south-western France at the Regional centre for organic agriculture, at Auch (near Toulouse, South-West of France). Four samplings were made at 17, 24, 27 and 35 days after flowering (DAF). These dates of sampling correspond to stages 7–8 (fruit development and maturity) of BBCH scale. Oil content, fatty acid composition and sterols and tocopherols contents and profiles were determined. The highest levels of oil and tocopherols were reached at 27 DAF. In contrast, phytosterols content was highest at 17 DAF (726.2 mg/100 g of oil) and decreased after this date. β-sitosterol was the main sterol in chia seed (63.4 to 89.1% of total sterols, depending of stage of fruit development). γ-tocopherol represented more than 92% of the total tocopherols present in the seed. High levels of polyunsaturated fatty acids (74.4 to 80% of total fatty acids) were observed in our study confirming those already reported in this species. High levels of saturated and monounsaturated fatty acids were reported at earlier stages and decreased gradually during fruit development. Polyunsaturated fatty acids followed an opposite trend. Their level was lowest at 17 DAF (74.4%) and increased gradually to reach their higher level at 35 DAF (80%). These results suggested clearly the interest to harvest and use of seed before entire maturity of the grain

AZ-SMC Trial - Person-Time dataset

The person-time dataset includes all contacts for morbidity events, including the primary outcome of hospitalisations and deaths and other secondary outcomes such as clinical malaria, acute lower respiratory tract infection, gastroenteritis and others