Search

Background Children hospitalised with severe anaemia in malaria-endemic areas are at a high risk of dying or being readmitted within six months of discharge. A trial in Kenya and Uganda showed that three months of postdischarge malaria chemoprevention (PDMC) with monthly dihydroartemisinin-piperaquine (DP) substantially reduced this risk. The World Health Organization recently included PDMC in its malaria chemoprevention guidelines. We conducted a cost-effectiveness analysis of community-based PDMC delivery (supplying all three PDMC-DP courses to caregivers at discharge to administer at home), facility-based PDMC delivery (monthly dispensing of PDMC-DP at the hospital), and the standard of care (no PDMC). Methods We combined data from two recently completed trials; one placebo-controlled trial in Kenya and Uganda collecting efficacy data (May 6, 2016 until November 15, 2018; n=1049), and one delivery mechanism trial from Malawi collecting adherence data (March 24, 2016 until October 3, 2018; n=375). Cost data were collected alongside both trials. Three Markov decision models, one each for Malawi, Kenya, and Uganda, were used to compute incremental cost-effectiveness ratios expressed as costs per quality-adjusted life-year (QALY) gained. Deterministic and probabilistic sensitivity analyses were performed to account for uncertainty. Findings Both PDMC strategies were cost-saving in each country, meaning less costly and more effective in increasing health-adjusted life expectancy than the standard of care. The estimated incremental cost savings for community-based PDMC compared to the standard of care were US$ 22·10 (Malawi), 38·52 (Kenya), and 26·23 (Uganda) per child treated. The incremental effectiveness gain using either PDMC strategy varied between 0·3 and 0·4 QALYs. Community-based PDMC was less costly and more effective than facility-based PDMC. These results remained robust in sensitivity analyses. Interpretation PDMC under implementation conditions is cost-saving. Caregivers receiving PDMC at discharge is a cost-effective delivery strategy for implementation in malaria-endemic southeastern African settings. publishedVersion

Background: Globally, there are over 200 million cases of malaria annually and over 400,000 deaths. Early and accurate detection of low density parasitemia and asymptomatic individuals is key to achieving the WHO’s 2030 sustainable development goals of reducing malaria-related deaths by 90% and eradication in 35 countries. Current rapid diagnostic tests are neither sensitive nor specific enough to detect the low parasite concentrations in the blood of some asymptomatic individuals. Methods: Here, we combine an imaging-based sensing technique, particle diffusometry (PD), with loop mediated isothermal amplification (LAMP) on a smartphone-enabled device to detect low levels of parasitemia often associated with asymptomatic malaria. After amplification, PD quantifies the Brownian motion of fluorescent nanoparticles in the solution during a 30 second video taken on the phone. The resulting diffusion coefficient is used to detect the presence of Plasmodium DNA amplicons by comparing to coefficients of negative samples using a one-way ANOVA test.Results: As few as 1 parasite/µL of blood was detectable in 45 minutes without DNA extraction. We detected Plasmodium falciparum (P. falciparum) parasites from asymptomatic individuals’ whole blood samples with 89% sensitivity and 100% specificity when compared to quantitative polymerase chain reaction (qPCR). Conclusions: PD-LAMP is of value for the detection of low density parasitemia especially in areas where trained personnel may be scarce. The demonstration of this smartphone biosensor paired with the sensitivity of LAMP provides a proof of concept to achieve widespread asymptomatic malaria testing at the point of care.

Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 checklist: recommended items to address in a clinical trial protocol and related documents. (DOC 124 kb)

The response of a small lake or reservoir system to wind and streamflow forcing is examined in this paper using a numerical model based on Navier–Stokes equation and a numerical hydraulic model using the segment-node approach. The main mass transport in the lake has been found to be due to wind; the circulation caused by stream inflow and outflow of the lake contributes a relatively small fraction of the total transport. The above-mentioned models have been applied to different wind regimes and constant or variable inflow–outflow conditions of Long Lake (Nova Scotia). Comparisons are made between observed data and model results by both models. The model response has also been studied for generation of seiches and wind setup in the lake; and the response of the lake to these forcing functions has been presented. The comparison of model results with in situ field data establishes model's suitability to make predictions. Drogue and water level measurements were made at a number of locations in the Long Lake to validate the numerical models. The results from the numerical simulation using the two models compare favourably with the observed data. As may be expected, the segment-node modelling scheme was found to be computationally more efficient and relatively easy to run on a personal computer. Key words: numerical model, hydrodynamics, circulation, Long Lake, temperature, dissolved oxygen, stratification, Nova Scotia.

Harmonic tidal current constituents are computed using data obtained from self-recording current meters moored in the western Arabian Gulf. Tidal currents in the study area vary from mixed, mainly semi-diurnal at Station CM1 in the north to mixed mainly diurnal at Station CM3 in the south. Four main harmonic constituents (M2, S2, O1, and K1) govern tidal currents in the study area. The strongest currents were measured at Station CM1, which is near the location of an amphidromic point for M2 and S2 harmonic tidal constituents. At Station CM1, predominantly diurnal tidal elevations exist with mixed, mainly semi-diurnal tidal currents. However, at Station CM3, which is near the location of an amphidromic point for K1 and O1 constituents the opposite is observed i.e., predominantly semi-diurnal tidal elevations exist with mixed mainly diurnal tidal currents. Therefore, extreme care should be taken by designers in interpreting tide data at Station CM1 and Station CM3 to obtain tidal currents.

Current measurements at four offshore locations in the western Arabian Gulf from 1986 to 1989 show periods of stagnation or low currents, and steady Shamal -(northwest storms) driven currents which have significance to the mixing and transport of pollutants in this area. A major effect of Shamal on the net circulation was observed in June 1986 at the Station CM3 surface where the net drift increased from 50 km during the first two weeks to about 100 km during the next two weeks. The drift direction during this period was 45° clockwise from Shamal wind direction. At CM4, the net drift was even reversed from southward to northward when Shamal winds changed to ‘Kaus’ winds (southeast storms) in August 1987. Progressive vector diagrams show that the residual current in the region controls the pollutant transport of the surface water at CM1 generally towards the south and southwest and the bottom water towards the southeast. In contrast to CM1, the net drift at CM2 showed smaller southeastward drift. However, the near-bottom flows at all stations were towards the southeast and southwest, except near-bottom at Station CM3, where eastward and northeastward residual advective transport is observed during the whole observation period. This unique northeastward near-bottom current has a special significance to the overall residual circulation of the Arabian Gulf. The strongest tidal current transport occurs at Station CM1, which is near the location of an amphidromic point for M2 harmonic tidal constituent. Movement of pollutants offshore over a tidal cycle would be generally toward the southeast during flood and toward the northwest during ebb tide. Large tidal mixing is observed in the region and the associated turbulent diffusion causes pollutants to be rapidly dispersed and thereby shows almost uniform distribution in the vertical. Complex tidal mixing and transport exist at Station CM1 where predominantly diurnal tidal elevations exist with mixed, mainly semi-diurnal tidal currents and vice versa (predominantly semi-diurnal tidal elevations exist with mixed mainly diurnal tidal currents) at CM3. An earlier study by John et al. 1 indicated that the formation of high-salinity water in the Gulf of Salwah may be one of the most important sources of the salinity-related density gradient proposed by Hunter 2 to drive circulation in the Arabian Gulf. However, this study shows that the net displacement of water towards the southeast was also due to the predominant northerly and northwesterly winds.

Worldwide, there are an estimated 216 million cases of malaria annually and of those affected 655,000 will succumb to the disease. Antibody responses to infection have been shown to be critical in limiting infection and disease, but the mechanisms by which these are acquired or lost are poorly understood. Various hypotheses have been proposed for dysfunctional humoral responses including B cell exhaustion, germinal center architectural disruption, parasite antigenic variation and inhibitory innate immune signaling. However, the relative infrequency of malaria specific B cells in the periphery has limited targeted detection of these cells. We present a strategy for phenotypic analyses of malaria specific B cells in peripheral blood using tetramerized biotinylated malaria antigen coupled to phycoerythrin labeled streptavidin, magnetic bead enrichment and cytometric flow analysis. Using this technique, we demonstrate the detection of an antigen specific germinal center reaction in B6 mice after immunization with P.pastoris expressing recombinant Plasmodium falciparum apical membrane antigen-1 and circumsporozoite protein. Preliminary results in humans identified low frequency B cells specific to these two antigens. Overall, our results suggest that this technique will be a valuable tool in studying naturally acquired and vaccine derived malaria specific B cell responses.

Additional file 1. Sensitivity analyses and quality measures for clinical trial â Inhaled nitric oxide as adjunctive therapy for severe malariaâ . Description: Sensitivity analyses on the primary and secondary (mortality) endpoints are provided. Measures of the quality of blinding and quality of clinical care in the trial are described.

Full study protocol (including SPIRIT figure): v4.0, dated 06 Feb 2018. (PDF 3510 kb)

Additional file 1: Fig. S1. Sample scatter plots of AMA1 antibody concentrations versus against VL and CRP. Fig. S2. IgG3:IgG1 ratio for AMA1 and GLURP specific antibodies by CD4 counts. Table S1. Inter-assay and Intra-assay CV for IgM and IgG subclasses.

Additional file 1: Fig. S1. Sample scatter plots of AMA1 antibody concentrations versus against VL and CRP. Fig. S2. IgG3:IgG1 ratio for AMA1 and GLURP specific antibodies by CD4 counts. Table S1. Inter-assay and Intra-assay CV for IgM and IgG subclasses.

Additional file 1. Sensitivity analyses and quality measures for clinical trial â Inhaled nitric oxide as adjunctive therapy for severe malariaâ . Description: Sensitivity analyses on the primary and secondary (mortality) endpoints are provided. Measures of the quality of blinding and quality of clinical care in the trial are described.

Data type by country. (DOCX 14 kb)

Weight-for-age growth curves. (PDF 1202 kb)

Weight-for-age growth curves. (PDF 1202 kb)

I. Methods. Supplementary methods describing the study population and additional details on assessment of disease severity, kidney function, retinopathy, neurocognitive evaluation, and statistical analysis. II. Results. Relationship between AKI and nephrotoxic medication use during hospitalization. III. Supplementary tables. Table S1-S13. (DOCX 89 kb)

Data type by country. (DOCX 14 kb)

I. Methods. Supplementary methods describing the study population and additional details on assessment of disease severity, kidney function, retinopathy, neurocognitive evaluation, and statistical analysis. II. Results. Relationship between AKI and nephrotoxic medication use during hospitalization. III. Supplementary tables. Table S1-S13. (DOCX 89 kb)

Full study protocol (including SPIRIT figure): v4.0, dated 06 Feb 2018. (PDF 3123 kb)

Full study protocol (including SPIRIT figure): v4.0, dated 06 Feb 2018. (PDF 3123 kb)