Clinical trials to estimate the efficacy of preventive interventions against malaria in paediatric populations: a methodological review

BACKGROUND: Recent years have seen publication of a considerable number of clinical trials of preventive interventions against clinical malaria in children. There has been variability in the specification of end-points, case definitions, analysis methods and reporting and the relative lack of standardization complicates the ability to make comparative evaluations between trials. METHODS: To prepare for a WHO consultation on design issues in malaria vaccine trials, controlled trials of preventive interventions against malaria in children in endemic countries were identified in which clinical malaria, or death, had been one of the main end-points. Trials were included that evaluated the impact of vaccines, insecticide-treated bed nets (ITN), intermittent presumptive or preventive therapy in infants (IPTi) or, in one instance, vitamin A supplementation. Methods that had been used in these trials were summarized and compared in order to identify issues that were directly relevant to the design of malaria vaccine trials. RESULTS: 29 controlled trials of preventive malaria interventions were identified, of which eight were vaccine trials. Vaccine trials that were designed to detect an effect on clinical malaria all reported the incidence rate of first episodes of clinical malaria as their primary endpoint. Only one trial of a preventive intervention (of ITN) was identified that was designed to detect an effect on severe malaria. A group of larger trials were designed to detect an effect of impregnated bed nets or curtains on all-cause mortality as the primary end-point. Key methodological and reporting differences between trials are noted in the text. Two issues have been identified that are of some concern. Firstly, the choice of primary endpoint is not stated in the reports of a number of the trials and, secondly, the relationship between pre-specified analysis plans and trial reports is rarely made clear. CONCLUSION: This article reports an investigation into the ways in which trial design and reporting could be improved and standardized to enable comparative evaluation of the relative merits of malaria control measures, and specifically with respect to the design of malaria vaccine trials. The need for standardization of clinical trial design, conduct, analysis and reporting has been also affirmed as a priority area by the Malaria Vaccine Technology Roadmap

Global urban environmental change drives adaptation in white clover.

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale

Evaluating the Recombinant T24H Enzyme-Linked Immunoelectrotransfer Blot Assay for the Diagnosis of Neurocysticercosis in a Panel of Samples from a Large Community-Based Randomized Control Trial in 60 Villages in Burkina Faso.

Current guidelines for the diagnosis of neurocysticercosis (NCC) recommend the use of the lentil lectin-bound glycoprotein enzyme-linked immunoelectrotransfer blot assay (LLGP-EITB) as the reference standard for serological testing. In response to the drawbacks involved with the use of the LLGP-EITB, a recombinant T24H antigen (rT24H) EITB assay was developed, with promising results. However, the test has yet to be evaluated among individuals from sub-Saharan Africa (SSA). The aim of the present study was to investigate the performance of the rT24H EITB assay for the detection of NCC cases in a panel of serum samples (N = 366, of which 173 patients presented with epileptic seizures and/or severe chronic headaches, and 193 matched manifestation-free participants) collected as part of a large community-based trial in Burkina Faso. A perfect agreement between the rT24H EITB and the native gp24 (and its homodimer, gp42) LLGP-EITB was found (kappa value of 1.0). Furthermore, among patients with the neurological manifestations of interest who underwent a computed tomography scan, the rT24H EITB and native antigen LLGP-EITB had a comparable ability to correctly identify NCC cases with multiple viable (rT24H: sensitivity: 80.0%), single viable (66.7%), and calcified/degenerating cysts only (25.0%), albeit for multiple viable and calcified cysts, the rT24H estimated sensitivity seemed lower, but more uncertain, than previously reported. The rT24H EITB specificity was high (98.2%) and in line with previous studies. This study confirms the value of the recombinant rT24H EITB as an alternative to the native antigen LLGP-EITB for the diagnosis of NCC in a SSA community setting

Résultats d’une enquête d’incidence des cas d’infections nosocomiales à bactéries multirésistantes dans un centre hospitalier à Dakar (Sénégal)

Objectifs : Déterminer l’incidence et décrire le profil bactériologique des infections nosocomiales (IN) à bactéries multirésistantes au centre hospitalier universitaire de Fann à Dakar. Méthode : Enquête de surveillance prospective menée du 1erseptembre au 31 décembre 2010. Ont été inclus tous les patients hospitalisés depuis au moins 48 heures et ayant présenté une infection à bactérie multirésistante (BMR). L’analyse des données a éé effectuée grâce au logiciel SPSS16.0 Résultats : Durant la période d’étude, nous avons colligé 97 cas d’IN à BMR. L’incidence globale était de 5,5% avec une densité d’incidence de 5 cas pour 1000 patient-jours. Les densités les plus élevées étaient observées dans les services de Maladies Infectieuses (9,3 cas /1000 patient-jours) et de Pneumologie (7cas /1000 patient-jours). Les infections urinaires (53 %) et les bactériémies (21 %) étaient prédominantes. Les germes les plus fréquemment isolés étaient : entérobactéries productrices de bêtalactamase à spectre élargi (EBLSE) (62 %), Pseudomonas aeruginosa (13 %) et les staphylocoques à coagulase négative (12 %). Toutes les souches d’EBLSE étaient sensibles à l’imipénème et à la colistine. Aucune souche de staphylocoque n’était résistante à la vancomycine. La létalité était de 46 %. Conclusion : L’incidence des IN à BMR est élevée au CHNU de Fann. Les activités de prévention doivent être renforcées afin de réduire la morbidité et la mortalité liées à ces infections

Inhibiting amyloid-β cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design

Inhibiting the interaction between amyloid-β (Aβ) and a neuronal cell surface receptor, LilrB2, has been suggested as a potential route for treating Alzheimer's disease. Supporting this approach, Alzheimer's-like symptoms are reduced in mouse models following genetic depletion of the LilrB2 homologue. In its pathogenic, oligomeric state, Aβ binds to LilrB2, triggering a pathway to synaptic loss. Here we identify the LilrB2 binding moieties of Aβ (16KLVFFA21) and identify its binding site on LilrB2 from a crystal structure of LilrB2 immunoglobulin domains D1D2 complexed to small molecules that mimic phenylalanine residues. In this structure, we observed two pockets that can accommodate the phenylalanine side chains of KLVFFA. These pockets were confirmed to be 16KLVFFA21 binding sites by mutagenesis. Rosetta docking revealed a plausible geometry for the Aβ-LilrB2 complex and assisted with the structure-guided selection of small molecule inhibitors. These molecules inhibit Aβ-LilrB2 interactions in vitro and on the cell surface and reduce Aβ cytotoxicity, which suggests these inhibitors are potential therapeutic leads against Alzheimer's disease