Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data.

BACKGROUND: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). METHODS: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. RESULTS: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). CONCLUSIONS: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

Fast generation of spin-squeezed states in bosonic Josephson junctions

We describe methods for the fast production of highly coherent-spin-squeezed many-body states in bosonic Josephson junctions. We start from the known mapping of the two-site Bose-Hubbard (BH) Hamiltonian to that of a single effective particle evolving according to a Schrödinger-like equation in Fock space. Since, for repulsive interactions, the effective potential in Fock space is nearly parabolic, we extend recently derived protocols for shortcuts to adiabatic evolution in harmonic potentials to the many-body BH Hamiltonian. A comparison with current experiments shows that our methods allow for an important reduction in the preparation times of highly squeezed spin states.

Estudo comparativo do diagnóstico de câncer pulmonar entre tomografia computadorizada e broncoscopia

OBJETIVO: Analisar a tomografia computadorizada e a broncoscopia no diagnóstico do câncer pulmonar e verificar a eficácia destas técnicas perante a presença desta doença. Os parâmetros idade, gênero, hábitos tabágicos, tipos histológicos, estadiamento e terapêutica foram, igualmente, analisados. MATERIAIS E MÉTODOS: Foram analisados 70 pacientes do Serviço de Pneumologia do Hospital Distrital da Figueira da Foz, Coimbra, Portugal, que realizaram ambas as técnicas em estudo, tendo-se confirmado ou não a presença de câncer pulmonar. RESULTADOS: Diagnosticaram-se 37 tumores pulmonares, 23 casos no gênero masculino e 14 no feminino. Histologicamente, 40,54% eram adenocarcinomas, seguido do carcinoma escamoso (32,43% dos casos) e do carcinoma de pequenas células (18,92%). O estadiamento mostrou 6,70% no estádio IB, 23,30% no estádio IIIA comparativamente ao IIIB com 36,70%, encontrando-se 33,30% dos doentes no estádio IV. A quimioterapia isolada foi efetuada em 75,7% dos doentes. A sensibilidade da broncoscopia foi de 83,8%, a especificidade, de 81,8%, e a precisão, de 82,8%. A sensibilidade da tomografia computadorizada foi de 81,1%, a especificidade, de 63,6%, e a precisão, de 72,8%. CONCLUSÃO: Os resultados da broncoscopia confirmaram a sua importância no diagnóstico do câncer pulmonar, pela dependência deste no exame anatomopatológico do tecido ou células, obtido por várias técnicas de biópsia. A tomografia computadorizada apresentou boa sensibilidade, de 81,1%, contudo, a sua especificidade, de apenas 63,6%, resulta do número de falso-positivos (36,4%).

Direct Interrogation of Viral Peptides Presented by the Class I HLA of HIV-Infected T Cells

Identification of CD8+ cytotoxic T lymphocyte (CTL) epitopes has traditionally relied upon testing of overlapping peptide libraries for their reactivity with T cells in vitro. Here, we pursued deep ligand sequencing (DLS) as an alternative method of directly identifying those ligands that are epitopes presented to CTLs by the class I human leukocyte antigens (HLA) of infected cells. Soluble class I HLA-A*11:01 (sHLA) was gathered from HIV-1 NL4-3-infected human CD4+ SUP-T1 cells. HLA-A*11:01 harvested from infected cells was immunoaffinity purified and acid boiled to release heavy and light chains from peptide ligands that were then recovered by size-exclusion filtration. The ligands were first fractionated by high-pH high-pressure liquid chromatography and then subjected to separation by nano-liquid chromatography (nano-LC)–mass spectrometry (MS) at low pH. Approximately 10 million ions were selected for sequencing by tandem mass spectrometry (MS/MS). HLA-A*11:01 ligand sequences were determined with PEAKS software and confirmed by comparison to spectra generated from synthetic peptides. DLS identified 42 viral ligands presented by HLA-A*11:01, and 37 of these were previously undetected. These data demonstrate that (i) HIV-1 Gag and Nef are extensively sampled, (ii) ligand length variants are prevalent, particularly within Gag and Nef hot spots where ligand sequences overlap, (iii) noncanonical ligands are T cell reactive, and (iv) HIV-1 ligands are derived from de novo synthesis rather than endocytic sampling. Next-generation immunotherapies must factor these nascent HIV-1 ligand length variants and the finding that CTL-reactive epitopes may be absent during infection of CD4+ T cells into strategies designed to enhance T cell immunity.

rDock: A Fast, Versatile and Open Source Program for Docking Ligands to Proteins and Nucleic Acids

Identification of chemical compounds with specific biological activities is an important step in both chemical biology and drug discovery. When the structure of the intended target is available, one approach is to use molecular docking programs to assess the chemical complementarity of small molecules with the target; such calculations provide a qualitative measure of affinity that can be used in virtual screening (VS) to rank order a list of compounds according to their potential to be active. rDock is a molecular docking program developed at Vernalis for high-throughput VS (HTVS) applications. Evolved from RiboDock, the program can be used against proteins and nucleic acids, is designed to be computationally very efficient and allows the user to incorporate additional constraints and information as a bias to guide docking. This article provides an overview of the program structure and features and compares rDock to two reference programs, AutoDock Vina (open source) and Schrodinger's Glide (commercial). In terms of computational speed for VS, rDock is faster than Vina and comparable to Glide. For binding mode prediction, rDock and Vina are superior to Glide. The VS performance of rDock is significantly better than Vina, but inferior to Glide for most systems unless pharmacophore constraints are used; in that case rDock and Glide are of equal performance. The program is released under the Lesser General Public License and is freely available for download, together with the manuals, example files and the complete test sets, at http://rdock.sourceforge.net/

Eletrodos modificados com polímeros perfluorados e sulfonados: aplicações em análises ambientais

Perfluoro and sulfonated ion-exchange polymers are recognized as a very useful material for various mechanistic studies and applications in electrochemistry. These polymers are characterized by high equivalent weights and by a low number of ion-exchange sites interposed between long organic chains. The solubility enables a preparation of stable polyelectrolyte films on the electrode surface. Examples of the determination of trace metals and organic componds in real environmental samples are presented.