Dissection-independent production of Plasmodium sporozoites from whole mosquitoes.

Progress towards a protective vaccine against malaria remains slow. To date, only limited protection has been routinely achieved following immunisation with either whole-parasite (sporozoite) or subunit-based vaccines. One major roadblock to vaccine progress, and to pre-erythrocytic parasite biology in general, is the continued reliance on manual salivary gland dissection for sporozoite isolation from infected mosquitoes. Here, we report development of a multi-step method, based on batch processing of homogenised whole mosquitoes, slurry, and density-gradient filtration, which combined with free-flow electrophoresis rapidly produces a pure, infective sporozoite inoculum. Human-infective Plasmodium falciparum and rodent-infective Plasmodium berghei sporozoites produced in this way are two- to threefold more infective than salivary gland dissection sporozoites in in vitro hepatocyte infection assays. In an in vivo rodent malaria model, the same P. berghei sporozoites confer sterile protection from mosquito-bite challenge when immunisation is delivered intravenously or 60-70% protection when delivered intramuscularly. By improving purity, infectivity, and immunogenicity, this method represents a key advancement in capacity to produce research-grade sporozoites, which should impact delivery of a whole-parasite based malaria vaccine at scale in the future

FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0

The aim of this guideline is to provide a minimum standard for the acquisition and interpretation of PET and PET/CT scans with [18F]-fluorodeoxyglucose (FDG). This guideline will therefore address general information about [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) and is provided to help the physician and physicist to assist to carrying out, interpret, and document quantitative FDG PET/CT examinations, but will concentrate on the optimisation of diagnostic quality and quantitative information

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Health Promotion International

"vacuna social" El término está diseñado para fomentar el sector de la salud biomédica orientada a reconocer la legitimidad de la acción sobre los determinantes sociales y económicos distales de la salud. Se propone como un término para ayudar al movimiento de promoción de la salud en argumentar a favor de una visión social de la salud que es tan a menudo en contra de las concepciones médicas y populares de la salud. La idea de una vacuna social se basa en una larga tradición en la medicina social, así como en una tradición biomédica de prevención de enfermedades a través de las vacunas que protegen contra las enfermedades. Vacunas Sociales se promueven como un medio para fomentar la movilización popular y la defensa para cambiar las condiciones sociales y económicas estructurales que hacen que las personas y las comunidades vulnerables a las enfermedades. Se facilitarían los procesos sociales y políticos que se desarrollan la voluntad popular y político para proteger y promover la salud a través de acciones (especialmente los gobiernos preparados para intervenir y regular para proteger la salud de la comunidad) sobre los determinantes sociales y económicos. Ejemplos proporcionados por los efectos de las vacunas sociales son: la restauración de la propiedad de tierras a los pueblos indígenas, la regulación de la publicidad de los productos nocivos y los impuestos progresivos para la protección social universal. Vacunas Sociales requieren más investigaciones para mejorar la comprensión de los procesos sociales y políticos que son susceptibles de mejorar la equidad en salud en todo el mundo. La metáfora de la vacuna debe ser útil para argumentar a favor de una mayor acción sobre los determinantes sociales de la salud. Vacunas Sociales para resistir y cambiar las estructuras sociales y económicas no saludables: una metáfora útil para la promoción de la salud.The term ‘social vaccine’ is designed to encourage the biomedically orientated health sector to recognize the legitimacy of action on the distal social and economic determinants of health. It is proposed as a term to assist the health promotion movement in arguing for a social view of health which is so often counter to medical and popular conceptions of health. The idea of a social vaccine builds on a long tradition in social medicine as well as on a biomedical tradition of preventing illness through vaccines that protect against disease. Social vaccines would be promoted as a means to encourage popular mobilization and advocacy to change the social and economic structural conditions that render people and communities vulnerable to disease. They would facilitate social and political processes that develop popular and political will to protect and promote health through action (especially governments prepared to intervene and regulate to protect community health) on the social and economic determinants. Examples provided for the effects of social vaccines are: restoring land ownership to Indigenous peoples, regulating the advertising of harmful products and progressive taxation for universal social protection. Social vaccines require more research to improve understanding of social and political processes that are likely to improve health equity worldwide. The vaccine metaphor should be helpful in arguing for increased action on the social determinants of health.Cuencavolumen 24; número

The Role of Chromosome Missegregation in Cancer Development: A Theoretical Approach Using Agent-Based Modelling

<div><p>Many cancers are aneuploid. However, the precise role that chromosomal instability plays in the development of cancer and in the response of tumours to treatment is still hotly debated. Here, to explore this question from a theoretical standpoint we have developed an agent-based model of tissue homeostasis in which to test the likely effects of whole chromosome mis-segregation during cancer development. In stochastic simulations, chromosome mis-segregation events at cell division lead to the generation of a diverse population of aneuploid clones that over time exhibit hyperplastic growth. Significantly, the course of cancer evolution depends on genetic linkage, as the structure of chromosomes lost or gained through mis-segregation events and the level of genetic instability function in tandem to determine the trajectory of cancer evolution. As a result, simulated cancers differ in their level of genetic stability and in their growth rates. We used this system to investigate the consequences of these differences in tumour heterogeneity for anti-cancer therapies based on surgery and anti-mitotic drugs that selectively target proliferating cells. As expected, simulated treatments induce a transient delay in tumour growth, and reveal a significant difference in the efficacy of different therapy regimes in treating genetically stable and unstable tumours. These data support clinical observations in which a poor prognosis is correlated with a high level of chromosome mis-segregation. However, stochastic simulations run in parallel also exhibit a wide range of behaviours, and the response of individual simulations (equivalent to single tumours) to anti-cancer therapy prove extremely variable. The model therefore highlights the difficulties of predicting the outcome of a given anti-cancer treatment, even in cases in which it is possible to determine the genotype of the entire set of cells within the developing tumour.</p></div

Social vaccines to resist and change unhealthy social and economic structures: a useful metaphor for health promotion.

The term 'social vaccine' is designed to encourage the biomedically orientated health sector to recognize the legitimacy of action on the distal social and economic determinants of health. It is proposed as a term to assist the health promotion movement in arguing for a social view of health which is so often counter to medical and popular conceptions of health. The idea of a social vaccine builds on a long tradition in social medicine as well as on a biomedical tradition of preventing illness through vaccines that protect against disease. Social vaccines would be promoted as a means to encourage popular mobilization and advocacy to change the social and economic structural conditions that render people and communities vulnerable to disease. They would facilitate social and political processes that develop popular and political will to protect and promote health through action (especially governments prepared to intervene and regulate to protect community health) on the social and economic determinants. Examples provided for the effects of social vaccines are: restoring land ownership to Indigenous peoples, regulating the advertising of harmful products and progressive taxation for universal social protection. Social vaccines require more research to improve understanding of social and political processes that are likely to improve health equity worldwide. The vaccine metaphor should be helpful in arguing for increased action on the social determinants of health

Analysis of simulations.

<p><b>A.</b> The three genetic arrangements, in simulated diploid chromosomes. Key measurements of each configuration are represented in Broom Diagrams. <b>B.</b> Aspects of each simulation, from total number of cells to genetic diversity are represented as line of different colour, with the median as a thick, black line (calculated until one of the simulations came to an end). The behaviour observed for Gene Configuration A is a homeostatic one. Configurations B and C displayed an over-proliferative behaviour. This is due to the genetic up and down regulation reflected by the change in the average number of key genes across time. <b>C.</b> The average number of Division Genes. <b>D.</b> The average number of Apoptosis Genes. <b>E.</b> The average number of Segregation Genes. <b>F.</b> The genetic diversity, liked to the number of Segregation genes, had a profound effect on the Genotypic Diversity, being greatest in Configuration C. Colours are purely used to distinguish runs and do not denote genetic distribution.</p

Genotype configurations and Gene Key.

<p><b>A.</b> The different Gene Abstractions were placed into chromosomes in three different configurations. This led to different kinds of linkages between the Genes. <b>B.</b> For the notation of different genotypes, we have used the following key: (Number of Division Genes, Number of Death Genes, Number of Segregation Genes). The initial Genotype in every simulation is a diploid genome: (2,2,2). To better understand the proportions of the genes in a given phenotype, we have used the RGB model to represent the number of division genes as red, the number of death genes as green and the number of segregation genes as blue See Methods, Genotype Key).</p

Genotype diversity.

<p><b>A.</b> The two over-proliferative genetic arrangements, in simulated diploid chromosomes, and the RGB key in the middle. We have used the RGB colour model to visually describe the different genotypes that evolve in the system by normalizing the maximum observed Genotype State (See Methods, RGB Key). We have assigned a colour to each of the abstracted genes: Red for division, green for death and blue for segregation. By comparing via an RGB system the colours assigned to a given genotype, we are able to tell visually the proportions in which the genes are distributed, with intensity values corresponding to the number of genes: (0,0,0) being black, the initial genotype (2, 2, 2) being dark grey and the maximum observed genotype (5, 5, 5) being white. <b>B.</b> Representative Marble Diagram for a simulation with the Model. These diagrams display the stacked percentage of Genetic Diversity across time for a representative simulation of Gene Configurations B and C across different scenarios. The beginning of therapies (when reaching 1000 cells) are marked with a black vertical line, while relapse times (when reaching again 1000 cells) are marked using a dashed line. <b>C.</b> Representative Marble Diagram for a Simulation of Surgery. <b>D.</b> Representative Marble Diagram for a Simulation of Chemotherapy. <b>E.</b> Representative Marble Diagram of a therapy combination of Surgery followed by Chemotherapy.</p

The average ratio of apoptosis to division genes.

<p>These graphs show the tendency of reducing the number of apoptosis genes and increasing the number of division genes with respect to time across different scenarios: <b>A.</b> Surgery Scenario, <b>B.</b> Chemotherapy Scenario and <b>C.</b> Combination of both treatments (Surgery followed by Chemotherapy). The dark line is the median of the samples and the shadowed area represents the variance. Interventions were carried out at time step zero. The reported slopes were measured taking into account 25 time steps after each therapy.</p