Safety and immunogenicity of the candidate tuberculosis vaccine MVA85A in West Africa.

BACKGROUND: Vaccination with a recombinant modified vaccinia Ankara expressing antigen 85A from Mycobacterium tuberculosis, MVA85A, induces high levels of cellular immune responses in UK volunteers. We assessed the safety and immunogenicity of this new vaccine in West African volunteers. METHODS AND FINDINGS: We vaccinated 21 healthy adult male subjects (11 BCG scar negative and 10 BCG scar positive) with MVA85A after screening for evidence of prior exposure to mycobacteria. We monitored them over six months, observing for clinical, haematological and biochemical adverse events, together with assessment of the vaccine induced cellular immune response using ELISPOT and flow cytometry. MVA85A was well tolerated with no significant adverse events. Mild local and systemic adverse events were consistent with previous UK trials. Marked immunogenicity was found whether individuals had a previous BCG scar or not. There was not enhanced immunogenicity in those with a BCG scar, and induced T cell responses were better maintained in apparently BCG-naïve Gambians than previously studied BCG-naïve UK vaccinees. Although responses were predominantly attributable to CD4+ T cells, we also identified antigen specific CD8+ T cell responses, in subjects who were HLA B-35 and in whom enough blood was available for more detailed immunological analysis. CONCLUSIONS: These data on the safety and immunogenicity of MVA85A in West Africa support its accelerated development as a promising booster vaccine for tuberculosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00423839

Effects of maternal and paternal smoking on attentional control in children with and without ADHD

Maternal smoking during pregnancy is a risk factor for attention-deficit/hyperactivity disorder (ADHD), but data on its adverse effects on cognitive functioning are sparse and inconsistent. Since the effect of maternal smoking during pregnancy may be due to correlated genetic risk factors rather than being a pure environmental effect, we examined the effect of prenatal exposure to smoking on attentional control, taking into account the effects of both maternal and paternal smoking, and examined whether these effects were genetically mediated by parental genotypes. We further examined whether the effect of prenatal exposure to smoking on attentional control interacted with genotypes of the child. Participants were 79 children with ADHD, ascertained for the International Multi-centre ADHD Gene project (IMAGE), and 105 normal controls. Attentional control was assessed by a visual continuous performance task. Three genetic risk factors for ADHD (DRD4 7-repeat allele of the exon 3 variable number of tandem repeats (VNTR), DAT1 10/10 genotype of the VNTR located in the 3′ untranslated region, and the DAT1 6/6 genotype of the intron 8 VNTR) were included in the analyses. Paternal smoking had a negative effect on attentional control in children with ADHD and this effect appeared to be mediated by genetic risk factors. The prenatal smoking effect did not interact with genotypes of the child. Maternal smoking had no main effect on attentional control, which may be due to lower smoking rates. This study suggests that the effects of paternal smoking on attentional control in children with ADHD should be considered a proxy for ADHD and/or smoking risk genes. Future studies should examine if the results can be generalized to other cognitive domains

SOIL QUALITY IN RELATION TO FOREST CONVERSION TO PERENNIAL OR ANNUAL CROPPING IN SOUTHERN BRAZIL

Many forested areas have been converted to intensive agricultural use to satisfy food, fiber, and forage production for a growing world population. There is great interest in evaluating forest conversion to cultivated land because this conversion adversely affects several soil properties. We examined soil microbial, physical, and chemical properties in an Oxisol (Latossolo Vermelho distrófico) of southern Brazil 24 years after forest conversion to a perennial crop with coffee or annual grain crops (maize and soybeans) in conventional tillage or no-tillage. One goal was to determine which soil quality parameters seemed most sensitive to change. A second goal was to test the hypothesis that no-tillage optimized preservation of soil quality indicators in annual cropping systems on converted land. Land use significantly affected microbial biomass and its activity, C and N mineralization, and aggregate stability by depth. Cultivated sites had lower microbial biomass and mineralizable C and N than a forest used as control. The forest and no-tillage sites had higher microbial biomass and mineralizable C and N than the conventional tillage site, and the metabolic quotient was 65 and 43 % lower, respectively. Multivariate analysis of soil microbial properties showed a clear separation among treatments, displaying a gradient from conventional tillage to forest. Although the soil at the coffee site was less disturbed and had a high organic C content, the microbial activity was low, probably due to greater soil acidity and Al toxicity. Under annual cropping, microbial activity in no-tillage was double that of the conventional tillage management. The greater microbial activity in forest and no-tillage sites may be attributed, at least partially, to lower soil disturbance. Reducing soil disturbance is important for soil C sequestration and microbial activity, although control of soil pH and Al toxicity are also essential to maintain the soil microbial activity high

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Genetically elevated high-density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease

Introduction: There is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C. Methods: Ten single nucleotide polymorphisms within the CETP locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger. Results: Based on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the CETP locus, we found that HDL-C was not associated with risk of AD (P > .7). Discussion: Our study does not support the role of HDL-C on risk of AD through HDL-C altered by CETP. This study does not rule out other mechanisms by which HDL-C affects risk of AD

Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design.

Tuberculosis remains a substantial global health problem despite effective drug treatments. The efficacy of BCG, the only available vaccine, is variable, especially in tuberculosis-endemic regions. Recent advances in the development of new vaccines against tuberculosis mean that the first of these are now entering into early clinical trials. A recombinant modified vaccinia virus Ankara expressing a major secreted antigen from Mycobacterium tuberculosis, antigen 85A, was the first new tuberculosis vaccine to enter into clinical trials in September 2002. This vaccine is known as MVA85A. In a series of phase I clinical trials in the UK, MVA85A had an excellent safety profile and was highly immunogenic. MVA85A was subsequently evaluated in a series of phase I trials in The Gambia, a tuberculosis-endemic area in west Africa. This vaccine is the only new subunit tuberculosis vaccine to enter into clinical trials in Africa to date. Here, we discuss some of the issues that were considered in the protocol design of these studies including recruitment, inclusion and exclusion criteria, reimbursement of study participants, and HIV testing. These issues are highly relevant to early clinical trials with all new tuberculosis vaccines in the developing world

Small intestinal cancer in England & Wales and Scotland: time trends in incidence, mortality and survival.

BACKGROUND: Time trends in mortality from small intestinal cancer have not been studied for the 1990s. OBJECTIVE: To examine secular trends in incidence of, mortality from, and survival from, small intestinal cancer in England & Wales and Scotland from 1975 to 2002, considering also histological type (incidence), subsite (incidence) and indices of social deprivation (incidence and survival). METHODS: Data were extracted from the Scottish Cancer Registry database and the General Register Office for Scotland, and from the National Cancer Intelligence Centre at the Office for National Statistics for England & Wales. RESULTS: Incidence rates for small intestinal cancer increased for both England & Wales and Scotland over the study period. They were highest among older individuals and generally greater for males than for females. Despite the increase in incidence rates, mortality rates from small intestinal tumours tended to remain stable over the study period, and the general trend was towards increasing survival. Indices of social deprivation were not obviously related to the incidence of small intestinal cancer and did not influence survival. CONCLUSIONS: Incidence rates for small intestinal cancer for both England & Wales and Scotland increased in the last quarter of the 20th century, but survival rates improved and mortality rates declined

Going to ridiculous lengths-European coexistence regulations for GM crops

Even if a GM crop can surmount Europe's excessive product registration process, any farmer hoping to plant it must then navigate tortuous, arbitrary and scientifically unjustifiable coexistence regulations