A randomised trial of subcutaneous intermittent interleukin-2 without antiretroviral therapy in HIV-infected patients: the UK-Vanguard Study

Objective: The objective of the trial was to evaluate in a pilot setting the safety and efficacy of interleukin-2 (IL-2) therapy when used without concomitant antiretroviral therapy as a treatment for HIV infection. Design and Setting: This was a multicentre randomised three-arm trial conducted between September 1998 and March 2001 at three clinical centres in the United Kingdom. Participants: Participants were 36 antiretroviral treatment naive HIV-1-infected patients with baseline CD4 T lymphocyte counts of at least 350 cells/mm(3). Interventions: Participants were randomly assigned to receive IL-2 at 15 million international units (MIU) per day ( 12 participants) or 9 MIU/day ( 12 participants) or no treatment ( 12 participants). IL-2 was administered by twice-daily subcutaneous injections for five consecutive days every 8 wk. Outcome Measures: Primary outcome was the change from baseline CD4 T lymphocyte count at 24 wk. Safety and plasma HIV RNA levels were also monitored every 4 wk through 24 wk. The two IL-2 dose groups were combined for the primary analysis. Results: Area under curve (AUC) for change in the mean CD4 T lymphocyte count through 24 wk was 129 cells/mm(3) for those assigned IL-2 ( both dose groups combined) and 13 cells/mm(3) for control participants (95% CI for difference, 51.3 - 181.2 cells/mm(3); p = 0.0009). Compared to the control group, significant increases in CD4 cell count were observed for both IL-2 dose groups: 104.2/mm(3) ( p = 0.008) and 128.4 cells/mm(3) ( p = 0.002) for the 4.5 and 7.5 MIU dose groups, respectively. There were no significant differences between the IL-2 (0.13 log(10) copies/ ml) and control (0.09 log(10) copies/ml) groups for AUC of change in plasma HIV RNA over the 24-wk period of follow- up ( 95% CI for difference, - 0.17 to 0.26; p = 0.70). Grade 4 and dose-limiting side effects were in keeping with those previously reported for IL-2 therapy. Conclusions: In participants with HIV infection and baseline CD4 T lymphocyte counts of at least 350 cells/mm(3), intermittent subcutaneous IL-2 without concomitant antiretroviral therapy was well tolerated and produced significant increases in CD4 T lymphocyte counts and did not adversely affect plasma HIV RNA levels

Investigating awareness, fear and control associated with norovirus and other pathogens and pollutants using best–worst scaling

Pollutants found in the water and air environment represent an ever-growing threat to human health. Contact with some air-, water- and foodborne pathogens (e.g. norovirus) results in gastrointestinal diseases and outbreaks. For future risk mitigation, we aimed to measure people’s awareness of waterborne and foodborne norovirus relative to other environment-associated pollutants (e.g. pesticides, bioaerosols, antibiotic resistant bacteria) and well-known risks (e.g. diabetes, dementia, terrorist attack). We used an online survey, which included a best–worst scaling component to elicit personal levels of control and fear prompted by norovirus relative to 15 other risks. There was a negative correlation between levels of fear vs. control for all 16 measured risks. Perceived infection control levels were higher amongst women compared to men and correlated with age and the level of qualification in both groups. Participants who had sought advice regarding the symptoms caused by norovirus appeared to have more control over the risks. Norovirus is associated with high levels of fear, however, the levels of control over it is low compared to other foodborne illnesses, e.g. Salmonella. Addressing this deficit in the public’s understanding of how to control exposure to the pathogen in an important health need

Heterologous oligonucleotide microarrays for transcriptomics in a non-model species; a proof-of-concept study of drought stress in Musa

<p>Abstract</p> <p>Background</p> <p>'Systems-wide' approaches such as microarray RNA-profiling are ideally suited to the study of the complex overlapping responses of plants to biotic and abiotic stresses. However, commercial microarrays are only available for a limited number of plant species and development costs are so substantial as to be prohibitive for most research groups. Here we evaluate the use of cross-hybridisation to Affymetrix oligonucleotide GeneChip^®microarrays to profile the response of the banana (<it>Musa </it>spp.) leaf transcriptome to drought stress using a genomic DNA (gDNA)-based probe-selection strategy to improve the efficiency of detection of differentially expressed <it>Musa </it>transcripts.</p> <p>Results</p> <p>Following cross-hybridisation of <it>Musa </it>gDNA to the Rice GeneChip^®Genome Array, ~33,700 gene-specific probe-sets had a sufficiently high degree of homology to be retained for transcriptomic analyses. In a proof-of-concept approach, pooled RNA representing a single biological replicate of control and drought stressed leaves of the <it>Musa </it>cultivar 'Cachaco' were hybridised to the Affymetrix Rice Genome Array. A total of 2,910 <it>Musa </it>gene homologues with a >2-fold difference in expression levels were subsequently identified. These drought-responsive transcripts included many functional classes associated with plant biotic and abiotic stress responses, as well as a range of regulatory genes known to be involved in coordinating abiotic stress responses. This latter group included members of the ERF, DREB, MYB, bZIP and bHLH transcription factor families. Fifty-two of these drought-sensitive <it>Musa </it>transcripts were homologous to genes underlying QTLs for drought and cold tolerance in rice, including in 2 instances QTLs associated with a single underlying gene. The list of drought-responsive transcripts also included genes identified in publicly-available comparative transcriptomics experiments.</p> <p>Conclusion</p> <p>Our results demonstrate that despite the general paucity of nucleotide sequence data in <it>Musa </it>and only distant phylogenetic relations to rice, gDNA probe-based cross-hybridisation to the Rice GeneChip^®is a highly promising strategy to study complex biological responses and illustrates the potential of such strategies for gene discovery in non-model species.</p

Validating an inertial measurement unit for cricket fast bowling: a first step in assessing the feasibility of diagnosing back injury risk in cricket fast bowlers during a tele-sport-and-exercise medicine consultation

This study aimed to validate an array-based inertial measurement unit to measure cricket fast bowling kinematics as a first step in assessing feasibility for tele-sport-and-exercise medicine. We concurrently captured shoulder girdle relative to the pelvis, trunk lateral flexion, and knee flexion angles at front foot contact of eight cricket medium-fast bowlers using inertial measurement unit and optical motion capture. We used one sample t-tests and 95% limits of agreement (LOA) to determine the mean difference between the two systems and Smallest Worth-while Change statistic to determine whether any differences were meaningful. A statistically significant (p < 0.001) but small mean difference of −4.7° ± 8.6° (95% Confidence Interval (CI) [−3.1° to −6.4°], LOA [−22.2 to 12.7], SWC 3.9°) in shoulder girdle relative to the pelvis angle was found between the systems. There were no statistically significant differences between the two systems in trunk lateral flexion and knee flexion with the mean differences being 0.1° ± 10.8° (95% CI [−1.9° to 2.2°], LOA [−22.5 to 22.7], SWC 1.2°) and 1.6° ± 10.1° (95% CI [−0.2° to 3.3°], LOA [−19.2 to 22.3], SWC 1.9°) respectively. The inertial measurement unit-based system tested allows for accurate measurement of specific cricket fast bowling kinematics and could be used in determining injury risk in the context of tele-sport-and-exercise-medicine

An atlas of polygenic risk score associations to highlight putative causal relationships across the human phenome

The age of large-scale genome-wide association studies (GWAS) has provided us with an unprecedented opportunity to evaluate the genetic liability of complex disease using polygenic risk scores (PRS). In this study, we have analysed 162 PRS (p<5×10−05) derived from GWAS and 551 heritable traits from the UK Biobank study (N = 334,398). Findings can be investigated using a web application (http://mrcieu.mrsoftware.org/PRS_atlas/), which we envisage will help uncover both known and novel mechanisms which contribute towards disease susceptibility. To demonstrate this, we have investigated the results from a phenome-wide evaluation of schizophrenia genetic liability. Amongst findings were inverse associations with measures of cognitive function which extensive follow-up analyses using Mendelian randomization (MR) provided evidence of a causal relationship. We have also investigated the effect of multiple risk factors on disease using mediation and multivariable MR frameworks. Our atlas provides a resource for future endeavours seeking to unravel the causal determinants of complex disease

Educational attainment as a modifier for the effect of polygenic scores for cardiovascular risk factors:cross-sectional and prospective analysis of UK Biobank

BACKGROUND: Understanding the interplay between educational attainment and genetic predictors of cardiovascular risk may improve our understanding of the aetiology of educational inequalities in cardiovascular disease. METHODS: In up to 320 120 UK Biobank participants of White British ancestry (mean age = 57 years, female 54%), we created polygenic scores for nine cardiovascular risk factors or diseases: alcohol consumption, body mass index, low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes and stroke. We estimated whether educational attainment modified genetic susceptibility to these risk factors and diseases. RESULTS: On the additive scale, higher educational attainment reduced genetic susceptibility to higher body mass index, smoking, atrial fibrillation and type 2 diabetes, but increased genetic susceptibility to higher LDL-C and higher systolic blood pressure. On the multiplicative scale, there was evidence that higher educational attainment increased genetic susceptibility to atrial fibrillation and coronary heart disease, but little evidence of effect modification was found for all other traits considered. CONCLUSIONS: Educational attainment modifies the genetic susceptibility to some cardiovascular risk factors and diseases. The direction of this effect was mixed across traits considered and differences in associations between the effect of the polygenic score across strata of educational attainment was uniformly small. Therefore, any effect modification by education of genetic susceptibility to cardiovascular risk factors or diseases is unlikely to substantially explain the development of inequalities in cardiovascular risk

BioNetBuilder2.0: bringing systems biology to chicken and other model organisms

BACKGROUND:Systems Biology research tools, such as Cytoscape, have greatly extended the reach of genomic research. By providing platforms to integrate data with molecular interaction networks, researchers can more rapidly begin interpretation of large data sets collected for a system of interest. BioNetBuilder is an open-source client-server Cytoscape plugin that automatically integrates molecular interactions from all major public interaction databases and serves them directly to the user's Cytoscape environment. Until recently however, chicken and other eukaryotic model systems had little interaction data available.RESULTS:Version 2.0 of BioNetBuilder includes a redesigned synonyms resolution engine that enables transfer and integration of interactions across speciesthis engine translates between alternate gene names as well as between orthologs in multiple species. Additionally, BioNetBuilder is now implemented to be part of the Gaggle, thereby allowing seamless communication of interaction data to any software implementing the widely used Gaggle software. Using BioNetBuilder, we constructed a chicken interactome possessing 72,000 interactions among 8,140 genes directly in the Cytoscape environment. In this paper, we present a tutorial on how to do so and analysis of a specific use case.CONCLUSION:BioNetBuilder 2.0 provides numerous user-friendly systems biology tools that were otherwise inaccessible to researchers in chicken genomics, as well as other model systems. We provide a detailed tutorial spanning all required steps in the analysis. BioNetBuilder 2.0, the tools for maintaining its data bases, standard operating procedures for creating local copies of its back-end data bases, as well as all of the Gaggle and Cytoscape codes required, are open-source and freely available at http://err.bio.nyu.edu/cytoscape/bionetbuilder/ webcite.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]

Scale-up of reverse electrodialysis for energy generation from high concentration salinity gradients

Whilst reverse electrodialysis (RED) has been extensively characterised for saline gradient energy from seawater/river water (0.5 M/0.02 M), less is known about RED stack design for high concentration salinity gradients (4 M/0.02 M), important to closed loop applications (e.g. thermal-to-electrical, energy storage). This study therefore focuses on the scale-up of RED stacks for high concentration salinity gradients. Higher velocities were required to attain a maximum Open Circuit Voltage (OCV) for 4 M/0.02 M, which gives a measure of the electrochemical potential of the cell. The experimental OCV was also much below the theoretical OCV, due to the greater boundary layer resistance observed, which is distinct from 0.5 M/0.02 M. However, negative net power density (net produced electrical power divided by total membrane area) was demonstrated with 0.5 M/0.02 M for larger stacks using shorter residence times (three stack sizes tested: 10 × 10cm, 10 × 20cm and 10 × 40cm). In contrast, the highest net power density was observed at the shortest residence time for the 4 M/0.02 M concentration gradient, as the increased ionic flux compensated for the pressure drop. Whilst comparable net power densities were determined for the 10 × 10cm and 10 × 40cm stacks using the 4 M/0.02 M concentration gradient, the osmotic and ionic transport mechanisms are distinct. Increasing cell pair number improved maximum current density. This subsequently increased power density, due to the reduction in boundary layer resistance, and may therefore be used to improve thermodynamic efficiency and power density from RED for high concentrations. Although comparable power densities may be achieved for small and large stacks, large stacks maybe preferred for high concentration salinity gradients due to the comparative benefit in thermodynamic efficiency in single pass. The greater current achieved by large stacks may also be complemented by an increase in cell pair number and current density optimisation to increase power density and reduce exergy losses

Blood pressure variability and night-time dipping assessed by 24-hour ambulatory monitoring:cross-sectional association with cardiac structure in adolescents

Greater blood pressure (BP) is associated with greater left ventricular mass indexed to height2.7 (LVMi2.7) in adolescents. This study examined whether greater BP variability and reduced night-time dipping are associated with cardiac remodeling in a general population of adolescents. A cross-sectional analysis was undertaken in 587 UK adolescents (mean age 17.7 years; 43.1% male). BP was measured in a research clinic and using 24-hour ambulatory monitoring. We examined associations (for both systolic and diastolic BP) of: 1) clinic and 24-hour mean BP; 2) measures of 24-hour BP variability: standard deviation weighted for day/night (SDdn), variability independent of the mean (VIM) and average real variability (ARV); and 3) night-time dipping with cardiac structures. Cardiac structures were assessed by echocardiography: 1) LVMi2.7; 2) relative wall thickness (RWT); 3) left atrial diameter indexed to height (LADi) and 4) left ventricular internal diameter in diastole (LVIDD). Higher systolic BP was associated with greater LVMi2.7. Systolic and diastolic BP were associated with greater RWT. Associations were inconsistent for LADi and LVIDD. There was evidence for associations between both greater SDdn and ARV and higher RWT (per 1 SD higher diastolic ARV, mean difference in RWT was 0.13 SDs, 95% CI 0.045 to 0.21); these associations with RWT remained after adjustment for mean BP. There was no consistent evidence of associations between night-time dipping and cardiac structure. Measurement of BP variability, even in adolescents with blood pressure in the physiologic range, might benefit risk of cardiovascular remodeling assessment