Magnetic and physical characterisation of soft thin films for use in perpendicular recording heads

Abstract available : p.i-ii

Moorabool Shire project : Stage 1 - Local area planning

This project was funded by the Victorian Government Department of Human Services and the Moorabool Shire Council and is currently being used to inform future health and welfare service provision in the Moorabool Shire.K

The Leishmania donovani LD1 locus gene ORFG encodes a biopterin transporter (BT1)

We have previously described two genes, ORFF and ORFG, from the LD1 locus near one telomere of chromosome 35, which are frequently amplified in Leishmania isolates. In Leishmania donovani LSB-51.1, gene conversion of the rRNA gene locus on chromosome 27 with these two genes resulted in their over-expression, because of their transcription by the RNA polymerase I-mediated rRNA promoter. The predicted ORFG protein has substantial sequence homology to the ESAG10 gene product from the Trypanosoma brucei VSG expression site and both are putative membrane proteins. Using successive rounds of gene replacement of the three ORFG genes in L. donovani LSB-51.1, ORFG null mutants were obtained. These mutant cell lines show a direct relationship between ORFG mRNA, protein expression levels and active transport of biopterin into the cells. Transformation of the null mutant with a plasmid containing ORFG restores biopterin transport activity. In addition, the null mutants are unable to grow in the absence of supplemental biopterin. Thus, ORFG encodes a biopterin transporter and has been renamed BT1

Collaborating with front-line healthcare professionals: the clinical and cost effectiveness of a theory based approach to the implementation of a national guideline

Background Clinical guidelines are an integral part of healthcare. Whilst much progress has been made in ensuring that guidelines are well developed and disseminated, the gap between routine clinical practice and current guidelines often remains wide. A key reason for this gap is that implementation of guidelines typically requires a change in the behaviour of healthcare professionals – but the behaviour change component is often overlooked. We adopted the Theoretical Domains Framework Implementation (TDFI) approach for supporting behaviour change required for the uptake of a national patient safety guideline to reduce the risk of feeding through misplaced nasogastric tubes. Methods The TDFI approach was used in a pre-post study in three NHS hospitals with a fourth acting as a control (with usual care and no TDFI). The target behavior identified for change was to increase the use of pH testing as the first line method for checking the position of a nasogastric tube. Repeat audits were undertaken in each hospital following intervention implementation. We used Zou’s modified Poisson regression approach with robust standard errors to estimate risk ratios for the use of pH testing. The projected return on investment (ROI) was also calculated. Results Following intervention implementation, the use of pH first line increased significantly across intervention hospitals [risk ratio (95% CI) ranged from 3.1 (1.14 to8.43) p < .05, to 8.14 (3.06 to21.67) p < .001] compared to the control hospital, which remained unchanged [risk ratio (CI) = .77 (.47-1.26) p = .296]. The estimated savings and costs in the first year were £2.56 million and £1.41 respectively, giving an ROI of 82%, and this was projected to increase to 270% over five years. Conclusion The TDFI approach improved the uptake of a patient safety guideline across three hospitals. The TDFI approach is clinically and cost effective in comparison to the usual practice

Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors

Background: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p&lt;0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76–0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39–0·53; approximately 215 mL) in the 14-week group (p&lt;0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p&lt;0·0001 for each) than those observed in the standard frequency groups. Interpretation: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. Funding: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

Cut-points for waist circumference in Europids and South Asians

There is little strong evidence that currently recommended higher waist circumference cut-points for Europids compared with South Asians are associated with similar risk for type 2 diabetes. This study was designed to provide such evidence. Longitudinal studies over 5 years were conducted among 5,515 Europid and 2,214 ethnically South Asian participants. Age-standardized diabetes incidence at different levels of waist circumference and incidence difference relative to a reference value were calculated. The Youden Index was used to determine waist circumference cut-points. At currently recommended cut-points, estimated annual diabetes incidence for a 50-year-old Europid was &lt;0.6% for both sexes, and for a 50-year-old South Asian, 5.8% for men and 2.1% for women. Annual diabetes incidence of 1% was observed for a 50 year old at a waist circumference 35&ndash;40 cm greater in Europid compared to South Asian men and women. Incidence difference between recommended cut-points and a reference value (80 cm in men, 70 cm in women) was 0.3 and 4.4% per year for Europid and South Asian men, and 0.2 and 0.8% per year for Europid and South Asian women, respectively. Waist circumference cut-points chosen using the Youden Index were shown to be dependent on obesity levels in the population. The much higher observed risk of diabetes in South Asians compared to Europids at the respective recommended waist circumference cut-points suggests that differences between them should be greater. Approaches that use the Youden Index to select waist circumference cut-points are inappropriate and should not be used for this purpose.<br /

Mining Predicted Essential Genes of Brugia malayi for Nematode Drug Targets

We report results from the first genome-wide application of a rational drug target selection methodology to a metazoan pathogen genome, the completed draft sequence of Brugia malayi, a parasitic nematode responsible for human lymphatic filariasis. More than 1.5 billion people worldwide are at risk of contracting lymphatic filariasis and onchocerciasis, a related filarial disease. Drug treatments for filariasis have not changed significantly in over 20 years, and with the risk of resistance rising, there is an urgent need for the development of new anti-filarial drug therapies. The recent publication of the draft genomic sequence for B. malayi enables a genome-wide search for new drug targets. However, there is no functional genomics data in B. malayi to guide the selection of potential drug targets. To circumvent this problem, we have utilized the free-living model nematode Caenorhabditis elegans as a surrogate for B. malayi. Sequence comparisons between the two genomes allow us to map C. elegans orthologs to B. malayi genes. Using these orthology mappings and by incorporating the extensive genomic and functional genomic data, including genome-wide RNAi screens, that already exist for C. elegans, we identify potentially essential genes in B. malayi. Further incorporation of human host genome sequence data and a custom algorithm for prioritization enables us to collect and rank nearly 600 drug target candidates. Previously identified potential drug targets cluster near the top of our prioritized list, lending credibility to our methodology. Over-represented Gene Ontology terms, predicted InterPro domains, and RNAi phenotypes of C. elegans orthologs associated with the potential target pool are identified. By virtue of the selection procedure, the potential B. malayi drug targets highlight components of key processes in nematode biology such as central metabolism, molting and regulation of gene expression

Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth

Genome-wide association study of placental weight in 65,405 newborns and 113,620 parents reveals distinct and shared genetic influences between placental and fetal growth

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth