An investigation into unsteady base bleed for drag reduction in bluff two-box SUVs

This paper discusses a preliminary investigation into the use of base bleed on a production SUV using CFD analysis. The paper shows the methods used in creating the computational model and conducting the analysis, and present the findings to date. The paper shows that the reduction in drag increases as the mass flow rate of air is increased when the flow is deflected at the outlet. By controlling the turbulent wake to the rear of the vehicle, it is shown in the paper that mass flow rates of under 2kg/s can reduce drag coefficient by 8.2% with an outlet on the side of the vehicle, and that a mass flow rate of under 1.5kg/s can reduce the drag coefficient by 10.7% for an outlet on the upper section of the rear of the vehicle. The paper also discusses the feasibility of base bleed being applied to a production vehicle

Cost-utility of adjuvant zoledronic acid in patients with breast cancer and low estrogen levels

BACKGROUND: Adjuvant zoledronic acid (za) appears to improve disease-free survival (dfs) in women with early-stage breast cancer and low levels of estrogen (lle) because of induced or natural menopause. Characterizing the cost-utility (cu) of this therapy could help to determine its role in clinical practice. METHODS: Using the perspective of the Canadian health care system, we examined the cu of adjuvant endocrine therapy with or without za in women with early-stage endocrine-sensitive breast cancer and lle. A Markov model was used to compute the cumulative costs in Canadian dollars and the quality-adjusted life-years (qalys) gained from each adjuvant strategy, discounted at a rate of 5% annually. The model incorporated the dfs and fracture benefits of adjuvant za. Probabilistic and one-way sensitivity analyses were conducted to examine key model parameters. RESULTS: Compared with a no-za strategy, adjuvant za in the induced and natural menopause groups was associated with, respectively, $7,825 and$7,789 in incremental costs and 0.46 and 0.34 in qaly gains for cu ratios of $17,007 and$23,093 per qaly gained. In one-way sensitivity analyses, the results were most sensitive to changes in the za dfs benefit. Probabilistic sensitivity analysis suggested a 100% probability of adjuvant za being a cost-effective strategy at a threshold of $100,000 per qaly gained. CONCLUSIONS: Based on available data, adjuvant za appears to be a cost-effective strategy in women with endocrine-sensitive breast cancer and lle, having cu ratios well below accepted thresholds

The development of a ε-polycaprolactone (PCL) scaffold for CNS repair

Potential treatment strategies for the repair of spinal cord injury (SCI) currently favour a combinatorial approach incorporating several factors, including exogenous cell transplantation and biocompatible scaffolds. The use of scaffolds for bridging the gap at the injury site is very appealing although there has been little investigation into CNS neural cell interaction and survival on such scaffolds before implantation. Previously we demonstrated that aligned micro-grooves 12.5-25 µm wide on ε-polycaprolactone (PCL) promoted aligned neurite orientation and supported myelination. In this study we identify the appropriate substrate and its topographical features required for the design of a 3D scaffold intended for transplantation in SCI. Using an established myelinating culture system of dissociated spinal cord cells, recapitulating many of the features of the intact spinal cord, we demonstrate that astrocytes plated on the topography secrete soluble factors(s) that delay oligodendrocyte differentiation but do not prevent myelination. However, as myelination does occur after a further 10-12 days in culture this does not prevent the use of PCL as a scaffold material as part of a combined strategy for the repair of SCI

Impact of the PROFHER trial findings on surgeons' clinical practice : An online questionnaire survey

OBJECTIVES: To explore whether orthopaedic surgeons have adopted the Proximal Fracture of the Humerus: Evaluation by Randomisation (PROFHER) trial results routinely into clinical practice. METHODS: A questionnaire was piloted with six orthopaedic surgeons using a 'think aloud' process. The final questionnaire contained 29 items and was distributed online to surgeon members of the British Orthopaedic Association and British Elbow and Shoulder Society. Descriptive statistics summarised the sample characteristics and fracture treatment of respondents overall, and grouped them by whether they changed practice based on PROFHER trial findings. Free-text responses were analysed qualitatively for emerging themes using Framework Analysis principles. RESULTS: There were complete responses from 265 orthopaedic and trauma surgeons who treat patients with proximal humeral fractures. Around half (137) had changed practice to various extents because of PROFHER, by operating on fewer PROFHER-eligible fractures. A third (43) of the 128 respondents who had not changed practice were already managing patients non-operatively. Those who changed practice were more likely to be younger, work in a trauma unit rather than a major trauma centre, be specialist shoulder surgeons and treat fewer PROFHER-eligible fractures surgically. This group gave higher scores when assessing validity and applicability of PROFHER. In contrast, a quarter of the non-changers were critical, sometimes emphatically, of PROFHER. The strongest theme that emerged overall was the endorsement of evidence-based practice. CONCLUSION: PROFHER has had an impact on surgeons' clinical practice, both through changing it, and through underpinning existing non-operative practice. Although some respondents expressed reservations about the trial, evidence from such trials was found to be the most important influence on surgeons' decisions to change practice.Cite this article: L. Jefferson, S. Brealey, H. Handoll, A. Keding, L. Kottam, I. Sbizzera, A. Rangan. Impact of the PROFHER trial findings on surgeons' clinical practice: An online questionnaire survey. Bone Joint Res 2017;6:590-599. DOI: 10.1302/2046-3758.610.BJR-2017-0170

Profiles of physical, emotional and psychosocial wellbeing in the Lothian birth cohort 1936

<p>Abstract</p> <p>Background</p> <p>Physical, emotional, and psychosocial wellbeing are important domains of function. The aims of this study were to explore the existence of separable groups among 70-year olds with scores representing physical function, perceived quality of life, and emotional wellbeing, and to characterise any resulting groups using demographic, personality, cognition, health and lifestyle variables.</p> <p>Methods</p> <p>We used latent class analysis (LCA) to identify possible groups.</p> <p>Results</p> <p>Results suggested there were 5 groups. These included High (n = 515, 47.2% of the sample), Average (n = 417, 38.3%), and Poor Wellbeing (n = 37, 3.4%) groups. The two other groups had contrasting patterns of wellbeing: one group scored relatively well on physical function, but low on emotional wellbeing (Good Fitness/ Low Spirits,n = 60, 5.5%), whereas the other group showed low physical function but relatively well emotional wellbeing (Low Fitness/Good Spirits, n = 62, 5.7%). Salient characteristics that distinguished all the groups included smoking and drinking behaviours, personality, and illness.</p> <p>Conclusions</p> <p>Despite there being some evidence of these groups, the results also support a largely one-dimensional construct of wellbeing in old age—for the domains assessed here—though with some evidence that some individuals have uneven profiles.</p

Human RIF1 and protein phosphatase 1 stimulate DNA replication origin licensing but suppress origin activation

We thank David Stead at the Aberdeen Proteomics Service for help in mass spectrometry interpretation, and Raif Yücel and his team at the University of Aberdeen Iain Fraser Cytometry Centre for assistance with flow cytometry. We thank Robert Alver and Julian Blow at University of Dundee for advice on the use of tautomycetin. Peter Cherepanov of the Francis Crick Institute gifted XL413. Daniel Durocher of Lunenfeld-Tanenbaum Research Institute gifted DNA constructs. Work by ADD and SH was supported by Cancer Research UK Grant A13356, Cancer Research UK Programme Award A19059, and BBSRC grant (BB/K006304/1). AIL was supported by Wellcome Trust Awards (108058/Z/15/Z & 105024/Z/14/Z). This work was also supported by JSPS KAKENHI Grant # 16H04739, 25116004 to CO and 16J04327 to YO.Peer reviewedPublisher PD

Mouse models for preeclampsia: disruption of redox-regulated signaling

The concept that oxidative stress contributes to the development of human preeclampsia has never been tested in genetically-defined animal models. Homozygous deletion of catechol-Omethyl transferase (Comt-/-) in pregnant mice leads to human preeclampsia-like symptoms (high blood pressure, albuminurea and preterm birth) resulting from extensive vasculo-endothelial pathology, primarily at the utero-fetal interface where maternal cardiac output is dramatically increased during pregnancy. Comt converts estradiol to 2-methoxyestradiol 2 (2ME2) which counters angiogenesis by depleting hypoxia inducible factor-1 alpha (HIF-1 alpha) at late pregnancy. We propose that in wild type (Comt++) pregnant mice, 2ME2 destabilizes HIF-1 alpha by inhibiting mitochondrial superoxide dismutase (MnSOD). Thus, 2ME2 acts as a pro-oxidant, disrupting redox-regulated signaling which blocks angiogenesis in wild type (WT) animals in physiological pregnancy. Further, we suggest that a lack of this inhibition under normoxic conditions in mutant animals (Comt-/-) stabilises HIF-1 alpha by inactivating prolyl hydroxlases (PHD). We predict that a lack of inhibition of MnSOD, leading to persistent accumulation of HIF-1 alpha, would trigger inflammatory infiltration and endothelial damage in mutant animals. Critical tests of this hypothesis would be to recreate preeclampsia symptoms by inducing oxidative stress in WT animals or to ameliorate by treating mutant mice with Mn-SOD-catalase mimetics or activators of PHD

Targeted knock-down of miR21 primary transcripts using snoMEN vectors induces apoptosis in human cancer cell lines

We have previously reported an antisense technology, 'snoMEN vectors', for targeted knock-down of protein coding mRNAs using human snoRNAs manipulated to contain short regions of sequence complementarity with the mRNA target. Here we characterise the use of snoMEN vectors to target the knock-down of micro RNA primary transcripts. We document the specific knock-down of miR21 in HeLa cells using plasmid vectors expressing miR21-targeted snoMEN RNAs and show this induces apoptosis. Knock-down is dependent on the presence of complementary sequences in the snoMEN vector and the induction of apoptosis can be suppressed by over-expression of miR21. Furthermore, we have also developed lentiviral vectors for delivery of snoMEN RNAs and show this increases the efficiency of vector transduction in many human cell lines that are difficult to transfect with plasmid vectors. Transduction of lentiviral vectors expressing snoMEN targeted to pri-miR21 induces apoptosis in human lung adenocarcinoma cells, which express high levels of miR21, but not in human primary cells. We show that snoMEN-mediated suppression of miRNA expression is prevented by siRNA knock-down of Ago2, but not by knock-down of Ago1 or Upf1. snoMEN RNAs colocalise with Ago2 in cell nuclei and nucleoli and can be co-immunoprecipitated from nuclear extracts by antibodies specific for Ago2