Putting theory into practice - a case study in one U.K. Medical school of the nature and extent of unprofessional behaviour over a 6-year period

Producing a medical profession which is fit for the demands and expectations of society involves ensuring that practitioners learn what it means to behave in a 'professional' way. Codes of professional conduct have been developed for medical students in the UK, but the literature on how medical schools actually apply these is small. More detail is needed to evaluate approaches to assessing professionalism, or to analyse the extent to which students 'fail' this aspect

Exploiting Chordality in Optimization Algorithms for Model Predictive Control

In this chapter we show that chordal structure can be used to devise efficient optimization methods for many common model predictive control problems. The chordal structure is used both for computing search directions efficiently as well as for distributing all the other computations in an interior-point method for solving the problem. The chordal structure can stem both from the sequential nature of the problem as well as from distributed formulations of the problem related to scenario trees or other formulations. The framework enables efficient parallel computations.Comment: arXiv admin note: text overlap with arXiv:1502.0638

Runway Safety Analysis for 2015 to 2017

Reducing the risk of runway incursions or excursions in order to meet future aviation growth can be achieved two fold: by preventing and by limiting the level of damage. In order to reach an As Low As Reasonably Practicable (ALARP) level of runway safety is insight in the cost of runway safety events as well as in their mitigations required. Aircraft and Aerodrome operators could get this insight by combining the likelihood of future occurrences with their cumulative costs. On top of already existing prevention measures, new additional restrictions could face financial limits as indicated by the law of diminishing returns. That implies that either accepting the risk ‘as is’ and thus accepting higher levels of runway incursions and excursions or find cost-effective mitigations postponing the financial limits to safety. ; thus a cost-benefit approach. A method of estimating the costs of runway related an occurrence has recently been published. Combining this method with a model capable of predicting the likelihood of runway incursions or excursions tailor-made per aircraft or aerodrome operator and their mitigations opens the possibility of a cost benefit approach. Runway incidents and accidents in the period 2015-2017 are analyzed and their costs estimated at $ 11 Billion, corrected for purchasing power. Veer-offs are shown to be by far the most costly events, followed by overruns. Runway incursion analysis has showed to be the least cost event compared with the two aforementioned events. The number and severity of veer-offs are expected to rise. The costs of future veer-offs should be weighed against the costs of prevention and the cost of reducing the levels of damage. Damage reduction is the main objective of the runway strip (RESA for overruns). It appears that the level of damage and costs rise considerably when a runway strip or RESA is inadequate or inappropriate for the moment (e.g. bearing strength). A cost driven, flexible risk based system is recommended in order to reduce the risks and costs associated with runway excursions with emphasis on veer-offs and overruns. Concrete actions include a three step approach for aircraft and aerodrome operators

Large-scale binding affinity calculations on commodity compute clouds

In recent years, it has become possible to calculate binding affinities of compounds bound to proteins via rapid, accurate, precise and reproducible free energy calculations. This is imperative in drug discovery as well as personalized medicine. This approach is based on molecular dynamics (MD) simulations and draws on sequence and structural information of the protein and compound concerned. Free energies are determined by ensemble averages of many MD replicas, each of which requires hundreds of cores and/or GPU accelerators, which are now available on commodity cloud computing platforms; there are also requirements for initial model building and subsequent data analysis stages. To automate the process, we have developed a workflow known as the binding affinity calculator. In this paper, we focus on the software infrastructure and interfaces that we have developed to automate the overall workflow and execute it on commodity cloud platforms, in order to reliably predict their binding affinities on time scales relevant to the domains of application, and illustrate its application to two free energy methods

Mesangial cells are key contributors to the fibrotic damage seen in the lupus nephritis glomerulus.

Background: Lupus nephritis (LN) affects up to 80% of juvenile-onset systemic lupus erythematosus patients. Mesangial cells (MCs) comprise a third of the glomerular cells and are key contributors to fibrotic changes within the kidney. This project aims to identify the roles of MCs in an in vitro model of LN. Methods: Conditionally immortalised MCs were treated with pro-inflammatory cytokines or with patient sera in an in vitro model of LN and assessed for their roles in inflammation and fibrosis. Results: MCs were shown to produce pro-inflammatory cytokines in response to a model of the inflammatory environment in LN. Further the cells expressed increased levels of mRNA for extracellular matrix (ECM) proteins (COL1A1, COL1A2, COL4A1 and LAMB1), matrix metalloproteinase enzymes (MMP9) and tissue inhibitors of matrix metalloproteinases (TIMP1). Treatment of MCs with serum from patients with active LN was able to induce a similar, albeit milder phenotype. Treatment of MCs with cytokines or patient sera was able to induce secretion of TGF-β1, a known inducer of fibrotic changes. Inhibition of TGF-β1 actions through SB-431542 (an activin A receptor type II-like kinase (ALK5) inhibitor) was able to reduce these responses suggesting that the release of TGF-β1 plays a role in these changes. Conclusions: MCs contribute to the inflammatory environment in LN by producing cytokines involved in leukocyte recruitment, activation and maturation. Further the cells remodel the ECM via protein deposition and enzymatic degradation. This occurs through the actions of TGF-β1 on its receptor, ALK5. This may represent a potential therapeutic target for treatment of LN-associated fibrosis

Atomistic Modeling of Scattering Curves for Human IgG1/4 Reveals New Structure-Function Insights

Small angle x-ray and neutron scattering are techniques that give solution structures for large macromolecules. The creation of physically realistic atomistic models from known high-resolution structures to determine joint x-ray and neutron scattering best-fit structures offers a, to our knowledge, new method that significantly enhances the utility of scattering. To validate this approach, we determined scattering curves for two human antibody subclasses, immunoglobulin G (IgG) 1 and IgG4, on five different x-ray and neutron instruments to show that these were reproducible, then we modeled these by Monte Carlo simulations. The two antibodies have different hinge lengths that connect their antigen-binding Fab and effector-binding Fc regions. Starting from 231,492 and 190,437 acceptable conformations for IgG1 and IgG4, respectively, joint x-ray and neutron scattering curve fits gave low goodness-of-fit R factors for 28 IgG1 and 2748 IgG4 structures that satisfied the disulphide connectivity in their hinges. These joint best-fit structures showed that the best-fit IgG1 models had a greater separation between the centers of their Fab regions than those for IgG4, in agreement with their hinge lengths of 15 and 12 residues, respectively. The resulting asymmetric IgG1 solution structures resembled its crystal structure. Both symmetric and asymmetric solution structures were determined for IgG4. Docking simulations with our best-fit IgG4 structures showed greater steric clashes with its receptor to explain its weaker FcγRI receptor binding compared to our best-fit IgG1 structures with fewer clashes and stronger receptor binding. Compared to earlier approaches for fitting molecular antibody structures by solution scattering, we conclude that this joint fit approach based on x-ray and neutron scattering data, combined with Monte Carlo simulations, significantly improved our understanding of antibody solution structures. The atomistic nature of the output extended our understanding of known functional differences in Fc receptor binding between IgG1 and IgG4

Chandra observations of Cygnus OB2

Cygnus OB2 is the nearest example of a massive star forming region, containing over 50 O-type stars and hundreds of B-type stars. We have analyzed two Chandra pointings in Cyg OB2, detecting ~1700 X-ray sources, of which ~1450 are thought to be members of the association. Optical and near-IR photometry has been obtained for ~90% of these sources from recent deep Galactic plane surveys. We have performed isochrone fits to the near-IR color-magnitude diagram, deriving ages of 3.5(+0.75,-1.0) and 5.25(+1.5,-1.0) Myrs for sources in the two fields, both with considerable spreads around the pre-MS isochrones. The presence of a second population in the region, somewhat older than the present-day O-type stars, has been suggested by other authors and fits with the ages derived here. The fraction of sources with inner circumstellar disks (as traced by the K-band excess) is found to be very low, but appropriate for a population of age ~5 Myrs. We measure the stellar mass functions and find a power-law slope of Gamma = -1.09 +/- 0.13, in good agreement with the global mean value estimated by Kroupa. A steepening of the mass function at high masses is observed and we suggest this is due to the presence of the previous generation of stars that have lost their most massive members. Finally, combining our mass function and an estimate of the radial density profile of the association suggests a total mass of Cyg OB2 of ~30,000 Msun, similar to that of many of our Galaxy's most massive star forming regions.Comment: 6 pages, 4 figures, conference proceedings for JENAM 2010: Star Clusters in the Era of Large Surveys, Editors: A.Moitinho and J. Alve

Domain structure of human complement C4b extends with increasing NaCl concentration: implications for its regulatory mechanism

During the activation of complement C4 to C4b, the exposure of its thioester domain (TED) is crucial for the attachment of C4b to activator surfaces. In the C4b crystal structure, TED forms an Arg(104)-Glu(1032) salt bridge to tether its neighbouring macroglobulin (MG1) domain. Here, we examined the C4b domain structure to test whether this salt bridge affects its conformation. Dual polarisation interferometry of C4b immobilised at a sensor surface showed that the maximum thickness of C4b increased by 0.46 nm with increase in NaCl concentration from 50 mM to 175 mM NaCl. Analytical ultracentrifugation showed that the sedimentation coefficient s20, w of monomeric C4b of 8.41 S in 50 mM NaCl buffer decreased to 7.98 S in 137 mM NaCl buffer, indicating that C4b became more extended. Small angle X-ray scattering reported similar RG values of 4.89-4.90 nm for C4b in 137-250 mM NaCl. Atomistic scattering modelling of the C4b conformation showed that TED and the MG1 domain were separated by 4.7 nm in 137-250 mM NaCl, this being greater than that of 4.0 nm in the C4b crystal structure. Our data reveal that in low NaCl concentrations, both at surfaces and in solution, C4b forms compact TED-MG1 structures. In solution, physiologically-relevant NaCl concentrations lead to the separation of the TED and MG1 domain, making C4b less able to bind to its complement regulators. These conformational changes are similar to those seen previously for complement C3b, confirming the importance of this salt bridge for regulating both C4b and C3b

The academic radiography workforce: Age profile, succession planning and academic development.

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Introduction: Academia is one area of practice in which radiographers can specialise; they compile approximately 2% of the total radiography profession in the UK, but are highly influential and essential for the education and development of the workforce in addition to undertaking research. However, the academic environment is very different to clinical practice and a period of transition is required. Methods: Data were collated to explore the age and retirement profile of the academic radiography workforce in the UK; to understand the research time allocated to this workforce; the time required to develop a clinical radiographer into an academic and the mentorship and succession planning provisions nationally. An online UK wide survey was conducted and sent to all 24 Universities delivering radiography education within the UK. Results: Eighteen out of 24 Universities in the UK responded to the survey. Approximately 30% of radiography academics are due to retire over the next ten years, with over 25% of radiographers who currently hold a doctorate qualification included within this figure. Those entering academia have notably lower qualifications as a group than those who are due to retire. Developing clinical radiographers into academics was thought to take 1-3 years on average, or longer if they are required to undertake research. Conclusion: There is vulnerability in the academic radiography workforce. Higher education institutions need to invest in developing the academic workforce to maintain research and educational expertise, which is underpinned by master’s and doctorate level qualifications