The Influence Of The Reliability Of The Dependent Variable On Statistical Power

PROBLEM: In the planning phase of developing quality educational research there are several critical decision points. Some of these decisions are made to en sure that the research will have adequate statistical power, that is, the capability to detect meaningful differences, if they do exist. In an unpublished article, K. D. Hopkins from the Laboratory of Educational Research, University of Colorado and B. R. Hopkins from the University of the Pacific commented that all theoretical and empirical options for increasing statistical power had been investigated except for the reliability of the dependent variable. In this article, they derived a method for estimating the statistical power of the analysis of variance (ANOVA) and the analysis of covariance (ANCOVA) which factored out the influence of the reliability of the dependent variable. This method involved modifying the non-centrality parameters used in estimating the power of the ANOVA and ANCOVA tests. This modification required some untested mathematical assumptions and therefore needed to be empirically verified

Synthetic studies toward the brasilinolides: controlled assembly of a protected C1-C38 polyol based on fragment union by complex aldol reactions.

The brasilinolides are an architecturally complex family of 32-membered macrolides, characterised by potent immunosuppressant and antifungal properties, which represent challenging synthetic targets. By adopting a highly convergent strategy, a range of asymmetric aldol/reduction sequences and catalytic protocols were employed to assemble a series of increasingly elaborate fragments. The controlled preparation of suitable C1-C19 and C20-C38 acyclic fragments 5 and 6, containing seven and 12 stereocentres respectively, was first achieved. An adventurous C19-C20 fragment union was then explored to construct the entire carbon chain of the brasilinolides. This pivotal coupling step could be performed in a complex boron-mediated aldol reaction to install the required C19 hydroxyl stereocentre when alternative Mukaiyama-type aldol protocols proved unrewarding. A protected C1-C38 polyol 93 was subsequently prepared, setting the stage for future late-stage diversification toward the various brasilinolide congeners. Throughout this work, asymmetric boron-mediated aldol reactions of chiral ketones with aldehydes proved effective both for controlled fragment assembly and coupling with predictable stereoinduction from the enolate component.We thank the EPSRC (EP/F025734/1) and Syngenta for support, the Isaac Newton–Mays Wild Research Fellowship at Downing College (M.P.H.), the Herchel Smith Postdoctoral Fellowships Fund at Cambridge (C.J.C.) and the Deutsche Akademie der Naturforser Leopoldina (F.A.M.; BMBF-LPD 9901/8-148) for additional funding, and the EPSRC National Mass Spectrometry Centre (Swansea) for mass spectra.This is the final published version of the article. It was originally published in Organic & Biomolecular Chemistry (Paterson I, Housden MP, Cordier CJ, Burton PM, Mühlthau FA, Loiseleur O, Organic & Biomolecular Chemistry, 2015,13, 5716-5733 doi:10.1039/C5OB00498E). The final version is available at http://dx.doi.org/10.1039/C5OB00498

Automatic Probe Movement Guidance for Freehand Obstetric Ultrasound

We present the first system that provides real-time probe movement guidance for acquiring standard planes in routine freehand obstetric ultrasound scanning. Such a system can contribute to the worldwide deployment of obstetric ultrasound scanning by lowering the required level of operator expertise. The system employs an artificial neural network that receives the ultrasound video signal and the motion signal of an inertial measurement unit (IMU) that is attached to the probe, and predicts a guidance signal. The network termed US-GuideNet predicts either the movement towards the standard plane position (goal prediction), or the next movement that an expert sonographer would perform (action prediction). While existing models for other ultrasound applications are trained with simulations or phantoms, we train our model with real-world ultrasound video and probe motion data from 464 routine clinical scans by 17 accredited sonographers. Evaluations for 3 standard plane types show that the model provides a useful guidance signal with an accuracy of 88.8% for goal prediction and 90.9% for action prediction.Comment: Accepted at the 23rd International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI 2020

Pyocin S5 import into Pseudomonas aeruginosa reveals a generic mode of bacteriocin transport

Pyocin S5 (PyoS5) is a potent protein bacteriocin that eradicates the human pathogen Pseudomonas aeruginosa in animal infection models, but its import mechanism is poorly understood. Here, using crystallography, biophysical and biochemical analyses, and live-cell imaging, we define the entry process of PyoS5 and reveal links to the transport mechanisms of other bacteriocins. In addition to its C-terminal pore-forming domain, elongated PyoS5 comprises two novel tandemly repeated kinked 3-helix bundle domains that structure-based alignments identify as key import domains in other pyocins. The central domain binds the lipid-bound common polysaccharide antigen, allowing the pyocin to accumulate on the cell surface. The N-terminal domain binds the ferric pyochelin transporter FptA while its associated disordered region binds the inner membrane protein TonB1, which together drive import of the bacteriocin across the outer membrane. Finally, we identify the minimal requirements for sensitizing Escherichia coli toward PyoS5, as well as other pyocins, and suggest that a generic pathway likely underpins the import of all TonB-dependent bacteriocins across the outer membrane of Gram-negative bacteria

Diffusion tensor imaging profiles reveal specific neural tract distortion in normal pressure hydrocephalus

BACKGROUND: The pathogenesis of normal pressure hydrocephalus (NPH) remains unclear which limits both early diagnosis and prognostication. The responsiveness to intervention of differing, complex and concurrent injury patterns on imaging have not been well-characterized. We used diffusion tensor imaging (DTI) to explore the topography and reversibility of white matter injury in NPH pre- and early after shunting. METHODS: Twenty-five participants (sixteen NPH patients and nine healthy controls) underwent DTI, pre-operatively and at two weeks post-intervention in patients. We interrogated 40 datasets to generate a full panel of DTI measures and corroborated findings with plots of isotropy (p) vs. anisotropy (q). RESULTS: Concurrent examination of DTI measures revealed distinct profiles for NPH patients vs. controls. PQ plots demonstrated that patterns of injury occupied discrete white matter districts. DTI profiles for different white matter tracts showed changes consistent with i) predominant transependymal diffusion with stretch/ compression, ii) oedema with or without stretch/ compression and iii) predominant stretch/ compression. Findings were specific to individual tracts and dependent upon their proximity to the ventricles. At two weeks post-intervention, there was a 6·7% drop in axial diffusivity (p = 0·022) in the posterior limb of the internal capsule, compatible with improvement in stretch/ compression, that preceded any discernible changes in clinical outcome. On PQ plots, the trajectories of the posterior limb of the internal capsule and inferior longitudinal fasciculus suggested attempted 'round trips'. i.e. return to normality. CONCLUSION: DTI profiling with p:q correlation may offer a non-invasive biomarker of the characteristics of potentially reversible white matter injury.Nicole C Keong was supported by a Joint Royal College of Surgeons of England and Dunhill Medical Trust Fellowship and a Tunku Abdul Rahman Centenary Grant and other from National Medical Research Council Transition Award Grant, Singapore (supporting ongoing work). A Medical Research Council Programme Grant [Wolfson Brain Imaging Centre Cooperative] supported the study imaging work. Marek Czosnyka was supported by grants from Johnson and Johnson – Codman, Integra, Sophysa and Aesculap. Zofia Czosnyka was supported by grants from Johnson and Johnson – Codman, Integra, Sophysa and Aesculap. Elise DeVito was funded by the Pinsent-Darwin Studentship in Mental Pathology. Charlotte Housden took up employment with Cambridge Cognition Ltd following her PhD. Barbara J Sahakian was supported by a Medical Research Council Grant and reports personal fees from Cambridge Cognition, Lundbeck, Servier, grants from Janssen/J&J, other from Otsuka and personal fees from Peak (Brainbow). JDP was supported by an NIHR Senior Investigator Award, a Medical Research Council Programme grant and an NIHR Cambridge Biomedical Research Centre grant [brain injury theme] and also wishes to declare the following - Past advisor to Codman and Medtronic international advisory board, Director (unpaid) of Medicam, Scientific Collaboration with GSK (unpaid), Trustee of Brain Research Trust, Patron of Headway Cambridgeshire, Honorary Director of National Institute for Health Research Brain Injury Healthcare Technology Cooperative

Discovery, characterization and in vivo activity of pyocin SD2, a protein antibiotic from Pseudomonas aeruginosa

Increasing rates of antibiotic resistance among Gram-negative pathogens such as Pseudomonas aeruginosa means alternative approaches to antibiotic development are urgently required. Pyocins, produced by P. aeruginosa for intraspecies competition, are highly potent protein antibiotics known to actively translocate across the outer membrane of P. aeruginosa. Understanding and exploiting the mechanisms by which pyocins target, penetrate and kill P. aeruginosa is a promising approach to antibiotic development. In this work we show the therapeutic potential of a newly identified tRNase pyocin, pyocin SD2, by demonstrating its activity in vivo in a murine model of P. aeruginosa lung infection. In addition, we propose a mechanism of cell targeting and translocation for pyocin SD2 across the P. aeruginosa outer membrane. Pyocin SD2 is concentrated at the cell surface, via binding to the common polysaccharide antigen (CPA) of P. aeruginosa lipopolysaccharide (LPS), from where it can efficiently locate its outer membrane receptor FpvAI. This strategy of utilizing both the CPA and a protein receptor for cell targeting is common among pyocins as we show that pyocins S2, S5 and SD3 also bind to the CPA. Additional data indicate a key role for an unstructured N-terminal region of pyocin SD2 in the subsequent translocation of the pyocin into the cell. These results greatly improve our understanding of how pyocins target and translocate across the outer membrane of P. aeruginosa. This knowledge could be useful for the development of novel anti-pseudomonal therapeutics and will also support the development of pyocin SD2 as a therapeutic in its own right

Mechanically Powered Motion Imaging Phantoms: Proof of Concept

Motion imaging phantoms are expensive, bulky and difficult to transport and set-up. The purpose of this paper is to demonstrate a simple approach to the design of multi-modality motion imaging phantoms that use mechanically stored energy to produce motion. We propose two phantom designs that use mainsprings and elastic bands to store energy. A rectangular piece was attached to an axle at the end of the transmission chain of each phantom, and underwent a rotary motion upon release of the mechanical motor. The phantoms were imaged with MRI and US, and the image sequences were embedded in a 1D non linear manifold (Laplacian Eigenmap) and the spectrogram of the embedding was used to derive the angular velocity over time. The derived velocities were consistent and reproducible within a small error. The proposed motion phantom concept showed great potential for the construction of simple and affordable motion phantomsComment: Accepted for publication at IEEE EMBC (41st International Engineering in Medicine and Biology Conference) 201

‘Forgotten Europeans’: transnational minority activism in the age of European integration

YesThis article examines transnational activism by coalitions of national minorities in Europe from the early 20th century to the present, setting this within the broader ‘security versus democracy dilemma’ that continues to surround international discussions on minority rights. Specifically, we analyse two organisations – the European Nationalities Congress (1925–1938) and the Federal Union of European Nationalities (1949–) – which, while linked, have never been subject to a detailed comparison based on primary sources. In so far as comparisons do exist, they present these bodies in highly negative terms, as mere fronts for inherently particularistic nationalisms that threaten political stability, state integrity and peace. Our more in‐depth analysis provides a fresh and more nuanced perspective: it shows that, in both cases, concepts of European integration and ‘unity in diversity’ have provided the motivating goals and frameworks for transnational movements advocating common rights for all minorities and seeking positive interaction with the interstate world

Investigation of low 5-year relative survival for breast cancer in a London cancer network

BACKGROUND: Breast cancer 5-year relative survival is low in the North East London Cancer Network (NELCN). METHODS: We compared breast cancer that was diagnosed during 2001-2005 with that in the rest of London. RESULTS: North East London Cancer Network women more often lived in socioeconomic quintile 5 (42 vs 21%) and presented with advanced disease (11 vs 7%). Cox regression analysis showed the survival difference (hazard ratio: 1.27, 95% confidence interval (CI): 1.15-1.41) reduced to 1.00 (95% CI: 0.89-1.11) after adjustment for age, stage, socioeconomic deprivation, ethnicity and treatment. Major drivers were stage and deprivation. Excess mortality was in the first year. CONCLUSION: Late diagnosis occurs in NELCN