Experiences of Establishing an Academic Early Phase Clinical Trials Unit

Background: Early phase trials are essential in drug development, determining appropriate dose levels and assessing preliminary activity. These trials are undertaken by industry and academia, with increasing collaborations between the two. There is pressure to perform these trials quickly, safely and robustly. However, there are inherent differences between developing and managing early phase, compared to late phase, drug trials. This paper describes an approach to establishing an academically-led early phase trial portfolio, highlighting lessons learned and sharing experiences. Methods: In 2009 the University of Leeds Clinical Trials Research Unit became the Clinical Trials Coordinating Office for Myeloma UK’s phase I and II trials. We embarked on a transition from working extensively in phase III to early phase trials development and conduct. This involved evaluating and revising our well-established standard operating procedures, visiting other academic early phase units, and developing essential new documentation and processes. Results: A core team of trial and data managers and statisticians was established to facilitate expertise and knowledge retention. A detailed training plan was implemented focusing on essential standard practices for early phase. These included pharmacovigilance, recruitment, trial design and set-up, data and site monitoring, and oversight committees. Training in statistical methods for early phase trials was incorporated. Conclusion: Initial scoping of early phase trial management and conduct was essential in establishing this early phase portfolio. Many of the processes developed were successful. However, regular review and evaluation were implemented to enable changes and ensure efficiencies. It is recommended that others embarking on this venture build on the experiences described in this article

On Superpotentials and Charge Algebras of Gauge Theories

We propose a new "Hamiltonian inspired" covariant formula to define (without harmful ambiguities) the superpotential and the physical charges associated to a gauge symmetry. The criterion requires the variation of the Noether current not to contain any derivative terms in \partial_{\mu}\delta \f. The examples of Yang-Mills (in its first order formulation) and 3-dimensional Chern-Simons theories are revisited and the corresponding charge algebras (with their central extensions in the Chern-Simons case) are computed in a straightforward way. We then generalize the previous results to any (2n+1)-dimensional non-abelian Chern-Simons theory for a particular choice of boundary conditions. We compute explicitly the superpotential associated to the non-abelian gauge symmetry which is nothing but the Chern-Simons Lagrangian in (2n-1) dimensions. The corresponding charge algebra is also computed. However, no associated central charge is found for $n \geq 2$. Finally, we treat the abelian p-form Chern-Simons theory in a similar way.Comment: 32 pages, LaTex. The proposal is restricted to first order theories. An appendix is added. Some references are adde

The Expression Patterns of Minor Fibrillar Collagens During Development in Zebrafish

Minor fibrillar collagens are recognized as the organizers and nucleators during collagen fibrillogenesis but likely serve additional functions. The minor fibrillar collagens include collagens type V and type XI. Mutations of collagen type V and XI can cause Ehlers Danlos, Stickler\u27s, and Marshall\u27s syndromes in human. We have characterized the spatiotemporal expression patterns of Col11a1, Col11a2, Col5a1 as well as Col5a3 in zebrafish embryos by in situ hybridization. Col5a1 is expressed in developing somites, neural crest, the head mesenchyme, developing cranial cartilage, pharyngeal arches and vertebrae. Col5a3 is detected in the notochord, mesenchyme cells in the eyes and lens. Both Col11a1 and Col11a2 have similar expression patterns, including notochord, otic vesicle, and developing cranial cartilages. Zebrafish may therefore serve as a valuable vertebrate model system for the study of diseases associated with collagens type V and XI mutations

Time-like T-duality algebra

When compactifying M- or type II string-theories on tori of indefinite space-time signature, their low energy theories involve sigma models on E_{n(n)}/H_n, where H_n is a not necessarily compact subgroup of E_{n(n)} whose complexification is identical to the complexification of the maximal compact subgroup of E_{n(n)}. We discuss how to compute the group H_n. For finite dimensional E_{n(n)}, a formula derived from the theory of real forms of E_n algebra's gives the possible groups immediately. A few groups that have not appeared in the literature are found. For n=9,10,11 we compute and describe the relevant real forms of E_n and H_n. A given H_n can correspond to multiple signatures for the compact torus. We compute the groups H_n for all compactifications of M-, M*-, and M'-theories, and type II-, II*- and II'-theories on tori of arbitrary signature, and collect them in tables that outline the dualities between them. In an appendix we list cosets G/H, with G split and H a subgroup of G, that are relevant to timelike toroidal compactifications and oxidation of theories with enhanced symmetries.Comment: LaTeX, 37 pages, 1 eps-figure, uses JHEP.cls; v2. corrected typo's in tables 16 and 17, minor changes to tex

Demyelination and axonal preservation in a transgenic mouse model of Pelizaeus-Merzbacher disease

It is widely thought that demyelination contributes to the degeneration of axons and, in combination with acute inflammatory injury, is responsible for progressive axonal loss and persistent clinical disability in inflammatory demyelinating disease. In this study we sought to characterize the relationship between demyelination, inflammation and axonal transport changes using a Plp1-transgenic mouse model of Pelizaeus-Merzbacher disease. In the optic pathway of this non-immune mediated model of demyelination, myelin loss progresses from the optic nerve head towards the brain, over a period of months. Axonal transport is functionally perturbed at sites associated with local inflammation and 'damaged' myelin. Surprisingly, where demyelination is complete, naked axons appear well preserved despite a significant reduction of axonal transport. Our results suggest that neuroinflammation and/or oligodendrocyte dysfunction are more deleterious for axonal health than demyelination per se, at least in the short ter

Currents and Superpotentials in classical gauge theories: II. Global aspects and the example of Affine gravity

The conserved charges associated to gauge symmetries are defined at a boundary component of space-time because the corresponding Noether current can be rewritten on-shell as the divergence of a superpotential. However, the latter is afflicted by ambiguities. Regge and Teitelboim found a procedure to lift the arbitrariness in the Hamiltonian framework. An alternative covariant formula was proposed by one of us for an arbitrary variation of the superpotential, it depends only on the equations of motion and on the gauge symmetry under consideration. Here we emphasize that in order to compute the charges, it is enough to stay at a boundary of spacetime, without requiring any hypothesis about the bulk or about other boundary components, so one may speak of holographic charges. It is well known that the asymptotic symmetries that lead to conserved charges are really defined at infinity, but the choice of boundary conditions and surface terms in the action and in the charges is usually determined through integration by parts whereas each component of the boundary should be considered separately. We treat the example of gravity (for any space-time dimension, with or without cosmological constant), formulated as an Affine theory which is a natural generalization of the Palatini and Cartan-Weyl (vielbein) first order formulations. We then show that the superpotential associated to a Dirichlet boundary condition on the metric (the one needed to treat asymptotically flat or AdS spacetimes) is the one proposed by Katz, Bi\u{c}{\'a}k and Lynden-Bell and not that of Komar. We finally discuss the KBL superpotential at null infinity.Comment: 16 pages, minor corrections and references added. Final version to appear in CQ

E10 and SO(9,9) invariant supergravity

We show that (massive) D=10 type IIA supergravity possesses a hidden rigid SO(9,9) symmetry and a hidden local SO(9) x SO(9) symmetry upon dimensional reduction to one (time-like) dimension. We explicitly construct the associated locally supersymmetric Lagrangian in one dimension, and show that its bosonic sector, including the mass term, can be equivalently described by a truncation of an E10/K(E10) non-linear sigma-model to the level \ell<=2 sector in a decomposition of E10 under its so(9,9) subalgebra. This decomposition is presented up to level 10, and the even and odd level sectors are identified tentatively with the Neveu--Schwarz and Ramond sectors, respectively. Further truncation to the level \ell=0 sector yields a model related to the reduction of D=10 type I supergravity. The hyperbolic Kac--Moody algebra DE10, associated to the latter, is shown to be a proper subalgebra of E10, in accord with the embedding of type I into type IIA supergravity. The corresponding decomposition of DE10 under so(9,9) is presented up to level 5.Comment: 1+39 pages LaTeX2e, 2 figures, 2 tables, extended tables obtainable by downloading sourc

Predictors of drinking and functional outcomes for men and women following inpatient alcohol treatment

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106952/1/ajad12098.pd

‘If you look the part you’ll get the job’: should career professionals help clients to enhance their career image?

This article presents a critical exploration of the role of career professionals in supporting people to reflect on and enhance their appearance, attractiveness and self-presentation (career image). The article is conceptual and based on a review of the broader literature on career success, appearance and attractiveness. It explores the evidence for a relationship between attractiveness and career, and the authors propose a conceptual framework in which career image is comprised of three elements (interpersonal skills, aesthetic presentation and beauty). The paper examines a possible role for career professionals in relation to this and then critically examines this role and concludes with the proposition of a research agenda in this area

A Note on Conserved Charges of Asymptotically Flat and Anti-de Sitter Spaces in Arbitrary Dimensions

The calculation of conserved charges of black holes is a rich problem, for which many methods are known. Until recently, there was some controversy on the proper definition of conserved charges in asymptotically anti-de Sitter (AdS) spaces in arbitrary dimensions. This paper provides a systematic and explicit Hamiltonian derivation of the energy and the angular momenta of both asymptotically flat and asymptotically AdS spacetimes in any dimension D bigger or equal to 4. This requires as a first step a precise determination of the asymptotic conditions of the metric and of its conjugate momentum. These conditions happen to be achieved in ellipsoidal coordinates adapted to the rotating solutions.The asymptotic symmetry algebra is found to be isomorphic either to the Poincare algebra or to the so(D-1, 2) algebra, as expected. In the asymptotically flat case, the boundary conditions involve a generalization of the parity conditions, introduced by Regge and Teitelboim, which are necessary to make the angular momenta finite. The charges are explicitly computed for Kerr and Kerr-AdS black holes for arbitrary D and they are shown to be in agreement with thermodynamical arguments.Comment: 27 pages; v2 : references added, minor corrections; v3 : replaced to match published version forthcoming in General Relativity and Gravitatio