E11, generalised space-time and equations of motion in four dimensions

We construct the non-linear realisation of the semi-direct product of E11 and its first fundamental representation at low levels in four dimensions. We include the fields for gravity, the scalars and the gauge fields as well as the duals of these fields. The generalised space-time, upon which the fields depend, consists of the usual coordinates of four dimensional space-time and Lorentz scalar coordinates which belong to the 56-dimensional representation of E7. We demand that the equations of motion are first order in derivatives of the generalised space-time and then show that they are essentially uniquely determined by the properties of the E11 Kac-Moody algebra and its first fundamental representation. The two lowest equations correctly describe the equations of motion of the scalars and the gauge fields once one takes the fields to depend only on the usual four dimensional space-time

N = 2 supersymmetric sigma-models and duality

For two families of four-dimensional off-shell N = 2 supersymmetric nonlinear sigma-models constructed originally in projective superspace, we develop their formulation in terms of N = 1 chiral superfields. Specifically, these theories are: (i) sigma-models on cotangent bundles T*M of arbitrary real analytic Kaehler manifolds M; (ii) general superconformal sigma-models described by weight-one polar supermultiplets. Using superspace techniques, we obtain a universal expression for the holomorphic symplectic two-form \omega^{(2,0)} which determines the second supersymmetry transformation and is associated with the two complex structures of the hyperkaehler space T*M that are complimentary to the one induced from M. This two-form is shown to coincide with the canonical holomorphic symplectic structure. In the case (ii), we demonstrate that \omega^{(2,0)} and the homothetic conformal Killing vector determine the explicit form of the superconformal transformations. At the heart of our construction is the duality (generalized Legendre transform) between off-shell N = 2 supersymmetric nonlinear sigma-models and their on-shell N = 1 chiral realizations. We finally present the most general N = 2 superconformal nonlinear sigma-model formulated in terms of N = 1 chiral superfields. The approach developed can naturally be generalized in order to describe 5D and 6D superconformal nonlinear sigma-models in 4D N = 1 superspace.Comment: 31 pages, no figures; V2: reference and comments added, typos corrected; V3: more typos corrected, published versio

On the perturbative S-matrix of generalized sine-Gordon models

Motivated by its relation to the Pohlmeyer reduction of AdS_5 x S^5 superstring theory we continue the investigation of the generalized sine-Gordon model defined by SO(N+1)/SO(N) gauged WZW theory with an integrable potential. Extending our previous work (arXiv:0912.2958) we compute the one-loop two-particle S-matrix for the elementary massive excitations. In the N = 2 case corresponding to the complex sine-Gordon theory it agrees with the charge-one sector of the quantum soliton S-matrix proposed in hep-th/9410140. In the case of N > 2 when the gauge group SO(N) is non-abelian we find a curious anomaly in the Yang-Baxter equation which we interpret as a gauge artifact related to the fact that the scattered particles are not singlets under the residual global subgroup of the gauge group

Off-shell supergravity-matter couplings in three dimensions

We develop the superspace geometry of N-extended conformal supergravity in three space-time dimensions. General off-shell supergravity-matter couplings are constructed in the cases N=1,2,3,4.Comment: 73 pages; V5: typos in eqs. (3.4b), (3.17) and (4.24) correcte

Background independent action for double field theory

Double field theory describes a massless subsector of closed string theory with both momentum and winding excitations. The gauge algebra is governed by the Courant bracket in certain subsectors of this double field theory. We construct the associated nonlinear background-independent action that is T-duality invariant and realizes the Courant gauge algebra. The action is the sum of a standard action for gravity, antisymmetric tensor, and dilaton fields written with ordinary derivatives, a similar action for dual fields with dual derivatives, and a mixed term that is needed for gauge invariance.Comment: 45 pages, v2: minor corrections, refs. added, to appear in JHE

On duality symmetry in perturbative quantum theory

Non-compact symmetries of extended 4d supergravities involve duality rotations of vectors and thus are not manifest off-shell invariances in standard "second-order" formulation. To study how such symmetries are realised in the quantum theory we consider examples in 2 dimensions where vector-vector duality is replaced by scalar-scalar one. Using a "doubled" formulation, where fields and their momenta are treated on an equal footing and the duality becomes a manifest symmetry of the action (at the expense of Lorentz symmetry), we argue that the corresponding on-shell quantum effective action or S-matrix are duality symmetric as well as Lorentz invariant. The simplest case of discrete Z_2 duality corresponds to a symmetry of the S-matrix under flipping the sign of the negative-chirality scalars in 2 dimensions or phase rotations of chiral (definite-helicity) parts of vectors in 4 dimensions. We also briefly discuss some 4d models and comment on implications of our analysis for extended supergravities.Comment: 21 pages, Latex v2: comments and references added v3: references and minor comments adde

Off-shell superconformal nonlinear sigma-models in three dimensions

We develop superspace techniques to construct general off-shell N=1,2,3,4 superconformal sigma-models in three space-time dimensions. The most general N=3 and N=4 superconformal sigma-models are constructed in terms of N=2 chiral superfields. Several superspace proofs of the folklore statement that N=3 supersymmetry implies N=4 are presented both in the on-shell and off-shell settings. We also elaborate on (super)twistor realisations for (super)manifolds on which the three-dimensional N-extended superconformal groups act transitively and which include Minkowski space as a subspace.Comment: 67 pages; V2: typos corrected, one reference added, version to appear on JHE

Darolutamide does not interfere with OATP-mediated uptake of docetaxel

The addition of darolutamide, an androgen receptor signalling inhibitor, to therapy with docetaxel has recently been approved as a strategy to treat metastatic prostate cancer. OATP1B3 is an SLC transporter that is highly expressed in prostate cancer and is responsible for the accumulation of substrates, including docetaxel, into tumours. Given that darolutamide inhibits OATP1B3 in vitro, we sought to characterise the impact of darolutamide on docetaxel pharmacokinetics. We investigated the influence of darolutamide on OATP1B3 transport using in vitro and in vivo models. We assessed the impact of darolutamide on the tumour accumulation of docetaxel in a patient-derived xenograft (PDX) model and on an OATP1B biomarker in patients. Darolutamide inhibited OATP1B3 in vitro at concentrations higher than the reported Cmax. Consistent with these findings, in vivo studies revealed that darolutamide does not influence the pharmacokinetics of Oatp1b substrates, including docetaxel. Docetaxel accumulation in PDX tumours was not decreased in the presence of darolutamide. Metastatic prostate cancer patients had similar levels of OATP1B biomarkers, regardless of treatment with darolutamide. Consistent with a low potential to inhibit OATP1B3-mediated transport in vitro, darolutamide does not significantly impede the transport of Oatp1b substrates in vivo or in patients. Our findings support combined treatment with docetaxel and darolutamide, as no OATP1B3 transporter based drug–drug interaction was identified

Darolutamide does not interfere with OATP-mediated uptake of docetaxel

The addition of darolutamide, an androgen receptor signalling inhibitor, to therapy with docetaxel has recently been approved as a strategy to treat metastatic prostate cancer. OATP1B3 is an SLC transporter that is highly expressed in prostate cancer and is responsible for the accumulation of substrates, including docetaxel, into tumours. Given that darolutamide inhibits OATP1B3 in vitro, we sought to characterise the impact of darolutamide on docetaxel pharmacokinetics. We investigated the influence of darolutamide on OATP1B3 transport using in vitro and in vivo models. We assessed the impact of darolutamide on the tumour accumulation of docetaxel in a patient-derived xenograft (PDX) model and on an OATP1B biomarker in patients. Darolutamide inhibited OATP1B3 in vitro at concentrations higher than the reported Cmax. Consistent with these findings, in vivo studies revealed that darolutamide does not influence the pharmacokinetics of Oatp1b substrates, including docetaxel. Docetaxel accumulation in PDX tumours was not decreased in the presence of darolutamide. Metastatic prostate cancer patients had similar levels of OATP1B biomarkers, regardless of treatment with darolutamide. Consistent with a low potential to inhibit OATP1B3-mediated transport in vitro, darolutamide does not significantly impede the transport of Oatp1b substrates in vivo or in patients. Our findings support combined treatment with docetaxel and darolutamide, as no OATP1B3 transporter based drug–drug interaction was identified

How Clinical Integration of Pharmacists in General Practice has Impact on Medication Therapy Management: A Theory-oriented Evaluation.

Background: Data on medication-related hospital admissions suggest that there is an opportunity for improved pharmaceutical care. Hence, concerns about medication-related hospital admissions is a driver to extend and integrate the role of community pharmacists in general practice. Aim: The aim of this paper is to give a systematic description of 1) what integrating a non-dispensing pharmacist (NDP) in general practice entails and 2) how this integrated care model is expected to contribute to patients’ medication therapy management. Methods: Based on ethnographic data collected by NDPs in general practices in the Netherlands, we conducted a theory evaluation. Results: The impact of NDPs providing integrated care can be explained by 1) the specific expertise NDPs bring into general practice and the tailored solutions they offer for individual patients, including deviation from medical protocols when necessary, 2) the reconciliation of interprofessional tensions caused by overlapping tasks with practice nurses, which results in a distinct patient population, 3) the conduct of clinical medication reviews aligned to the work processes of the GP practice and 4) the integration of quality management work into clinical work. Conclusion: The success of integrated pharmaceutical care is dependent on how NDPs collaborate with GPs and practice nurses. NDPs need to mobilize clinical pharmaceutical expertise into general practice. Yet, integrating quality management into clinical work is key to integrate pharmaceutical care. Paradoxically, full integration requires from NDPs to develop a distinct role in general practice