Dynamics in Stationary, Non-Globally Hyperbolic Spacetimes

Classically, the dynamics in a non-globally hyperbolic spacetime is ill posed. Previously, a prescription was given for defining dynamics in static spacetimes in terms of a second order operator acting on a Hilbert space defined on static slices. The present work extends this result by giving a similar prescription for defining dynamics in stationary spacetimes obeying certain mild assumptions. The prescription is defined in terms of a first order operator acting on a different Hilbert space from the one used in the static prescription. It preserves the important properties of the earlier one: the formal solution agrees with the Cauchy evolution within the domain of dependence, and smooth data of compact support always give rise to smooth solutions. In the static case, the first order formalism agrees with second order formalism (using specifically the Friedrichs extension). Applications to field quantization are also discussed.Comment: 18 pages, 1 figure, AMSLaTeX; v2: expanded discussion of field quantization, new Proposition 3.1, revised Theorem 4.2, corrected typos, and updated reference

Volterra Distortions, Spinning Strings, and Cosmic Defects

Cosmic strings, as topological spacetime defects, show striking resemblance to defects in solid continua: distortions, which can be classified into disclinations and dislocations, are line-like defects characterized by a delta function-valued curvature and torsion distribution giving rise to rotational and translational holonomy. We exploit this analogy and investigate how distortions can be adapted in a systematic manner from solid state systems to Einstein-Cartan gravity. As distortions are efficiently described within the framework of a SO(3) {\rlap{\supset}\times}} T(3) gauge theory of solid continua with line defects, we are led in a straightforward way to a Poincar\'e gauge approach to gravity which is a natural framework for introducing the notion of distorted spacetimes. Constructing all ten possible distorted spacetimes, we recover, inter alia, the well-known exterior spacetime of a spin-polarized cosmic string as a special case of such a geometry. In a second step, we search for matter distributions which, in Einstein-Cartan gravity, act as sources of distorted spacetimes. The resulting solutions, appropriately matched to the distorted vacua, are cylindrically symmetric and are interpreted as spin-polarized cosmic strings and cosmic dislocations.Comment: 24 pages, LaTeX, 9 eps figures; remarks on energy conditions added, discussion extended, version to be published in Class. Quantum Gra

Particle detectors, geodesic motion, and the equivalence principle

It is shown that quantum particle detectors are not reliable probes of spacetime structure. In particular, they fail to distinguish between inertial and non-inertial motion in a general spacetime. To prove this, we consider detectors undergoing circular motion in an arbitrary static spherically symmetric spacetime, and give a necessary and sufficient condition for the response function to vanish when the field is in the static vacuum state. By examining two particular cases, we show that there is no relation, in general, between the vanishing of the response function and the fact that the detector motion is, or is not, geodesic. In static asymptotically flat spacetimes, however, all rotating detectors are excited in the static vacuum. Thus, in this particular case the static vacuum appears to be associated with a non-rotating frame. The implications of these results for the equivalence principle are considered. In particular, we discuss how to properly formulate the principle for particle detectors, and show that it is satisfied.Comment: 14 pages. Revised version, with corrections; added two references. Accepted for publication in Class. Quantum Gra

Selumetinib in combination with dacarbazine in patients with metastatic uveal melanoma: a phase III, multicentre, randomised trial (SUMIT)

Purpose: Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods: The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial (ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m2 intravenously on day 1 of every 21- day cycle) or placebo plus dacarbazine. The primary end point was progression-free survival (PFS) by blinded independent central radiologic review. Secondary end points included overall survival and objective response rate. Results: A total of 129 patients were randomly assigned to receive selumetinib plus dacarbazine (n = 97) or placebo plus dacarbazine (n = 32). In the selumetinib plus dacarbazine group, 82 patients (85%) experienced a PFS event, compared with 24 (75%) in the placebo plus dacarbazine group (median, 2.8 v 1.8 months); the hazard ratio for PFS was 0.78 (95% CI, 0.48 to 1.27; two-sided P = .32). The objective response rate was 3% with selumetinib plus dacarbazine and 0% with placebo plus dacarbazine (two-sided P = .36). At 37% maturity (n = 48 deaths), analysis of overall survival gave a hazard ratio of 0.75 (95% CI, 0.39 to 1.46; two-sided P = .40). The most frequently reported adverse events (selumetinib plus dacarbazine v placebo plus dacarbazine) were nausea (62% v 19%), rash (57% v 6%), fatigue (44% v 47%), diarrhea (44% v 22%), and peripheral edema (43% v 6%). Conclusion: In patients with metastatic uveal melanoma, the combination of selumetinib plus dacarbazine had a tolerable safety profile but did not significantly improve PFS compared with placebo plus dacarbazine

Quantum Cosmological Multidimensional Einstein-Yang-Mills Model in a R×S3×SdR \times S^3 \times S^d Topology

The quantum cosmological version of the multidimensional Einstein-Yang-Mills model in a $R \times S^3 \times S^d$ topology is studied in the framework of the Hartle-Hawking proposal. In contrast to previous work in the literature, we consider Yang-Mills field configurations with non-vanishing time-dependent components in both $S^3$ and $S^d$ spaces. We obtain stable compactifying solutions that do correspond to extrema of the Hartle-Hawking wave function of the Universe. Subsequently, we also show that the regions where 4-dimensional metric behaves classically or quantum mechanically (i.e. regions where the metric is Lorentzian or Euclidean) will depend on the number, $d$, of compact space dimensions.Comment: Plain Latex. Version that appeared in the October 15th, 1997 issue of Physical Review

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)