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

Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis

BackgroundDespite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune‐related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life‐threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment‐related encephalitis, and provide practical guidance on diagnosis and management.MethodsWe searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8‐year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol‐Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned.ResultsIn our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy (n = 22), noninfective meningitis (n = 5), encephalitis (n = 6), neuromuscular disorders (n = 3), and nonspecific adverse events (n = 7). Study drug was discontinued (n = 20), interrupted (n = 8), or unchanged (n = 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1–170) and to resolution was 32 days (2–809+). Median time to onset of encephalitis was 55.5 days (range 18–297); four cases resolved and one was fatal.ConclusionBoth oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs.Implications for PracticeWith increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune‐related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab.Melanoma is a particularly immunogenic cancer, and immune checkpoint inhibitors have been extensively studied in this tumor type. This review focuses on the incidence of serious neurologic immune‐related adverse events, specifically encephalitis, in patients with advanced melanoma treated with nivolumab alone or in sequence or combination with ipilimumab. Practical guidance is provided for the diagnosis and management of treatment‐related encephalitis associated with nivolumab and ipilimumab.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139998/1/onco12130.pd

Applications of a New Proposal for Solving the "Problem of Time" to Some Simple Quantum Cosmological Models

We apply a recent proposal for defining states and observables in quantum gravity to simple models. First, we consider a Klein-Gordon particle in an ex- ternal potential in Minkowski space and compare our proposal to the theory ob- tained by deparametrizing with respect to a time slicing prior to quantiza- tion. We show explicitly that the dynamics of the deparametrization approach depends on the time slicing. Our proposal yields a dynamics independent of the choice of time slicing at intermediate times but after the potential is turned off, the dynamics does not return to the free particle dynamics. Next we apply our proposal to the closed Robertson-Walker quantum cosmology with a massless scalar field with the size of the universe as our time variable, so the only dynamical variable is the scalar field. We show that the resulting theory has the semi-classical behavior up to the classical turning point from expansion to contraction, i.e., given a classical solution which expands for much longer than the Planck time, there is a quantum state whose dynamical evolution closely approximates this classical solution during the expansion. However, when the "time" gets larger than the classical maximum, the scalar field be- comes "frozen" at its value at the maximum expansion. We also obtain similar results in the Taub model. In an Appendix we derive the form of the Wheeler- DeWitt equation for the Bianchi models by performing a proper quantum reduc- tion of the momentum constraints; this equation differs from the usual one ob- tained by solving the momentum constraints classically, prior to quantization.Comment: 30 pages, LaTeX 3 figures (postscript file or hard copy) available upon request, BUTP-94/1

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

Health-related quality of life and pain with selinexor in patients with advanced dedifferentiated liposarcoma

[Objective] Compare health-related quality of life (HRQoL) of selinexor versus placebo in patients with dedifferentiated liposarcoma.[Materials & methods] HRQoL was assessed at baseline and day 1 of each cycle using the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire. Results were reported from baseline to day 169 (where exposure to treatment was maximized while maintaining adequate sample size).[Results] Pain scores worsened for placebo versus selinexor across all postbaseline visits, although differences in HRQoL at some visits were not significant. Other domains did not exhibit significant differences between arms; however, scores in both arms deteriorated over time.[Conclusion] Patients treated with selinexor reported lower rates and slower worsening of pain compared with patients who received placebo.This study was funded by Karyopharm Therapeutics, Inc. M Gounder: reports an institutional research grant from Karyopharm, personal fees from Karyopharm, Epizyme, Springworks, Daiichi, Bayer, Amgen, Tracon, Flatiron, Medscape, Physicians Education Resource, Guidepoint, GLG and UpToDate; and grants from the National Cancer Institute, National Institutes of Health (P30CA008748) – core grant (CCSG shared resources and core facility). ARA Razak: consulting/Ad board: Merck & Adaptimmune Research support: Karyopharm Therapeutics, Deciphera, Blueprint Medicines, Pfizer, Adaptimmune, Merck, Roche/Genentech, Bristol-Myers Squibb, Medimmune, Amgen, GSK, AbbVie, Iterion Therapeutics. AM Gilligan: employee of Karyopharm Therapeutics, Inc. H Leong: employee of Karyopharm Therapeutics, Inc. X Ma: employee of Karyopharm Therapeutics, Inc. N Somaiah: consultant for Deciphera, Blueprint, Bayer Research Support from Ascentage, Astra-Zeneca, Daiichi-Sankyo, Deciphera, Eli Lilly, Karyopharm and GSK. SP Chawla: consultant for Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC: Sarcoma Alliance for Research though Collaboration, Janssen, Advenchen Laboratories, Bayer, NKMax, InhibRx. Grants or contracts from Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC: Sarcoma Alliance for Research though Collaboration, Janssen, Advenchen Laboratories, Bayer, InhibRx, NKMax. G Grignani: consultant for Eli Lilly, Novartis, Glaxo, Pharmamar, EISAI, Bayer, Merck. SM Schuetze: consultant – NanoCarrier, UpToDate. Research funding to institution – Adaptimmune, Amgen, Blueprint, Glaxo-SmithKline, Karyopharm. B Vincenzi: Consultant for Pharmamar Eisai, Lilly, Abbott, Novartis, Accord AJ Wagner: consultant for Daiichi-Sankyo, Deciphera, Eli Lilly, Epizyme, NovoCarrier, Mundipharma, and Research Support to My Institution from Aadi Bioscience, Daiichi-Sankyo, Deciphera, Eli Lilly, Karyopharm and Plexxikon. RL Jones: consultant for Adaptimmune, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, Pharmamar, Springworks, Tracon, Upto Date. J Shah: employee of Karyopharm Therapeutics, Inc. S Shacham: employee of Karyopharm Therapeutics, Inc. M Kauffman: employee of Karyopharm Therapeutics, Inc. RF Riedel: ownership - Limbguard, LLC (Spouse); Institutional Clinical Research Support - AADi, AROG, Blueprint, Daiichi-Sankyo, Deciphera, Glaxo-SmithKline, Karyopharm, Ignyta, Immune Design, NanoCarrier, Oncternal, Philogen, Plexxikon, Roche, Springworks, Tracon; Consultant/Advisor - Bayer, Blueprint, Daiichi-Sankyo, Deciphera, Ignyta, NanoCarrier. S Attia: reports research funding from Desmoid Tumor Research Foundation and research funding to their institution from: AB Science, TRACON Pharma, Bayer, Novartis, Lilly, Immune Design, Karyopharm Therapeutics, Epizyme, Blueprint Medicines, Genmab, CBA Pharma, Merck, Philogen, Gradalis, Deciphera, Takeda, Incyte, Springworks, Adaptimmune, Advenchen Laboratories, Bavarian Nordic, BTG, PTC Therapeutics, GlaxoSmithKline, FORMA Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Peer reviewe

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)