Prescribing a Change to the FDA\u27s Drug Labeling Rules After the 21st Century Cures Act

Signed into law in 2016, the 21st Century Cures Act offers new hope to patients by empowering the FDA to expedite review of innovative, potentially lifesaving drugs. But these expedited approvals raise the risk that pivotal drug safety and efficacy data will not arise until after the drug is already on the market. The Cures Act failed to respond to two key aspects of shifting the discovery of safety and efficacy data to the postmarket phase. First, the Cures Act did not correspondingly enhance the FDA’s authority to require manufacturers to generate and disclose postmarket information. Second, it did not guard against the potential rise in postmarket failure-to-warn liability for manufacturers, which could discourage them from investing in the development of lifesaving drugs. As interpreted by the Supreme Court, the FDA’s current brand-name labeling rules exacerbate these two issues by discouraging meaningful postmarket disclosures to the FDA and enabling costly failure-to-warn suits against manufacturers. This Note discusses these two postmarket issues and proposes new drug labeling rules that would minimize their impact while maintaining the Cures Act’s efforts to promote patient access to potentially lifesaving treatments

Fear and its implications for stock markets

The value of stocks, indices and other assets, are examples of stochastic processes with unpredictable dynamics. In this paper, we discuss asymmetries in short term price movements that can not be associated with a long term positive trend. These empirical asymmetries predict that stock index drops are more common on a relatively short time scale than the corresponding raises. We present several empirical examples of such asymmetries. Furthermore, a simple model featuring occasional short periods of synchronized dropping prices for all stocks constituting the index is introduced with the aim of explaining these facts. The collective negative price movements are imagined triggered by external factors in our society, as well as internal to the economy, that create fear of the future among investors. This is parameterized by a ``fear factor'' defining the frequency of synchronized events. It is demonstrated that such a simple fear factor model can reproduce several empirical facts concerning index asymmetries. It is also pointed out that in its simplest form, the model has certain shortcomings.Comment: 5 pages, 5 figures. Submitted to the Proceedings of Applications of Physics in Financial Analysis 5, Turin 200

Value at Risk models with long memory features and their economic performance

We study alternative dynamics for Value at Risk (VaR) that incorporate a slow moving component and information on recent aggregate returns in established quantile (auto) regression models. These models are compared on their economic performance, and also on metrics of first-order importance such as violation ratios. By better economic performance, we mean that changes in the VaR forecasts should have a lower variance to reduce transaction costs and should lead to lower exceedance sizes without raising the average level of the VaR. We find that, in combination with a targeted estimation strategy, our proposed models lead to improved performance in both statistical and economic terms

Coherent states, constraint classes, and area operators in the new spin-foam models

Recently, two new spin-foam models have appeared in the literature, both motivated by a desire to modify the Barrett-Crane model in such a way that the imposition of certain second class constraints, called cross-simplicity constraints, are weakened. We refer to these two models as the FKLS model, and the flipped model. Both of these models are based on a reformulation of the cross-simplicity constraints. This paper has two main parts. First, we clarify the structure of the reformulated cross-simplicity constraints and the nature of their quantum imposition in the new models. In particular we show that in the FKLS model, quantum cross-simplicity implies no restriction on states. The deeper reason for this is that, with the symplectic structure relevant for FKLS, the reformulated cross-simplicity constraints, in a certain relevant sense, are now \emph{first class}, and this causes the coherent state method of imposing the constraints, key in the FKLS model, to fail to give any restriction on states. Nevertheless, the cross-simplicity can still be seen as implemented via suppression of intertwiner degrees of freedom in the dynamical propagation. In the second part of the paper, we investigate area spectra in the models. The results of these two investigations will highlight how, in the flipped model, the Hilbert space of states, as well as the spectra of area operators exactly match those of loop quantum gravity, whereas in the FKLS (and Barrett-Crane) models, the boundary Hilbert spaces and area spectra are different.Comment: 21 pages; statements about gamma limits made more precise, and minor phrasing change

Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase II clinical trials.

Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses

Two are better than one: Volatility forecasting using multiplicative component GARCH‐MIDAS models

We examine the properties and forecast performance of multiplicative volatility specifications that belong to the class of generalized autoregressive conditional heteroskedasticity–mixed-data sampling (GARCH-MIDAS) models suggested in Engle, Ghysels, and Sohn (Review of Economics and Statistics, 2013, 95, 776–797). In those models volatility is decomposed into a short-term GARCH component and a long-term component that is driven by an explanatory variable. We derive the kurtosis of returns, the autocorrelation function of squared returns, and the R2 of a Mincer–Zarnowitz regression and evaluate the QMLE and forecast performance of these models in a Monte Carlo simulation. For S&P 500 data, we compare the forecast performance of GARCH-MIDAS models with a wide range of competitor models such as HAR (heterogeneous autoregression), realized GARCH, HEAVY (high-frequency-based volatility) and Markov-switching GARCH. Our results show that the GARCH-MIDAS based on housing starts as an explanatory variable significantly outperforms all competitor models at forecast horizons of 2 and 3 months ahead

One vertex spin-foams with the Dipole Cosmology boundary

We find all the spin-foams contributing in the first order of the vertex expansion to the transition amplitude of the Bianchi-Rovelli-Vidotto Dipole Cosmology model. Our algorithm is general and provides spin-foams of arbitrarily given, fixed: boundary and, respectively, a number of internal vertices. We use the recently introduced Operator Spin-Network Diagrams framework.Comment: 23 pages, 30 figure

Multipole Moments of Isolated Horizons

To every axi-symmetric isolated horizon we associate two sets of numbers, $M_n$ and $J_n$ with $n = 0, 1, 2, ...$, representing its mass and angular momentum multipoles. They provide a diffeomorphism invariant characterization of the horizon geometry. Physically, they can be thought of as the `source multipoles' of black holes in equilibrium. These structures have a variety of potential applications ranging from equations of motion of black holes and numerical relativity to quantum gravity.Comment: 25 pages, 1 figure. Minor typos corrected, reference adde

Positron emission tomography in detection of metastatic leiomyosarcoma in a postoperative patient: a case report

In leiomyosarcoma (LMS) abnormal vaginal bleeding is the most common reported symptom in patients (56%), followed by pelvic mass (54%), and pain (22%). LMS is often hard to diagnosis on a uterine biopsy because it does not originate in the endometrium and may not invade into the cavity. Non-specific symptoms as well as difficulty in diagnosis being made by biopsy, means that many LMS tumors are often mistaken for fibroids preoperatively. To our knowledge this is the only reported case of FDG-PET being used in the postoperative evaluation of a patient with LMS and a suspicious lung mass. Our case shows there may be a place for PET scans in the post-op surveillance of LMS. This method would be ideally suited, considering the metastatic spread pattern of LMS

A New Spin Foam Model for 4d Gravity

Starting from Plebanski formulation of gravity as a constrained BF theory we propose a new spin foam model for 4d Riemannian quantum gravity that generalises the well-known Barrett-Crane model and resolves the inherent to it ultra-locality problem. The BF formulation of 4d gravity possesses two sectors: gravitational and topological ones. The model presented here is shown to give a quantization of the gravitational sector, and is dual to the recently proposed spin foam model of Engle et al. which, we show, corresponds to the topological sector. Our methods allow us to introduce the Immirzi parameter into the framework of spin foam quantisation. We generalize some of our considerations to the Lorentzian setting and obtain a new spin foam model in that context as well.Comment: 40 pages; (v2) published versio