Cost of innovation in the pharmaceutical industry.

The research and development costs of 93 randomly selected new chemical entities (NCEs) were obtained from a survey of 12 U.S.-owned pharmaceutical firms. These data were used to estimate the pre-tax average cost of new drug development. The costs of abandoned NCEs were linked to the costs of NCEs that obtained marketing approval. For base case parameter values, the estimated out-of-pocket cost per approved NCE is $114 million (1987 dollars). Capitalizing out-of-pocket costs to the point of marketing approval at a 9% discount rate yielded an average cost estimate of $231 million (1987 dollars).

Construction of invisibility cloaks of arbitrary shape and size using planar layers of metamaterials

Transformation optics (TO) is a powerful tool for the design of electromagnetic and optical devices with novel functionality derived from the unusual properties of the transformation media. In general, the fabrication of TO media is challenging, requiring spatially varying material properties with both anisotropic electric and magnetic responses. Though metamaterials have been proposed as a path for achieving such complex media, the required properties arising from the most general transformations remain elusive, and cannot implemented by state-of-the-art fabrication techniques. Here, we propose faceted approximations of TO media of arbitrary shape in which the volume of the TO device is divided into flat metamaterial layers. These layers can be readily implemented by standard fabrication and stacking techniques. We illustrate our approximation approach for the specific example of a two-dimensional, omnidirectional "invisibility cloak", and quantify its performance using the total scattering cross section as a practical figure of merit. © 2012 American Institute of Physics.

Changes to the North Atlantic subtropical high and its role in the intensification of summer rainfall variability in the southeastern United States

This study investigates the changes of the North Atlantic subtropical high (NASH) and its impact on summer precipitation over the southeastern (SE) United States using the 850-hPa geopotential height field in the National Centers forEnvironmental Prediction (NCEP) reanalysis, the 40-yr European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERA-40), long-term rainfall data, and Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4) model simulations during the past six decades (1948-2007). The results show that the NASH in the last 30 yr has become more intense, and its western ridge has displaced westward with an enhanced meridional movement compared to the previous 30 yr. When the NASH moved closer to the continental United States in the three most recent decades, the effect of the NASH on the interannual variation of SE U.S. precipitation is enhanced through the ridge's north-south movement. The study's attribution analysis suggested that the changes of the NASH are mainly due to anthropogenic warming. In the twenty-first century with an increase of the atmospheric CO2 concentration, the center of the NASH would be intensified and the western ridge of the NASH would shift farther westward. These changes would increase the likelihood of both strong anomalously wet and dry summers over the SEUnited States in the future, as suggested by the IPCC AR4 models. © 2011 American Meteorological Society.

Recruiting young adults into a weight loss trial: report of protocol development and recruitment results.

Obesity has spread to all segments of the U.S. population. Young adults, aged 18-35 years, are rarely represented in clinical weight loss trials. We conducted a qualitative study to identify factors that may facilitate recruitment of young adults into a weight loss intervention trial. Participants were 33 adults aged 18-35 years with BMI ≥25 kg/m(2). Six group discussions were conducted using the nominal group technique. Health, social image, and "self" factors such as emotions, self-esteem, and confidence were reported as reasons to pursue weight loss. Physical activity, dietary intake, social support, medical intervention, and taking control (e.g. being motivated) were perceived as the best weight loss strategies. Incentives, positive outcomes, education, convenience, and social support were endorsed as reasons young adults would consider participating in a weight loss study. Incentives, advertisement, emphasizing benefits, and convenience were endorsed as ways to recruit young adults. These results informed the Cellphone Intervention for You (CITY) marketing and advertising, including message framing and advertising avenues. Implications for recruitment methods are discussed.

Veterans health administration hepatitis B testing and treatment with anti-CD20 antibody administration.

AIM: To evaluate pretreatment hepatitis B virus (HBV) testing, vaccination, and antiviral treatment rates in Veterans Affairs patients receiving anti-CD20 Ab for quality improvement. METHODS: We performed a retrospective cohort study using a national repository of Veterans Health Administration (VHA) electronic health record data. We identified all patients receiving anti-CD20 Ab treatment (2002-2014). We ascertained patient demographics, laboratory results, HBV vaccination status (from vaccination records), pharmacy data, and vital status. The high risk period for HBV reactivation is during anti-CD20 Ab treatment and 12 mo follow up. Therefore, we analyzed those who were followed to death or for at least 12 mo after completing anti-CD20 Ab. Pretreatment serologic tests were used to categorize chronic HBV (hepatitis B surface antigen positive or HBsAg+), past HBV (HBsAg-, hepatitis B core antibody positive or HBcAb+), resolved HBV (HBsAg-, HBcAb+, hepatitis B surface antibody positive or HBsAb+), likely prior vaccination (isolated HBsAb+), HBV negative (HBsAg-, HBcAb-), or unknown. Acute hepatitis B was defined by the appearance of HBsAg+ in the high risk period in patients who were pretreatment HBV negative. We assessed HBV antiviral treatment and the incidence of hepatitis, liver failure, and death during the high risk period. Cumulative hepatitis, liver failure, and death after anti-CD20 Ab initiation were compared by HBV disease categories and differences compared using the χ(2) test. Mean time to hepatitis peak alanine aminotransferase, liver failure, and death relative to anti-CD20 Ab administration and follow-up were also compared by HBV disease group. RESULTS: Among 19304 VHA patients who received anti-CD20 Ab, 10224 (53%) had pretreatment HBsAg testing during the study period, with 49% and 43% tested for HBsAg and HBcAb, respectively within 6 mo pretreatment in 2014. Of those tested, 2% (167/10224) had chronic HBV, 4% (326/7903) past HBV, 5% (427/8110) resolved HBV, 8% (628/8110) likely prior HBV vaccination, and 76% (6022/7903) were HBV negative. In those with chronic HBV infection, ≤ 37% received HBV antiviral treatment during the high risk period while 21% to 23% of those with past or resolved HBV, respectively, received HBV antiviral treatment. During and 12 mo after anti-CD20 Ab, the rate of hepatitis was significantly greater in those HBV positive vs negative (P = 0.001). The mortality rate was 35%-40% in chronic or past hepatitis B and 26%-31% in hepatitis B negative. In those pretreatment HBV negative, 16 (0.3%) developed acute hepatitis B of 4947 tested during anti-CD20Ab treatment and follow-up. CONCLUSION: While HBV testing of Veterans has increased prior to anti-CD20 Ab, few HBV+ patients received HBV antivirals, suggesting electronic health record algorithms may enhance health outcomes.

Hierarchical random walks in trace fossils and the origin of optimal search behavior

Efficient searching is crucial for timely location of food and other resources. Recent studies show diverse living animals employ a theoretically optimal scale-free random search for sparse resources known as a Lévy walk, but little is known of the origins and evolution of foraging behaviour and the search strategies of extinct organisms. Here we show using simulations of self-avoiding trace fossil trails that randomly introduced strophotaxis (U-turns) – initiated by obstructions such as ¬¬¬self-trail avoidance or innate cueing – leads to random looping patterns with clustering across increasing scales that is consistent with the presence of Lévy walks. This predicts optimal Lévy searches can emerge from simple behaviours observed in fossil trails. We then analysed fossilized trails of benthic marine organisms using a novel path analysis technique and find the first evidence of Lévy-like search strategies in extinct animals. Our results show that simple search behaviours of extinct animals in heterogeneous environments give rise to hierarchically nested Brownian walk clusters that converge to optimal Lévy patterns. Primary productivity collapse and large-scale food scarcity characterising mass extinctions evident in the fossil record may have triggered adaptation of optimal Lévy-like searches. The findings suggest Lévy-like behaviour has been employed by foragers since at least the Eocene but may have a more ancient origin, which could explain recent widespread observations of such patterns among modern taxa.

Speeds of sound and isentropic compressibilities of binary mixtures containing trialkylamines with alkanes and mono-alkylamines at 303.15 and 313.15 K

Isentropic compressibilities ?S, and excess isentropic compressibilities ?SE have been determined from measurements of speeds of sound u and densities ? of 14 binary mixtures of triethylamine (TEA) and tri-n-butylamine (TBA) with n-hexane, n-octane, iso-octane, n-propylamine, n-butylamine, n-hexylamine and n-octylamine. The relative magnitude and sign of ?SE have been interpreted in terms of molecular interactions and interstitial accommodation. The values of ?SE for TEA + alkane are positive while for TBA + alkane are negative. The values of ?SE for TEA + primary amine become progressively less positive and eventually to negative with the increase in chain length of alkylamine. In case of TBA + primary amine, the values of ?SE increase from n-propylamine to n-butylamine, and then decrease with chain length of primary amine. The experimental speeds of sound u have been analyzed in terms of collision factor theory, free length theory and Prigogine–Flory–Patterson statistical theory of solutions.

Acoustic, volumetric, compressibility and refractivity properties and Flory’s reduction parameters of some homologous series of alkyl alkanoates from 298.15 to 333.15 K

The speeds of sound u in, densities ? and refractive indices nD of some homologous series, such as n-alkyl ethanoates, n-alkyl propionates, methyl alkanoates, ethyl alkanoates, dialkyl malonates, and alkyl haloalkanoates, were measured in the temperature range from 298.15 to 333.15 K. Molar volume V, isentropic and isothermal compressibilities ?S and ?T, molar refraction Rm, Eykman’s constant Cm, molecular radius r, Rao’s molar function R, thermal expansion coefficient a, thermal pressure coefficient ?, and Flory’s characteristic parameters image, P*, V*, and T* have been calculated from the measured experimental data. Applicability of Rao theory and Flory–Patterson–Pandey (FPP) theory have been examined and discussed for these alkanoates.

Speeds of sound, isentropic compressibilities, and excess molar volumes of cycloalkanes, alkanes and aromatic hydrocarbons at 303.15 K. II. Results for cycloalkanes+aromatic hydrocarbons

The speeds of sound u, isentropic compressibilities ?S, molar sound functions R, excess isentropic compressibilities ?SE and excess molar volumes VE for eight binary mixtures of cyclopentane, cyclohexane, cyclooctane and methylcyclohexane with benzene and of cyclohexane with toluene, ethyl benzene, p-xylene and propyl benzene at 303.15 K are reported. The effects of molecular sizes and shapes of the component molecules and of interaction energy in the mixture have been discussed. The Prigogine–Flory–Patterson theory has been applied to analyze the present binary mixtures along with the mixtures of cis- and trans-decalins with benzene and toluene taken from the literature.

Acoustic, volumetric, compressibility and refractivity properties and reduction parameters for the ERAS and Flory models of some homologous series of amines from 298.15 to 328.15 K

The speeds of sound u, densities ? and refractive indices nD of homologous series of mono-, di-, and tri-alkylamines were measured in the temperature range from 298.15 to 328.15 K. Isentropic and isothermal compressibilities ?S and ?T, molar refraction Rm, Eykman’s constant Cm, Rao’s molar sound function R, thermal expansion coefficient a, thermal pressure coefficient ?, and reduction parameters P*, V*, and T* in frameworks of the ERAS model for associated amines and Flory model for tertiary amines have been calculated from the measured experimental data. Applicability of the Rao theory and the ERAS and Flory models have been examined and discussed for the alkyl amines.

Densities, speeds of sound, isentropic compressibilities, refractive indexes, and viscosities of tetrahydrofuran with haloalkane or alkyl ethanoate at T = 303.15 K

Isentropic compressibilities ?S, excess isentropic compressibilities image, excess molar volumes VE, viscosity deviations ??, and excess Gibbs energy of activation of viscous flow ?G*E for nine binary mixtures of C4H8O with CCl4, CHCl3, CHCl2CHCl2, 1-C6H13Cl, 1-C6H13Br, CH3CO2CH3, CH3CO2C2H5, CH3CO2C4H9, and CH3CO2C5H11 at 303.15 K have been derived from experimental densities ?, speeds of sound u, refractive indexes nD and viscosities ?. The limiting values of excess partial molar volumes of C4H8O at infinite dilution image in different solvents have been estimated. The results obtained for dynamic viscosity of binary mixtures were used to test the semi-empirical relations of Grunberg–Nissan, Tamura–Kurata, Hind–McLaughlin–Ubbelohde, Katti–Chaudhri, McAllister, Heric, and Auslaender. Finally, the experimental refractive indexes were compared with the predicted results for Lorentz–Lorenz, Dale–Gladstone, Eykman, Arago–Boit, Newton, Oster, Heller, and Wiener equations.

Speeds of sound, isentropic compressibilities, viscosities, and excess molar volumes of binary mixtures of alkanoates with tetra- and trichloromethanes at 303.15 K

Speeds of sound u, isentropic compressibilities ?S, viscosities ?, excess isentropic compressibilities ?SE, excess molar volumes VE, viscosity deviations ??, and excess Gibbs energies of activation ?G*E of viscous flow have been investigated for six binary mixtures of diethyl malonate, diethyl bromomalonate, and ethyl chloroacetate with tetra- and trichloromethane at 303.15 K. The values of ?SE, VE, ??, and ?G*E are highly dependent on the type of components involved and the composition curves are unsymmetrical. The results obtained for viscosity of binary mixtures were used to test the semi-empirical relations of Grunberg-Nissan, Tamura-Kurata, Hind-McLaughlin-Ubbelohde, Katti-Chaudhri, McAllister, Heric-Brewer and Auslaender. The experimental speeds of sound have been analyzed in terms of collision factor theory and free length theory of solutions.

Estimation of speed of sound of ionic liquids using surface tensions and densities: A volume based approach

The limited availability of experimental data and their quality have been preventing the development of predictive methods and Computer Aided Molecular Design (CAMD) of ionic liquids (ILs). Based on experimental speed of sound data collected from the literature, the inter-relationship of surface tension (s), density (?), and speed of sound (u) has been examined for imidazolium based ILs containing hexafluorophosphate (PF6), tetrafluoroborate (BF4), bis(trifluoromethanesulphonyl) amide (NTf2), methyl sulphate (MeSO4), ethyl sulphate (EtSO4), and trifluoromethanesulphonate (CF3SO3) anions, covering wide ranges of temperature, 278.15–343.15 K and speed of sound, 1129.0–1851.0 m s-1. The speed of sound was correlated with a modified Auerbach's relation, by using surface tension and density data obtained from volume based predictive methods previously proposed by the authors. It is shown that a good agreement with literature data is obtained. For 133 data points of 14 ILs studied a mean percent deviation (MPD) of 1.96% with a maximum deviation inferior to 5% was observed. The correlations developed here can thus be used to evaluate the speeds of sound of new ionic liquids.

Paternity frequency and maternity of males in some stingless bee species

In monogynous hymenopteran societies, the number of mates of a queen strongly influences the potential for conflict between workers and queens over the maternity of males. Queens always 'prefer' their own sons to sons of workers, regardless of queen mating frequency. When a queen mates once, workers are more closely related to, and therefore are expected to prefer, their own sons and then sons of sisters to sons of the queen. However, if effective paternity frequency exceeds 2, workers on average should prefer queen-produced males to males produced by their sisters. We studied the queen mating frequency of seven stingless bee species: the Mexican species Scaptotrigona mexicana , S. pectoralis and the Australian species Austroplebeia symei , Trigona clypearis , T. hockingsi , T. mellipes and T. sapiens . We then determined whether males arise from eggs laid by workers or queens in A. symei , T. clypearis , T. hockingsi and T. mellipes . We show that all seven species investigated are most likely singly mated and that the queen dominates reproduction. This indicates that the queen's mating frequency alone does not determine whether workers or the queen produces the males.

El Ser como mediación. Ontología, estética y analogía en la interpretación del ‘esse’ tomasiano de H. U. von Balthasar

El presente artículo expone los fundamentos de la interpretación que del esse tomasiano lleva a cabo Hans Urs von Balthasar. En ella ofrece von Balthasar, a partir de una interpretación en la línea de Siewerth, y como tal novedosa para la historia de la crítica, las directrices fundamentales de su propio pensamiento filosóficoteológico, cuyo eje lo constituye la diferencia entre esse y Dios como modelo para una hermenéutica no monista de la realidad. Con todo, la propuesta no está exenta de algunas dificultades y arbitrariedades que, desde una perspectiva crítica y aconfesional (por la que aquí se opta), conviene ineludiblemente subrayar.