Innovation and Foreign Investment Behavior of the U.S. Pharmaceutical Industry

This paper deals with the links between the development of new drugs, and particularly of innovative new drugs, and the international activities of U.S. drug companies. While U.S. drug companies have developed new production processes - the most notable being the fermentation process for making penicillin - we concentrate in this paper on new products. Since production costs comprise less than 40 percent of the selling price of drugs and since the person choosing the drug rarely pays for it, growth in company sales and profits comes more from introducing new products than from cutting costs and prices of old products. The main novelty of our study is our examination of "innovative" as contrasted with "imitative" new drugs. Previous studies have generally focused on the total number of new drugs produced each year, but since our interest is in the causes and consequences of innovation, we have concentrated on the products we have rated as innovative. Section I explains our criteria for this distinction and presents our enumeration of the innovative new drugs for each of the 22 companies in our sample. In Section II we discuss trends in the rate of drug innovation and the factors influencing those trends. Section III describes our sample of drug companies and characterizes them with respect to their size, research investment, and innovativeness. Section IV examines the relation of innovativeness to the foreign activities of individual firms. In Section V we analyze, for a sample of 7 new drugs introduced by two companies, the rate at which use of the drugs was diffused among various countries arid the impact of the presence of manufacturing plants on the rate of diffusion.

Iron-enriched diet contributes to early onset of osteoporotic phenotype in a mouse model of hereditary hemochromatosis

Osteoporosis is associated with chronic iron overload secondary to hereditary hemochromatosis (HH), but the causative mechanisms are incompletely understood. The main objective of this study was to investigate the role of dietary iron on osteoporosis, using as biological model the Hfe-KO mice, which have a systemic iron overload. We showed that these mice show an increased susceptibility for developing a bone loss phenotype compared to WT mice, which can be exacerbated by an iron rich diet. The dietary iron overload caused an increase in inflammation and iron incorporation within the trabecular bone in both WT and Hfe-KO mice. However, the osteoporotic phenotype was only evident in Hfe-KO mice fed the iron-enriched diet. This appeared to result from an imbalance between bone formation and bone resorption driven by iron toxicity associated to Hfe-KO and confirmed by a decrease in bone microarchitecture parameters (identified by micro-CT) and osteoblast number. These findings were supported by the observed downregulation of bone metabolism markers and upregulation of ferritin heavy polypeptide 1 (Fth1) and transferrin receptor-1 (Tfrc), which are associated with iron toxicity and bone loss phenotype. In WT mice the iron rich diet was not enough to promote a bone loss phenotype, essentially due to the concomitant depression of bone resorption observed in those animals. In conclusion the dietary challenge influences the development of osteoporosis in the HH mice model thus suggesting that the iron content in the diet may influence the osteoporotic phenotype in systemic iron overload conditions.National Funds through Foundation for Science and Technology (FCT) Norte-01-0145-FEDER-000012 Portuguese Foundation for Science and Technology (FCT) SFRH/BD/77056/2011 European Regional Development Fund (FEDER) Norte-01-0145-FEDER-000012info:eu-repo/semantics/publishedVersio

Structural and Microanalytical Studies of CrO2 Thin Films on c-Sapphire by High Resolution Electron Microscopy Methods

Chromium dioxide (CrO2) has been extensively used in the magnetic recording industry. However, it is its ferromagnetic half-metallic nature that has more recently attracted much attention, primarily for the development of spintronic devices. CrO2 is the only stoichiometric binary oxide theoretically predicted to be fully spin polarized at the Fermi level. It presents a Curie temperature of ∼ 396 K, i.e. well above room temperature, and a magnetic moment of 2 mB per formula unit. However an antiferromagnetic native insulating layer of Cr2O3 is always present on the CrO2 surface which enhances the CrO2 magnetoresistance and might be used as a barrier in magnetic tunnel junctions

Chemical evolution of the Galactic bulge as traced by microlensed dwarf and subgiant stars: IV. Two bulge populations

Based on high-resolution (R ≈ 42 000 to 48 000) and high signal-to-noise (S/N ≈ 50 to 150) spectra obtained with UVES/VLT, we present detailed elemental abundances (O, Na, Mg, Al, Si, Ca, Ti, Cr, Fe, Ni, Zn, Y, and Ba) and stellar ages for 12 new mic

Non-equilibrium work relations

This is a brief review of recently derived relations describing the behaviour of systems far from equilibrium. They include the Fluctuation Theorem, Jarzynski's and Crooks' equalities, and an extended form of the Second Principle for general steady states. They are very general and their proofs are, in most cases, disconcertingly simple.Comment: Brief Summer School Lecture Note

The influence of thermal evolution in the magnetic protection of terrestrial planets

Magnetic protection of potentially habitable planets plays a central role in determining their actual habitability and/or the chances of detecting atmospheric biosignatures. Here we develop a thermal evolution model of potentially habitable Earth-like planets and super-Earths (SEs). Using up-to-date dynamo-scaling laws, we predict the properties of core dynamo magnetic fields and study the influence of thermal evolution on their properties. The level of magnetic protection of tidally locked and unlocked planets is estimated by combining simplified models of the planetary magnetosphere and a phenomenological description of the stellar wind. Thermal evolution introduces a strong dependence of magnetic protection on planetary mass and rotation rate. Tidally locked terrestrial planets with an Earth-like composition would have early dayside magnetopause distances between 1.5 and 4.0 Rp , larger than previously estimated. Unlocked planets with periods of rotation ~1 day are protected by magnetospheres extending between 3 and 8 Rp . Our results are robust in comparison with variations in planetary bulk composition and uncertainties in other critical model parameters. For illustration purposes, the thermal evolution and magnetic protection of the potentially habitable SEs GL 581d, GJ 667Cc, and HD 40307g were also studied. Assuming an Earth-like composition, we found that the dynamos of these planets are already extinct or close to being shut down. While GL 581d is the best protected, the protection of HD 40307g cannot be reliably estimated. GJ 667Cc, even under optimistic conditions, seems to be severely exposed to the stellar wind, and, under the conditions of our model, has probably suffered massive atmospheric losses

Influenza vaccine effectiveness estimates in Europe in a season with three influenza type/subtypes circulating: the I-MOVE multicentre case–control study, influenza season 2012/13

In the fifth season of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE), we undertook a multicentre case–control study (MCCS) in seven European Union (EU) Member States to measure 2012/13 influenza vaccine effectiveness against medically attended influenza-like illness (ILI) laboratory confirmed as influenza. The season was characterised by substantial co-circulation of influenza B, A(H1N1)pdm09 and A(H3N2) viruses. Practitioners systematically selected ILI patients to swab ≤7 days of symptom onset. We compared influenza-positive by type/subtype to influenza-negative patients among those who met the EU ILI case definition. We conducted a complete case analysis using logistic regression with study as fixed effect and calculated adjusted vaccine effectiveness (AVE), controlling for potential confounders (age, sex, symptom onset week and presence of chronic conditions). We calculated AVE by type/subtype. Study sites sent 7,954 ILI/acute respiratory infection records for analysis. After applying exclusion criteria, we included 4,627 ILI patients in the analysis of VE against influenza B (1,937 cases), 3,516 for A(H1N1)pdm09 (1,068 cases) and 3,340 for influenza A(H3N2) (730 cases). AVE was 49.3% (95% confidence interval (CI): 32.4 to 62.0) against influenza B, 50.4% (95% CI: 28.4 to 65.6) against A(H1N1)pdm09 and 42.2% (95% CI: 14.9 to 60.7) against A(H3N2). Our results suggest an overall low to moderate AVE against influenza B, A(H1N1)pdm09 and A(H3N2), between 42 and 50%. In this season with many co-circulating viruses, the high sample size enabled stratified AVE by type/subtype. The low estimates indicate seasonal influenza vaccines should be improved to achieve acceptable protection levels

Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination target groups in Europe: results from the I-MOVE multicentre case-control study

Within the Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) project we conducted a multicentre case–control study in eight European Union (EU) Member States to estimate the 2011/12 influenza vaccine effectiveness against medically attended influenza-like illness (ILI) laboratory-confirmed as influenza A(H3) among the vaccination target groups. Practitioners systematically selected ILI / acute respiratory infection patients to swab within seven days of symptom onset. We restricted the study population to those meeting the EU ILI case definition and compared influenza A(H3) positive to influenza laboratory-negative patients. We used logistic regression with study site as fixed effect and calculated adjusted influenza vaccine effectiveness (IVE), controlling for potential confounders (age group, sex, month of symptom onset, chronic diseases and related hospitalisations, number of practitioner visits in the previous year). Adjusted IVE was 25% (95% confidence intervals (CI): -6 to 47) among all ages (n=1,014), 63% (95% CI: 26 to 82) in adults aged between 15 and 59 years and 15% (95% CI: -33 to 46) among those aged 60 years and above. Adjusted IVE was 38% (95%CI: -8 to 65) in the early influenza season (up to week 6 of 2012) and -1% (95% CI: -60 to 37) in the late phase. The results suggested a low adjusted IVE in 2011/12. The lower IVE in the late season could be due to virus changes through the season or waning immunity. Virological surveillance should be enhanced to quantify change over time and understand its relation with duration of immunological protection. Seasonal influenza vaccines should be improved to achieve acceptable levels of protection.ECD

Diets containing sea cucumber (Isostichopus badionotus) meals are hypocholesterolemic in young rats

Peer reviewedPublisher PD

Chemical evolution of the Galactic bulge as traced by microlensed dwarf and subgiant stars : V. Evidence for a wide age distribution and a complex MDF

Based on high-resolution spectra obtained during gravitational microlensing events we present a detailed elemental abundance analysis of 32 dwarf and subgiant stars in the Galactic bulge. Combined with the sample of 26 stars from the previous papers in this series, we now have 58 microlensed bulge dwarfs and subgiants that have been homogeneously analysed. The main characteristics of the sample and the findings that can be drawn are: (i) the metallicity distribution (MDF) is wide and spans all metallicities between [Fe/H] = -1.9 to +0.6; (ii) the dip in the MDF around solar metallicity that was apparent in our previous analysis of a smaller sample (26 microlensed stars) is no longer evident; instead it has a complex structure and indications of multiple components are starting to emerge. A tentative interpretation is that there could be different stellar populations at interplay, each with a different scale height: the thin disk, the thick disk, and a bar population; (iii) the stars with [Fe/H] ≤ -0.1 are old with ages between 10 and 12 Gyr; (iv) the metal-rich stars with [Fe/H] ≥ -0.1 show a wide variety of ages, ranging from 2 to 12 Gyr with a distribution that has a dominant peak around 4-5 Gyr and a tail towards higher ages; (v) there are indications in the [α/Fe]-[Fe/H] abundance trends that the "knee" occurs around [Fe/H] = -0.3to -0.2, which is a slightly higher metallicity as compared to the "knee" for the local thick disk. This suggests that the chemical enrichment of the metal-poor bulge has been somewhat faster than what is observed for the local thick disk. The results from the microlensed bulge dwarf stars in combination with other findings in the literature, in particular the evidence that the bulge has cylindrical rotation, indicate that the Milky Way could be an almost pure disk galaxy. The bulge would then just be a conglomerate of the other Galactic stellar populations (thin disk, thick disk, halo, and.?), residing together in the central parts of the Galaxy, influenced by the Galactic bar