Pareto-improving asymmetric information in a dynamic insurance market

This paper explored the dynamics of insurance markets under incomplete information. Various information structures are examined, according to the degree of communication between companies. We get equilibrium existence even when adverse selection arises through differentiated learning. This and the Pareto-dominance of private information structures seem to mitigate the prevalent view that adverse selection and competition do not match well in insurance markets; moreover, it provides a new scope for empirical studies. Technically, we extend to dynamics Rothschild-Stiglitz' equilibrium concept, and get to reconsider the "no-malus" property, which we prove to result from the non-consideration of feed-back effects of future on present

Multiple interactions and complex viscosity: The impact of frequency rheology for the development of high concentration protein formulations

Clinical doses of therapeutic proteins range up to 2 mg/kg bodyweigth per patient and even higher. For patient convenience and competitiveness, subcutaneous (s.c.) applications are required. Therefore, liquid formulations for s.c. applications can reach concentrations of up to 200 mg/ml. One key parameter for the development of biotherapeutics as high concentrated liquid formulations (HCLF) is viscosity. Consequently, high solution viscosity is challenging due to e.g. impeded syringeablitiy and injectability that directly link to patient inconvenience, and high shear stress that potentially impair protein inherent stability. Following Jezek et al. 2011, we consider protein concentrations of \u3e100 mg/ml as “highly concentrated”. During early phases in development of biopharmaceutics only limited material is available. Therefore, prediction of the solution viscosity at higher concentrations (e.g. for HCLF conditions), if required, will be of great benefit. In this study, we applied different approaches comprehensively investigating parameters describing protein-protein interaction, protein hydration, protein conformation at different concentrations, and the volume fraction of the protein molecule in solution. At a molecular level, Protein-Protein Interaction (PPI) are a result of electrostatic-interaction, van-der-Waal (vdW)-forces and hydrophobic forces of bi- or multimodal interaction as well as protein-excipients interaction. At the macroscopic level, these parameters describe a crucial influence on the protein-stability and its rheological behavior in solution. However, during formulation development commonly evaluated PPI parameter such as the second virial coefficient (B22), and/or the concentration- dependent diffusion coefficient (kD). These parameters only describe interactions in dilute conditions, which poses limitations in predicting interactions at high protein concentrations. At dilute conditions, mostly electrostatic double layer repulsion and charge-shielding effects of buffer and excipients components dominate. In contrast, at high concentration, distances between individual molecules are narrowed, and thus attractive forces such as vdW interactions are predominantly present. Therefore, a direct correlation of PPI parameter obtained from dilute to crowded conditions is only a shaky compromise. The mechanisms and principles driving the formation of highly viscose systems are not fully understood, especially at the molecular level. As a consequence, the attempts to reduce viscosity are often left to chance. In a case study, we evaluated the behaviour of concentrated protein formulations under high-frequency shear excitation in the MHz range. As a result, we propose an explanation for interaction potentials between individual protein molecules linked to high solution viscosity by extending the complex colloid theory. Multiple attraction forces result in a complex viscous behavior, the formation of a transient micro-rheological network of multiple interacting protein molecules, and the formation of an elastic modulus. In order to lower the viscosity, such multiple interactions have to be disrupted and disordered by different excipients. However, the interaction potential is correlated to the characteristics of each mAb molecule and can be altered by excipients in a defined way. By relating low concentration PPI measurements and wet-lab determined molecular characteristics (e.g. effective surface charge, dipole moment) it is possible to predicts the potency for describing a high viscosity for each mAb. Knowing the effects of pH and different buffer and excipients, a guided development for decreasing the viscosity by different excipients and formulation conditions is possible. High frequency rheology allows a rapid and early evaluation of the viscosity properties of early candidates and thus support subsequent formulation development

Activation energies define kinetic (in)stabilities of therapeutic antibodies

Antibody degradation pathways are many-fold and can result in loss of function, efficacy and even to adverse effects in patients. Among others, aggregation and fragmentation is still the major challenge. The identification of the primary degradation pathway can be very complex. Monoclonal antibodies (mAbs) are large, multi-domain macromolecules. Due to their complex nature and inherent properties, temperature induced unfolding leads to rather complex unfolding kinetics. In this study, we determined activation energies (Ea) of thermal intrinsic fluorescence (IF) unfolding profiles unique for each individual antibody. The analyzed activation energies give insights both into kinetic (in)stabilities of single domains and the overall structure of the antibody. To realize this, we used a novel developed experimental setup to perform temperature dependent fluorescence unfolding profiles of various mAbs. In conclusion, the activation energies can be used as descriptors for kinetic (in)stabilities of therapeutic antibodies. Moreover, we show that lower activation energies correlate to monomer loss in long-term storage stabilities and can thus likely be used for shelf-life prediction

Nutritional status of nongravid female adolescents, their knowledge, and attitudes about pregnancy

The purposes of this study were (1) to measure the knowledge and attitudes of nongravid female adolescents about health care and nutrition during pregnancy, and (2) to examine both dietary intake and pyridoxine status. The sample population was composed of 199 teenagers 12, 14, and 16 years of age from Guilford County, North Carolina. A questionnaire was developed which measured responses regarding knowledge of proper weight gain and diet during pregnancy; the recommended amount of caffeine, drugs, alcohol, food, exercise, and cigarettes during pregnancy; the effect of maternal age on the outcome of pregnancy; the timing and frequency of prenatal care; and the knowledge and use of contraception by female adolescents. Dietary intake was obtained by two 24-hour recalls. Pyridoxine status was assessed by stimulation of alanine aminotransferase

The effect of selected socio-environmental variables on the dietary intake of preschool children

This investigation was undertaken to obtain information on the dietary intake of Oregon preschool children and to determine the effect of certain socio-environmental variables on the nutrient intake of these children. Three hundred boys and girls who were attending Well Child or Multiphasic Screening Clinics in 11 counties participated in this project. A home economist interviewed the parent to obtain the child's dietary intake and socio-environmental data of the family. Dietary intake was determined by 24-hour recall or 3-day records. Nutrient intake was compared to the 1974 Recommended Dietary Allowances (RDA); intakes below 67 percent of the RDA were considered low. Correlations of socio-environmental factors with nutrient intake were determined by simple linear regression and multiple regression analysis. The mean and median of the children's intake of vitamin A, exceeded the RDA. While the median of their niacin intake was just below the RDA, the mean and median of their iron intake was below the recommended level. Protein and riboflavin were consumed abundantly, with 0 and 3.3 percent of the subjects, respectively, failing to receive two-thirds of the RDA. Sixty-three percent of the children ingested diets that supplied two to three times the RDA for protein. The nutrients most commonly lacking were iron, ascorbic acid, calcium and thiamin, with 39.7, 18.7, 15.3, and 13.0 percent, respectively, of the children having low intakes. Forty-one percent of the children received a nutrient supplement, which was not included in these calculations. The percentage of children consuming diets containing less than 67 percent of the RDA increased with age for the intakes of vitamin A, thiamin, and kilocalories. Low intakes of iron, on the other hand, declined with age. Riboflavin intake was lowest among the four- to six-year-old children. Adequacy of ascorbic acid, niacin and calcium did not show any relation to age. The socio-environmental variables examined were geographic location (urban, rural, or metropolitan), number of siblings as well as education and occupation of each parent. Other socio-environmental variables considered were whether or not the family received public assistance or had contact with the Cooperative Extension Service personnel and bulletins. When multiple regression analysis was ascorbic acid, thiamin, riboflavin, calcium, protein, and kilocalories performed, the only significant correlation (p < 0.05) was observed between the intake of ascorbic acid, mother's education, and mother's profession. Four socio-environmental variables were significantly correlated (p < 0.05) with the intake of one or more nutrients by simple linear regression. A significant correlation was found between mother's education and the intakes of ascorbic acid, calories, and thiamin. A significant correlation was observed between mother's profession and the intakes of niacin and ascorbic acid. Father's education was found to be significantly related to the intake of thiamin. The only significant, negative correlation was found between the intake of thiamin and the number of siblings

Dynamique climatique de l'océan Pacifique ouest équatorial au cours du Pléistocène récent

M. Edouard BARD, Professeur, Collège de France - Co-directeur M. Luc BEAUFORT, Chargé de Recherche CNRS, Aix-en-Provence - Directeur de thèse Mme. Elsa CORTIJO, Chargée de Recherche CNRS, Gif-sur-Yvette - Examinateur M. Patrick DE DECKKER, Professeur, Australian National University - Rapporteur M. Dick KROON, Professeur, Vrije Universteit Amsterdam - Rapporteur M. Nicolas THOUVENY, Professeur, Université de la Méditerranée -ExaminateurThe western equatorial Pacific warm pool (WPWP), warmest ocean area of the globe, fuels the meridian monsoon and zonal Walker atmospheric circulation cells. Using planktonic foraminifera assemblages, stable isotope geochemistry and morphometry, and coccolithophorids assemblages, we investigated past climate dynamics of this area during the Late Pleistocene. We developped a new planktonic foraminifera transfer function which is not biased by the ecosystem structure like was the CLIMAP study. Using this method, the last 185 kyrs SSTs in the WPWP oscillated between 27 and 29.5°C, in agreement with alkenones estimates. The “deep” atmospheric convection over the WPWP was thus a stable feature of the Late Pleistocene climate. These temperatures appear to be modulated by the precession cycles which also force a rocking of the Indo-Pacific thermocline, following an “El Niño-Southern Oscillation-like” mechanism. At millenial time-scale, the high-latitudes Dansgaard-Oeschger cycles were find in past changes in East Asian winter monsoon strength from the northern edge of the WPWP. A 1500 yrs cycle imprints this monsoon record, which is not ice volume modulated, and thus not driven by some high-latitude process. A potential climatic feedback is attributed to thermal dissociation of methane gas-hydrates from low-latitude sedimentary margins. Indeed, a high-resolution of carbon isotopic changes in the WPWP, exhibits the occurrence of large methane gas-hydrates releases during the last glacial stage.L'océan Pacifique ouest équatorial, zone océanique la plus chaude du globe, est au cœur des cellules de circulation atmosphérique de mousson (méridienne) et de Walker (zonale). Les assemblages des foraminifères planctoniques, leur géochimie et leur morphométrie ainsi que les assemblages de coccolithophoridés nous ont permis de reconstruire la dynamique climatique de cette zone au Pléistocène récent Nous avons développé une nouvelle fonction de transfert non biaisée par la structure des écosystèmes comme dans l'étude CLIMAP. Les températures de surface des derniers 185 ka reconstruites par cette méthode varient entre 27 et 29.5°C, en accord avec les estimations des alcénones. La convection atmosphérique liée à ces températures élevées a donc persisté au cours du Pléistocène récent. Ces températures sont modulées par les cycles orbitaux de précession qui forcent également à cette échelle de temps le balancement de la thermocline des océans Indo-Pacifique, suivant un mécanisme similaire à l'El Niño-Oscillation Australe. A l'échelle du millénaire, la dynamique climatique rapide des cycles de Dansgaard-Oeschger des hautes latitudes est décelée dans les variations d'intensité de la mousson d'hiver Est Asiatique du Pacifique ouest équatorial. Cette mousson est marquée par un cycle de 1500 ans, indépendant du volume global des glaces, donc d'un forcage des hautes latitudes. Un rôle d'amplificateur des changements climatiques rapides est attribué à la dissociation thermale des clathrates de méthane des marges sédimentaires de basses latitudes. En effet, un enregistrement isotopique à haute résolution des isotopes du carbone démontre l'existence de dégazages catastrophiques de ces clathrates de méthane pendant le dernier stade glaciaire

Physicochemical characterization of the endotoxins from Coxiella burnetii strain Priscilla in relation to their bioactivities

BACKGROUND: Coxiella burnetii is the etiological agent of Q fever found worldwide. The microorganism has like other Gram-negative bacteria a lipopolysaccharide (LPS, endotoxin) in its outer membrane, which is important for the pathogenicity of the bacteria. In order to understand the biological activity of LPS, a detailed physico-chemical analysis of LPS is of utmost importace. RESULTS: The lipid A moiety of LPS is tetraacylated and has longer (C-16) acyl chains than most other lipid A from enterobacterial strains. The two ester-linked 3-OH fatty acids found in the latter are lacking. The acyl chains of the C. burnetii endotoxins exhibit a broad melting range between 5 and 25°C for LPS and 10 and 40°C for lipid A. The lipid A moiety has a cubic inverted aggregate structure, and the inclination angle of the D-glucosamine disaccharide backbone plane of the lipid A part with respect to the membrane normal is around 40°. Furthermore, the endotoxins readily intercalate into phospholipid liposomes mediated by the lipopolysaccharide-binding protein (LBP). The endotoxin-induced tumor necrosis factor α (TNFα) production in human mononuclear cells is one order of magnitude lower than that found for endotoxins from enterobacterial strains, whereas the same activity as in the latter compounds is found in the clotting reaction of the Limulus amebocyte lysate assay. CONCLUSIONS: Despite a considerably different chemical primary structure of the C. burnetii lipid A in comparison with enterobacterial lipid A, the data can be well understood by applying the previously presented conformational concept of endotoxicity, a conical shape of the lipid A moiety of LPS and a sufficiently high inclination of the sugar backbone plane with respect to the membrane plane. Importantly, the role of the acyl chain fluidity in modulating endotoxicity now becomes more evident

Worldwide Genotyping in the Planktonic Foraminifer Globoconella inflata: Implications for Life History and Paleoceanography

The planktonic foraminiferal morpho-species Globoconella inflata is widely used as a stratigraphic and paleoceanographic index. While G. inflata was until now regarded as a single species, we show that it rather constitutes a complex of two pseudo-cryptic species. Our study is based on SSU and ITS rDNA sequence analyses and genotyping of 497 individuals collected at 49 oceanic stations covering the worldwide range of the morpho-species. Phylogenetic analyses unveil the presence of two divergent genotypes. Type I inhabits transitional and subtropical waters of both hemispheres, while Type II is restricted to the Antarctic subpolar waters. The two genetic species exhibit a strictly allopatric distribution on each side of the Antarctic Subpolar Front. On the other hand, sediment data show that G. inflata was restricted to transitional and subtropical environments since the early Pliocene, and expanded its geographic range to southern subpolar waters ∼700 kyrs ago, during marine isotopic stage 17. This datum may correspond to a peripatric speciation event that led to the partition of an ancestral genotype into two distinct evolutionary units. Biometric measurements performed on individual G. inflata from plankton tows north and south of the Antarctic Subpolar Front indicate that Types I and II display slight but significant differences in shell morphology. These morphological differences may allow recognition of the G. inflata pseudo-cryptic species back into the fossil record, which in turn may contribute to monitor past movements of the Antarctic Subpolar Front during the middle and late Pleistocene