Price linkages in pharmaceutical markets

This paper studies the existing price linkage between generics and branded pharmaceuticals, in which the generic price must be a fraction of the latter. Using a vertical differentiation model, we look at the market equilibrium, the effects on the incentives for the brand producer to develop new products, and the possibility of predation by the brand producer over the generic firm. We find that the price linkage increases prices compared to no indexation and it may increase the incentives for the brand producer to expand its set of products. When prices are freely set, the branded firm may also want to expand a new product with a higher quality, but will prefer to remove the original one from the market. Predation may equally occur in both schemes but the price linkage may give fewer incentives for the branded firm to predate while compensating losses with a new drug.

Essays on bounded rationality: Individual decision and strategic interaction

Economics is a social science which, therefore, focuses on people and on the decisions they make, be it in an individual context, or in group situations. It studies human choices, in face of needs to be fulfilled, and a limited amount of resources to fulfill them. For a long time, there was a convergence between the normative and positive views of human behavior, in that the ideal and predicted decisions of agents in economic models were entangled in one single concept. That is, it was assumed that the best that could be done in each situation was exactly the choice that would prevail. Or, at least, that the facts that economics needed to explain could be understood in the light of models in which individual agents act as if they are able to make ideal decisions. However, in the last decades, the complexity of the environment in which economic decisions are made and the limits on the ability of agents to deal with it have been recognized, and incorporated into models of decision making in what came to be known as the bounded rationality paradigm. This was triggered by the incapacity of the unboundedly rationality paradigm to explain observed phenomena and behavior. This thesis contributes to the literature in three different ways. Chapter 1 is a survey on bounded rationality, which gathers and organizes the contributions to the field since Simon (1955) first recognized the necessity to account for the limits on human rationality. The focus of the survey is on theoretical work rather than the experimental literature which presents evidence of actual behavior that differs from what classic rationality predicts. The general framework is as follows. Given a set of exogenous variables, the economic agent needs to choose an element from the choice set that is avail- able to him, in order to optimize the expected value of an objective function (assuming his preferences are representable by such a function). If this problem is too complex for the agent to deal with, one or more of its elements is simplified. Each bounded rationality theory is categorized according to the most relevant element it simplifes. Chapter 2 proposes a novel theory of bounded rationality. Much in the same fashion as Conlisk (1980) and Gabaix (2014), we assume that thinking is costly in the sense that agents have to pay a cost for performing mental operations. In our model, if they choose not to think, such cost is avoided, but they are left with a single alternative, labeled the default choice. We exemplify the idea with a very simple model of consumer choice and identify the concept of isofin curves, i.e., sets of default choices which generate the same utility net of thinking cost. Then, we apply the idea to a linear symmetric Cournot duopoly, in which the default choice can be interpreted as the most natural quantity to be produced in the market. We find that, as the thinking cost increases, the number of firms thinking in equilibrium decreases. More interestingly, for intermediate levels of thinking cost, an equilibrium in which one of the firms chooses the default quantity and the other best responds to it exists, generating asymmetric choices in a symmetric model. Our model is able to explain well-known regularities identified in the Cournot experimental literature, such as the adoption of different strategies by players (Huck et al. , 1999), the inter temporal rigidity of choices (Bosch-Dom enech & Vriend, 2003) and the dispersion of quantities in the context of di cult decision making (Bosch-Dom enech & Vriend, 2003). Chapter 3 applies a model of bounded rationality in a game-theoretic set- ting to the well-known turnout paradox in large elections, pivotal probabilities vanish very quickly and no one should vote, in sharp contrast with the ob- served high levels of turnout. Inspired by the concept of rhizomatic thinking, introduced by Bravo-Furtado & Côrte-Real (2009a), we assume that each per- son is self-delusional in the sense that, when making a decision, she believes that a fraction of the people who support the same party decides alike, even if no communication is established between them. This kind of belief simplifies the decision of the agent, as it reduces the number of players he believes to be playing against { it is thus a bounded rationality approach. Studying a two-party first-past-the-post election with a continuum of self-delusional agents, we show that the turnout rate is positive in all the possible equilibria, and that it can be as high as 100%. The game displays multiple equilibria, at least one of which entails a victory of the bigger party. The smaller one may also win, provided its relative size is not too small; more self-delusional voters in the minority party decreases this threshold size. Our model is able to explain some empirical facts, such as the possibility that a close election leads to low turnout (Geys, 2006), a lower margin of victory when turnout is higher (Geys, 2006) and high turnout rates favoring the minority (Bernhagen & Marsh, 1997).

The absence of the human platelet antigen polymorphism effect on fibrosis progression in human immunodeficiency virus-1/hepatitis C virus coinfected patients

AbstractINTRODUCTION:Hepatic fibrosis progression in patients with chronic hepatitis C virus infections has been associated with viral and host factors, including genetic polymorphisms. Human platelet antigen polymorphisms are associated with the rapid development of fibrosis in HCV-monoinfected patients. This study aimed to determine whether such an association exists in human immunodeficiency virus-1/hepatitis C virus-coinfected patients.METHODS:Genomic deoxyribonucleic acid from 36 human immunodeficiency virus-1/hepatitis C virus-coinfected patients was genotyped to determine the presence of human platelet antigens-1, -3, or -5 polymorphisms. Fibrosis progression was evaluated using the Metavir scoring system, and the patients were assigned to two groups, namely, G1 that comprised patients with F1, portal fibrosis without septa, or F2, few septa (n = 23) and G2 that comprised patients with F3, numerous septa, or F4, cirrhosis (n = 13). Fisher's exact test was utilized to determine possible associations between the human platelet antigen polymorphisms and fibrosis progression.RESULTS:There were no deviations from the Hardy-Weinberg equilibrium in the human platelet antigen systems evaluated. Statistically significant differences were not observed between G1 and G2 with respect to the distributions of the allelic and genotypic frequencies of the human platelet antigen systems.CONCLUSION:The greater stimulation of hepatic stellate cells by the human immunodeficiency virus and, consequently, the increased expression of transforming growth factor beta can offset the effect of human platelet antigen polymorphism on the progression of fibrosis in patients coinfected with the human immunodeficiency virus-1 and the hepatitis C virus.

The implications of mandatory low-cost fuel provision

This work studies fuel retail firms’ strategic behavior in a two-dimensional product differentiation framework. Following the mandatory provision of “low-cost” fuel we consider that capacity constraints force firms to eliminate of one the previously offered qualities. Firms play a two-stage game choosing fuel qualities from three possibilities (low-cost, medium quality and high quality fuel) and then prices having exogenous opposite locations. In the highest level of consumers’ heterogeneity, a subgame perfect Nash equilibrium exists in which firms both choose minimum quality differentiation. Consumers’ are worse off if no differentiation occurs in medium and high qualities. The effect over prices from the mandatory “low-cost” fuel law is ambiguous.

Design of bio-inspired ionic liquids for protein stabilisation

Ionic Liquids (ILs) consist in organic salts that are liquid at/or near room temperature. Since ILs are entirely composed of ions, the formation of ion pairs is expected to be one essential feature for describing solvation in ILs. In recent years, protein - ionic liquid (P-IL) interactions have been the subject of intensive studies mainly because of their capability to promote folding/unfolding of proteins. However, the ion pairs and their lifetimes in ILs in P-IL thematic is dismissed, since the action of ILs is therefore the result of a subtle equilibrium between anion-cation interaction, ion-solvent and ion-protein interaction. The work developed in this thesis innovates in this thematic, once the design of ILs for protein stabilisation was bio-inspired in the high concentration of organic charged metabolites found in cell milieu. Although this perception is overlooked, those combined concentrations have been estimated to be ~300 mM among the macromolecules at concentrations exceeding 300 g/L (macromolecular crowding) and transient ion-pair can naturally occur with a potential specific biological role. Hence the main objective of this work is to develop new bio-ILs with a detectable ion-pair and understand its effects on protein structure and stability, under crowding environment, using advanced NMR techniques and calorimetric techniques. The choline-glutamate ([Ch][Glu]) IL was synthesized and characterized. The ion-pair was detected in water solutions using mainly the selective NOE NMR technique. Through the same technique, it was possible to detect a similar ion-pair promotion under synthetic and natural crowding environments. Using NMR spectroscopy (protein diffusion, HSQC experiments, and hydrogen-deuterium exchange) and differential scanning calorimetry (DSC), the model protein GB1 (production and purification in isotopic enrichment media) it was studied in the presence of [Ch][Glu] under macromolecular crowding conditions (PEG, BSA, lysozyme). Under dilute condition, it is possible to assert that the [Ch][Glu] induces a preferential hydration by weak and non-specific interactions, which leads to a significant stabilisation. On the other hand, under crowding environment, the [Ch][Glu] ion pair is promoted, destabilising the protein by favourable weak hydrophobic interactions , which disrupt the hydration layer of the protein. However, this capability can mitigates the effect of protein crowders. Overall, this work explored the ion-pair existence and its consequences on proteins in conditions similar to cell milieu. In this way, the charged metabolites found in cell can be understood as key for protein stabilisation.

Biotransformation/separation routes to obtain pure enantiomers

The objective of the work presented in this thesis was the development of an innovative approach for the separation of enantiomers of secondary alcohols, combining the use of an ionic liquid (IL) - both as solvent for conducting enzymatic kinetic resolution and as acylating agent - with the use of carbon dioxide (CO2) as solvent for extraction. Menthol was selected for testing this reaction/separation approach due to the increasing demand for this substance, which is widely used in the pharmaceutical, cosmetics and food industries. With a view to using an ionic ester as acylating agent, whose conversion led to the release of ethanol, and due to the need to remove this alcohol so as to drive reaction equilibrium forward, a phase equilibrium study was conducted for the ehtanol/(±)-menthol/CO2 system, at pressures between 8 and 10 MPa and temperatures between 40 and 50 oC. It was found that CO2 is more selective towards ethanol, especially at the lowest pressure and highest temperature tested, leading to separation factors in the range 1.6-7.6. The pressure-temperature-composition data obtained were correlated with the Peng-Robinson equation of state and the Mathias-Klotz-Prausnitz mixing rule. The model fit the experimental results well, with an average absolute deviation (AAD) of 3.7 %. The resolution of racemic menthol was studied using two lipases, namely lipase from Candida rugosa (CRL) and immobilized lipase B from Candida antarctica (CALB), and two ionic acylating esters. No reaction was detected in either case. (R,S)-1-phenylethanol was used next, and it was found that with CRL low, nonselective, conversion of the alcohol took place, whereas CALB led to an enantiomeric excess (ee) of the substrate of 95%, at 30% conversion. Other acylating agents were tested for the resolution of (±)-menthol, namely vinyl esters and acid anhydrides, using several lipases and varying other parameters that affect conversion and enantioselectivity, such as substrate concentration, solvent and temperature. One such acylating agent was propionic anhydride. It was thus performed a phase equilibrium study on the propionic anhydride/CO2 system, at temperatures between 35 and 50 oC. This study revealed that, at 35 oC and pressures from 7 MPa, the system is monophasic for all compositions. The enzymatic catalysis studies carried out with propionic anhydride revealed that the extent of noncatalyzed reaction was high, with a negative effect on enantioselectivity. These studies showed also that it was possible to reduce considerably the impact of the noncatalyzed reaction relative to the reaction catalyzed by CRL by lowering temperature to 4 oC. Vinyl decanoate was shown to lead to the best results at conditions amenable to a process combining the use of supercritical CO2 as agent for post-reaction separation. The use of vinyl decanoate in a number of IL solvents, namely [bmim][PF6], [bmim][BF4], [hmim][PF6], [omim][PF6], and [bmim][Tf2N], led to an enantiomeric excess of product (eep) values of over 96%, at about 50% conversion, using CRL. In n-hexane and supercritical CO2, reaction progressed more slowly.(...)

Estudo e caracterização de espécies portuguesas de madeira termicamente modificada.

A modificação térmica tem-se revelado um método eficaz na melhoria da durabilidade de elementos de madeira. Até ao momento, as aplicações da madeira termicamente modificada (MTM) têm sido limitadas a revestimentos já que o tratamento térmico de tratamento conduz a uma redução significativa das resistências mecânicas da madeira. Contudo, este tratamento térmico poderá valorizar e potenciar a utilização de espécies de madeira menos utilizadas na construção, como são o Eucalipto e o Pinho bravo nacional. Com o objetivo de avaliar o efeito do tratamento térmico nas espécies referidas e, complementarmente, na madeira de Faia e Freixo, realizou-se uma campanha experimental composta por ensaios de caracterização mecânica (compressão paralela às fibras e flexão) e de estabilidade dimensional (retração, inchamento e teor de água de equilíbrio (TAE)). Para efeitos de comparação, todos os ensaios envolveram séries de provetes de cada espécie de madeira natural e MTM. Os resultados obtidos são coerentes com a bibliografia disponível, o aumento da estabilidade dimensional, assim como a diminuição do TAE e das propriedades mecânicas de flexão foram verificadas, permitindo, assim, avaliar a influência da modificação térmica nas propriedades de espécies de madeira presentes em Portugal.

Influence of the wood mechanical properties in the dovetail joint behavior

The force distribution inside a dovetail joint is complex. Wood is simultaneously loaded in different directions in the several connected surfaces. The analytical solutions available for the analysis of the behavior of those carpentry joints rely on the mechanical properties of wood. In particular, the stiffness properties of wood under compression are crucial for the forces equilibrium. Simulations showed that the stiffness values considered in each of the springs normally assumed in the analytical models, have great influence in the bearing capacity and stiffness of the dovetail joints, with important consequence on the stress distribution over the overall structure. In a wide experimental campaign, the properties under compression of the most common wood species of existing timber structures have been determined. Then, a solved example of a dovetail joint is presented assuming different wood species and the corresponding strength and stiffness properties values obtained in the tests.

Preliminary observations on the effect of sudden changes of temperature on survival of young Matrinxã (Brycon cephalus) under laboratory conditions

Matrinxã is a very promising amazonian fish for fish culture in Brazil. This study is aimed at determining the approximate tolerated temperature range in this species. Groups of ten young matrinxã specimens (15.1±0.8 cm average length and 58.3±10.3 g average weight) were subjected to 9 different temperatures for 24 hours without previous acclimation. Fish were transferred from an initial temperature of 27ºC to those ranging from 12 to 39ºC at 3ºC intervals. Both 12ºC and 39ºC temperatures were lethal for this species with 100% mortality rate. Following 2 minutes of exposure to 39ºC fish changed behavior, showing an increase in opercular movements and erratic swimming; mortality reached 100% after 18 minutes. At 12ºC, fish lost equilibrium immediately after exposure and started swimming erratically; after only 4 minutes fish became lethargic and remained immobile on the bottom of the tank. Total mortality was only evident following 24 hours. At 15ºC matrinxã lost equilibrium after 5 to 6 minutes of exposure but mortality was only 20% after 24 hours. Fish tolerated well temperatures ranging from 18 to 36ºC with 100% survival after 24 hours. This preliminary study suggests that temperatures between 18 and 36ºC are the approximate range normally tolerated by this species, although survival at other temperatures may be increased by gradually acclimating fish to the more severe increases or decreases in temperature. In addition, it indicates that matrinxã may be cultivated over a wide geographical area.

Entre Tapas e Beijos: estudo sobre a violência doméstica contra a mulher no Estado da Paraíba (Brasil), após a entrada em vigor da Lei Maria da Penha (Lei nº 11.340/2006)

Dissertação de mestrado em Direitos Humanos

Otimização com restrições de complementaridade: algoritmos e aplicações

Tese de Doutoramento em Engenharia Industrial e de Sistemas (PDEIS)

Rényi entropy and the thermodynamic stability of black holes

Thermodynamic stability of black holes, described by the Rényi formula as equilibrium compatible entropy function, is investigated. It is shown that within this approach, asymptotically flat, Schwarzschild black holes can be in stable equilibrium with thermal radiation at a fixed temperature. This implies that the canonical ensemble exists just like in anti-de Sitter space, and nonextensive effects can stabilize the black holes in a very similar way as it is done by the gravitational potential of an anti-de Sitter space. Furthermore, it is also shown that a Hawking–Page-like black hole phase transition occurs at a critical temperature which depends on the q-parameter of the Rényi formula.

Population Dynamics Modeling of Arapaima gigas

Pirarucu (Arapaima gigas) has been of the most important natural fishing resources of the Amazon region. Due to its economic importance, and the necessity to preserve the species hand, field research concerning the habits and behavior of the pirarucu has been increasing for the last 20 years. The aim of this paper is to present a mathematical model for the pirarucu population dynamics considering the species peculiarities, particularly the male parental care over the offspring. The solution of the dynamical systems indicates three possible equilibrium points for the population. The first corresponds to extinction; the third corresponds to a stable population close to the environmental carrying capacity. The second corresponds to an unstable equilibrium located between extinction and full use of the carrying capacity. It is shown that lack of males’ parental care closes the gap between the point corresponding to the unstable equilibrium and the point of stable non-trivial equilibrium. If guarding failure reaches a critical point the two points coincide and the population tends irreversibly to extinction. If some event tends to destabilize the population equilibrium, as for instance inadequate parental care, the model responds in such a way as to restore the trajectory towards the stable equilibrium point avoiding the route to extinction. The parameters introduced to solve the system of equations are partially derived from limited but reliable field data collected at the Mamirauá Sustainable Development Reserve (MSDR) in the Brazilian Amazonian Region.

Removal of Erythrosine B dye from water effluents using crop waste pumpkin seed hulls as adsorbent

Erythrosine B is widely used for coloring in various applications, especially in the food industry, despite its already proved toxicity and carcinogenicity. The agrowaste pumpkin seed hulls were applied as potential adsorbent for the removal of Erythrosine from aqueous solutions. Adsorption mechanism and kinetics were analyzed for design purposes. The seed hulls were characterized by specific techniques before and after dye retention. It was found that the attachment of Erythrosine B molecules on adsorbent surface may be attributed to the interactions between carboxyl and/or carbonyl groups of both dye and agrowaste wall components. A univariate approach followed by a factorial design was applied to study and analyze the experimental results as well as to estimate the combined effects of the process factors on the removal efficiency and dye uptake. Adsorption mechanism may be predominantly due to intraparticle diffusion, dependent on pore size. The four equilibrium models applied fitted the data well; the maximum adsorption capacity for Erythrosine was 16.4 mg/g. The results showed that adsorbent is effective for Erythrosine B removal for a large concentration range in aqueous solutions (5400 mg/L) in batch systems.

Outcrossing rate of Couratari multiflora (J.Smith) Eyma (Lecythidaceae), a low-density tropical tree species from a central Amazonian rainforest

A multilocus mixed-mating model was used to evaluate the mating system of a population of Couratari multiflora, an emergent tree species found in low densities (1 individual/10 ha) in lowland forests of central Amazonia. We surveyed and observed phenologically 41 trees in an area of 400 ha. From these, only four mother trees were analyzed here because few of them set fruits, which also suffered high predation. No difference was observed between the population multilocus outcrossing rate (t mp = 0.953 ± 0.040) and the average single locus rate (t sp = 0.968 ± 0.132). The four mother trees were highly outcrossed (t m ~ 1). Two out of five loci showed departures from the Hardy-Weinberg Equilibrium (HWE) expectations, and the same results occurred with the mixed-mating model. Besides the low number of trees analyzed, the proportion of loci in HWE suggests random mating in the population. However, the pollen pool was heterogeneous among families, probably due to both the small sample number and the flowering of trees at different times of the flowering season. Reproductive phenology of the population and the results presented here suggest, at least for part of the population, a long-distance pollen movement, around 1,000 m.