Prices of medicines: a case-study on the impact of the rate-of-return regulation in the United Kingdom

This work carries out an empirical evaluation of the impact of the main mechanism for regulating the prices of medicines in the UK on a variety ofpharmaceutical price indices. The empirical evidence shows that the overall impact of the rate of return cap appears to have been slight or even null, and in any case that the impact would differ across therapeutic areas. These empiricalfindings suggest that the price regulation has managed to encourage UK-based firms¿ diversification in many therapeutic areas

High prevalence and lineage diversity of avian malaria in wild populations of great tits (Parus major) and mosquitoes (Culex pipiens).

Avian malaria studies have taken a prominent place in different aspects of evolutionary ecology. Despite a recent interest in the role of vectors within the complex interaction system of the malaria parasite, they have largely been ignored in most epidemiological studies. Epidemiology of the disease is however strongly related to the vector's ecology and behaviour, and there is a need for basic investigations to obtain a better picture of the natural associations between Plasmodium lineages, vector species and bird hosts. The aim of the present study was to identify the mosquito species involved in the transmission of the haemosporidian parasites Plasmodium spp. in two wild populations of breeding great tits (Parus major) in western Switzerland. Additionally, we compared Plasmodium lineages, based on mitochondrial DNA cytochrome b sequences, between the vertebrate and dipteran hosts, and evaluated the prevalence of the parasite in the mosquito populations. Plasmodium spp. were detected in Culex pipiens only, with an overall 6.6% prevalence. Among the six cytochrome b lineages of Plasmodium identified in the mosquitoes, three were also present in great tits. The results provide evidence for the first time that C. pipiens can act as a natural vector of avian malaria in Europe and yield baseline data for future research on the epidemiology of avian malaria in European countries.

Subplate subpopulations in the hypoxic-ischemic neonatal rat brain

Subplate neurons are among the earliest born cells of the neocortex and play a fundamental role in cortical development, in particular in the formation of thalamocortical connections. Subplate abnormalities have been described in several neuropathological disorders including schizophrenia, autism and periventricular eukomalacia (Eastwood and Harrison, Schizophr Res, 79, 2005; McQuillen and Ferriero, Brain Pathol, 15, 2005). We have identified and confirmed a range of specific markers for murine subplate using a microarray based approach and found that different subplate subpopulations are characterized by distinct expression patterns of these genes (Hoerder-Suabedissen et al., Cereb Cortex, 19, 2009). In this current study, we are making use of these markers to investigate neuropathological changes of the subplate after cerebral hypoxia-ischemia (HI) in the neonatal rat. First, we characterized the expression of a number of murine subplate markers in the postnatal rat using immunohistochemistry and in situ hybridization. While several genes (Nurr1, Cplx3, Ctgf and Tmem163) presented very similar expression patterns as in the mouse, others (Ddc, MoxD1 and TRH) were completely absent in the rat cortex. This finding suggests important differences in the subplate populations of these two rodent species. In a neonatal rat model of HI, selective vulnerability of subplate has been suggested using BrdU birthdating methods (McQuillen et al., J Neurosci, 15, 2003). We hypothesized that certain subplate subpopulations could be more susceptible than others and analyzed the above subplate markers in a similar yet slightly milder HI model. Two-day old male rat pups underwent permanent occlusion of the right common carotid artery followed by a period of hypoxia (6% O2, 1.5h or 2h) and were analyzed six days later. Preliminary counts on three subplate subpopulations (Nurr1+, Cplx3+ and Ctgf+ cells, respectively) showed similar reductions in cell numbers for all three groups. In addition, we found that the majority of cases which show changes in the subplate also exhibit lesions in the deep cortical layers VI (identified by FoxP2 expression) and sometimes even layer V (revealed by Er81 immunoreactivity), which questions the selective susceptibility of subplate over other cortical layers under the conditions we used in our model. Supported by MRC, FMO holds a Berrow Scholarship, Lincoln College, Oxford.

Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer.

The recognition that colorectal cancer (CRC) is a heterogeneous disease in terms of clinical behaviour and response to therapy translates into an urgent need for robust molecular disease subclassifiers that can explain this heterogeneity beyond current parameters (MSI, KRAS, BRAF). Attempts to fill this gap are emerging. The Cancer Genome Atlas (TGCA) reported two main CRC groups, based on the incidence and spectrum of mutated genes, and another paper reported an EMT expression signature defined subgroup. We performed a prior free analysis of CRC heterogeneity on 1113 CRC gene expression profiles and confronted our findings to established molecular determinants and clinical, histopathological and survival data. Unsupervised clustering based on gene modules allowed us to distinguish at least five different gene expression CRC subtypes, which we call surface crypt-like, lower crypt-like, CIMP-H-like, mesenchymal and mixed. A gene set enrichment analysis combined with literature search of gene module members identified distinct biological motifs in different subtypes. The subtypes, which were not derived based on outcome, nonetheless showed differences in prognosis. Known gene copy number variations and mutations in key cancer-associated genes differed between subtypes, but the subtypes provided molecular information beyond that contained in these variables. Morphological features significantly differed between subtypes. The objective existence of the subtypes and their clinical and molecular characteristics were validated in an independent set of 720 CRC expression profiles. Our subtypes provide a novel perspective on the heterogeneity of CRC. The proposed subtypes should be further explored retrospectively on existing clinical trial datasets and, when sufficiently robust, be prospectively assessed for clinical relevance in terms of prognosis and treatment response predictive capacity. Original microarray data were uploaded to the ArrayExpress database (http://www.ebi.ac.uk/arrayexpress/) under Accession Nos E-MTAB-990 and E-MTAB-1026. © 2013 Swiss Institute of Bioinformatics. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Regulation of Electricity Transmission and Distribution in Russia

The regulation of electricity transmission and distribution business is an essential issue for any electricity market; it is widely introduced in developed electricity markets of Great Britain, Scandinavian countries and United States of America and other. Those markets which were liberalized recently also need well planned regulation model to be chosen and implemented. In open electricity markets the sectors of electricity distribution and transmission remain monopolies, so called "natural monopolies", as introducing the competition into these sectors in most cases appears to be inefficient. Thatis why regulation becomes very important as its main tasks are: to set reasonable tariffs for customers, to ensure non-discriminating process of electricity transmission and distribution, at the same time to provide distribution companies with incentives to operate efficiently and the owners of the companies with reasonable profits as well; the problem of power quality should be solved at the same time. It should be mentioned also, that there is no incentive scheme which will be suitable for any conditions, that is why it is essential to study differentregulation models in order to form the best one for concrete situation. The aim of this Master's Thesis is to give an overview over theregulation of electricity transmission and distribution in Russia. First, the general information about theory of regulation of natural monopolies will be described; the situation in Russian network business and the importance of regulation process for it will be discussed next. Then there is a detailed description ofexisting regulatory system and the process of tariff calculation with an example. And finally, in the work there is a brief analysis of problems of present scheme of regulation, an attempt to predict the following development of regulationin Russia and the perspectives and risks connected to regulation which could face the companies that try to enter Russian electricity market (such as FORTUM OY).

PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification.

PURPOSE: To improve the risk stratification of patients with rhabdomyosarcoma (RMS) through the use of clinical and molecular biologic data. PATIENTS AND METHODS: Two independent data sets of gene-expression profiling for 124 and 101 patients with RMS were used to derive prognostic gene signatures by using a meta-analysis. These and a previously published metagene signature were evaluated by using cross validation analyses. A combined clinical and molecular risk-stratification scheme that incorporated the PAX3/FOXO1 fusion gene status was derived from 287 patients with RMS and evaluated. RESULTS: We showed that our prognostic gene-expression signature and the one previously published performed well with reproducible and significant effects. However, their effect was reduced when cross validated or tested in independent data and did not add new prognostic information over the fusion gene status, which is simpler to assay. Among nonmetastatic patients, patients who were PAX3/FOXO1 positive had a significantly poorer outcome compared with both alveolar-negative and PAX7/FOXO1-positive patients. Furthermore, a new clinicomolecular risk score that incorporated fusion gene status (negative and PAX3/FOXO1 and PAX7/FOXO1 positive), Intergroup Rhabdomyosarcoma Study TNM stage, and age showed a significant increase in performance over the current risk-stratification scheme. CONCLUSION: Gene signatures can improve current stratification of patients with RMS but will require complex assays to be developed and extensive validation before clinical application. A significant majority of their prognostic value was encapsulated by the fusion gene status. A continuous risk score derived from the combination of clinical parameters with the presence or absence of PAX3/FOXO1 represents a robust approach to improving current risk-adapted therapy for RMS.

The First World War and Coal Trade Geography in Latin America and the Caribbean, 1890-1930

This paper aims to illustrate the dynamics of coal trade between Latin America and its main trade partners, i.e., the USA, Great Britain, and Germany, before and after the enormous disruption caused by the First World War. The coal trade was used as an indicator of modernization for Latin American countries, given that oil was at that time of secondary importance. Energy imports have determined the possibilities of each Latin American country in its process of development. Here, we address this question and place special emphasis on supply channels, concluding that the trade link with main suppliers was of key significance. Although this was very clear by the end of the period, the process had started well before the First World War, at least for the majority of LA&C countries. These points are developed through a gravity model applied to the bilateral coal trade. The importance of the market supplier share is addressed through cluster methodologies.

Copy number variations and cognitive phenotypes in unselected populations

IMPORTANCE: The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. OBJECTIVE: To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency ≤0.05%; size ≥250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS: The population biobank of Estonia contains 52,000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURES: Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTS: Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE: Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.

Generation and interconnection capacity expansion in cross-border electricity markets : the need for policy coordination

Electricity is a strategic service in modern societies. Thus, it is extremely important for governments to be able to guarantee an affordable and reliable supply, which depends to a great extent on an adequate expansion of the generation and transmission capacities. Cross- border integration of electricity markets creates new challenges for the regulators, since the evolution of the market is now influenced by the characteristics and policies of neighbouring countries. There is still no agreement on why and how regions should integrate their electricity markets. The aim of this thesis is to improve the understanding of integrated electricity markets and how their behaviour depends on the prevailing characteristics of the national markets and the policies implemented in each country. We developed a simulation model to analyse under what circumstances integration is desirable. This model is used to study three cases of interconnection between two countries. Several policies regarding interconnection expansion and operation, combined with different generation capacity adequacy mechanisms, are evaluated. The thesis is composed of three papers. The first paper presents a detailed description of the model and an analysis of the case of Colombia and Ecuador. It shows that market coupling can bring important benefits, but the relative size of the countries can lead to import dependency issues in the smaller country. The second paper compares the case of Colombia and Ecuador with the case of Great Britain and France. These countries are significantly different in terms of electricity sources, hydro- storage capacity, complementarity and demand growth. We show that complementarity is essential in order to obtain benefits from integration, while higher demand growth and hydro- storage capacity can lead to counterintuitive outcomes, thus complicating policy design. In the third paper, an extended version of the model presented in the first paper is used to analyse the case of Finland and its interconnection with Russia. Different trading arrangements are considered. We conclude that unless interconnection capacity is expanded, the current trading arrangement, where a single trader owns the transmission rights and limits the flow during peak hours, is beneficial for Finland. In case of interconnection expansion, market coupling would be preferable. We also show that the costs of maintaining a strategic reserve in Finland are justified in order to limit import dependency, while still reaping the benefits of interconnection. In general, we conclude that electricity market integration can bring benefits if the right policies are implemented. However, a large interconnection capacity is only desirable if the countries exhibit significant complementarity and trust each other. The outcomes of policies aimed at guaranteeing security of supply at a national level can be quite counterintuitive due to the interactions between neighbouring countries and their effects on interconnection and generation investments. Thus, it is important for regulators to understand these interactions and coordinate their decisions in order to take advantage of the interconnection without putting security of supply at risk. But it must be taken into account that even when integration brings benefits to the region, some market participants lose and might try to hinder the integration process. -- Dans les sociétés modernes, l'électricité est un service stratégique. Il est donc extrêmement important pour les gouvernements de pouvoir garantir la sécurité d'approvisionnement à des prix abordables. Ceci dépend en grande mesure d'une expansion adéquate des capacités de génération et de transmission. L'intégration des marchés électriques pose des nouveaux défis pour les régulateurs, puisque l'évolution du marché est maintenant influencée par les caractéristiques et les politiques des pays voisins. Il n'est pas encore claire pourquoi ni comment les marches électriques devraient s'intégrer. L'objectif de cette thèse est d'améliorer la compréhension des marchés intégrés d'électricité et de leur comportement en fonction des caractéristiques et politiques de chaque pays. Un modèle de simulation est proposé pour étudier les conditions dans lesquelles l'intégration est désirable. Ce modèle est utilisé pour étudier trois cas d'interconnexion entre deux pays. Plusieurs politiques concernant l'expansion et l'opération de l'interconnexion, combinées avec différents mécanismes de rémunération de la capacité, sont évalués. Cette thèse est compose de trois articles. Le premier présente une description détaillée du modèle et une analyse du cas de la Colombie et de l'Equateur. Il montre que le couplage de marchés peut amener des bénéfices importants ; cependant, la différence de taille entre pays peut créer des soucis de dépendance aux importations pour le pays le plus petit. Le second papier compare le cas de la Colombie et l'Equateur avec le cas de la Grande Bretagne et de la France. Ces pays sont très différents en termes de ressources, taille des réservoirs d'accumulation pour l'hydro, complémentarité et croissance de la demande. Nos résultats montrent que la complémentarité joue un rôle essentiel dans l'obtention des bénéfices potentiels de l'intégration, alors qu'un taux élevé de croissance de la demande, ainsi qu'une grande capacité de stockage, mènent à des résultats contre-intuitifs, ce qui complique les décisions des régulateurs. Dans le troisième article, une extension du modèle présenté dans le premier article est utilisée pour analyser le cas de la Finlande et de la Russie. Différentes règles pour les échanges internationaux d'électricité sont considérées. Nos résultats indiquent qu'à un faible niveau d'interconnexion, la situation actuelle, où un marchand unique possède les droits de transmission et limite le flux pendant les heures de pointe, est bénéfique pour la Finlande. Cependant, en cas d'expansion de la capacité d'interconnexion, «market coupling» est préférable. préférable. Dans tous les cas, la Finlande a intérêt à garder une réserve stratégique, car même si cette politique entraine des coûts, elle lui permet de profiter des avantages de l'intégration tout en limitant ca dépendance envers les importations. En général, nous concluons que si les politiques adéquates sont implémentées, l'intégration des marchés électriques peut amener des bénéfices. Cependant, une grande capacité d'interconnexion n'est désirable que si les pays ont une complémentarité importante et il existe une confiance mutuelle. Les résultats des politiques qui cherchent à préserver la sécurité d'approvisionnement au niveau national peuvent être très contre-intuitifs, étant données les interactions entre les pays voisins et leurs effets sur les investissements en génération et en interconnexion. Il est donc très important pour les régulateurs de comprendre ces interactions et de coordonner décisions à fin de pouvoir profiter de l'interconnexion sans mettre en danger la sécurité d'approvisionnement. Mais il faut être conscients que même quand l'intégration amène de bénéfices pour la région, certains participants au marché sont perdants et pourraient essayer de bloquer le processus d'intégration.

The Role of Trade in the Structural Transformations of South Korea and the United Kingdom

[cat] El comerç internacional en béns agrícoles té el potencial d'accelerar la transformació estructural dels països amb baixa productivitat agrícola perquè els dóna la possiblitat d'importar aliments. L'objectiu d'aquest article és estudiar l'importància del comerç internacional en aquest context a través dels exemples de Corea del Sud i el Regne Unit. Per fer l'anàlisi, introdueixo comerç internacional en un model de creixement neoclàssicc amb dos sectors, agricultura i no-agricultura. Una característica clau del model és la baixa elasticitat-ingrés del bé agrícola.

The Role of Trade in the Structural Transformations of South Korea and the United Kingdom

[cat] El comerç internacional en béns agrícoles té el potencial d'accelerar la transformació estructural dels països amb baixa productivitat agrícola perquè els dóna la possiblitat d'importar aliments. L'objectiu d'aquest article és estudiar l'importància del comerç internacional en aquest context a través dels exemples de Corea del Sud i el Regne Unit. Per fer l'anàlisi, introdueixo comerç internacional en un model de creixement neoclàssicc amb dos sectors, agricultura i no-agricultura. Una característica clau del model és la baixa elasticitat-ingrés del bé agrícola.

Cultural Diversity, Social Cohesion, Religion: Core Values and Educational Policies in Four European Nations

In my doctoral thesis I evaluate strategies designed to cope with the multicultural nature of four European nations: Great Britain, The Netherlands, Sweden, and Denmark. I also analyse and clarify the question of the place of religion in present-day Europe. The empirical material analysed in the study consists of politicians’ statements and policy documents dealing with immigration policy and religious and values education in the four countries. In addition, I analyse statements issued by the Council of Europe regarding religious education, along with all cases relevant to religious education brought before the United Nations Human Rights Committee or the European Court of Human Rights. The theoretical framework is formed by the scholarly debate – among philosophers, sociologists and scholars of religion in education – concerning the question of a just society. Special emphasis is given to philosophical theories that are in favour of granting special group rights to religious minorities in the name of equal treatment. With regard to the question of the appropriate place of religion, I apply Kim Knott’s methodological model for locating religion in secular contexts, and Émile Durkheim’s theory as to the significance of religion and collective sentiments in uniting adherents or members of a group into a single moral community. The study shows that even when the positive side of immigration, as a potential force for the enrichment of the public culture, is acknowledged, there is anxiety as to the successful integration of immigrants. The premises and goals of immigration policies have also been questioned. One central problem is the incommensurability between the values upheld by Western liberal democracies and certain religious traditions, above all those of Islam. Great Britain, The Netherlands, Sweden, and Denmark have tightened control over their citizens’ ethical attitudes and want to regulate these as well. In coping with cultural diversity, the significance of education, especially religious education, plays a significant role; as future citizens, pupils are expected to internalise the society’s core values as well as gaining an understanding of different cultures and ways of life. It is also worth noting that both the Council of Europe and the European Court of Human Rights have recently expressed the view that one important goal of religious education is to enable pupils to be critical and autonomous with regard to different religions and moral positions. The study shows that religion is not seen as purely a personal matter. Religion is closely linked to individual and national identity, and religious traditions thus have a place in the public domain. It should be noted, however, that a religious tradition – more precisely, an interpretation of religious tradition – qualifies as a legitimate partner in the democratic decision-making process only if it shares similar values with Western European nations.

A compressed view of the points to be discussed, in treating with the United States of America : with an appendix /

Appendix: On the conduct of the government of United States towards the Indian tribes: p.[129]-139.