Superiority of the Triple Combination of Bortezomib-Thalidomide-Dexamethasone Over the Dual Combination of Thalidomide-Dexamethasone in Patients With Multiple Myeloma Progressing or Relapsing After Autologous Transplantation: The MMVAR/IFM 2005-04 Randomized Phase III Trial From the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

PURPOSE This prospective multicenter phase III study compared the efficacy and safety of a triple combination (bortezomib-thalidomide-dexamethasone [VTD]) versus a dual combination (thalidomide-dexamethasone [TD]) in patients with multiple myeloma (MM) progressing or relapsing after autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS Overall, 269 patients were randomly assigned to receive bortezomib (1.3 mg/m(2) intravenous bolus) or no bortezomib for 1 year, in combination with thalidomide (200 mg per day orally) and dexamethasone (40 mg orally once a day on 4 days once every 3 weeks). Bortezomib was administered on days 1, 4, 8, and 11 with a 10-day rest period (day 12 to day 21) for eight cycles (6 months), and then on days 1, 8, 15, and 22 with a 20-day rest period (day 23 to day 42) for four cycles (6 months). Results Median time to progression (primary end point) was significantly longer with VTD than TD (19.5 v 13.8 months; hazard ratio, 0.59; 95% CI, 0.44 to 0.80; P = .001), the complete response plus near-complete response rate was higher (45% v 25%; P = .001), and the median duration of response was longer (17.2 v 13.4 months; P = .03). The 24-month survival rate was in favor of VTD (71% v 65%; P = .093). Grade 3 peripheral neuropathy was more frequent with VTD (29% v 12%; P = .001) as were the rates of grades 3 and 4 infection and thrombocytopenia. CONCLUSION VTD was more effective than TD in the treatment of patients with MM with progressive or relapsing disease post-ASCT but was associated with a higher incidence of grade 3 neurotoxicity.

Two different epidemiological scenarios of border disease in the populations of Pyrenean chamois (Rupicapra p. pyrenaica) after the first disease outbreaks

Since 2001 several outbreaks of a new disease associated with Border disease virus (BDV) infection have caused important declines in Pyrenean chamois (Rupicapra pyrenaica) populations in the Pyrenees. The goal of this study was to analyze the post-outbreak BDV epidemiology in the first two areas affected by disease with the aim to establish if the infection has become endemic. We also investigated if BDV infected wild and domestic ruminants sharing habitat with chamois. Unexpectedly, we found different epidemiological scenarios in each population. Since the disease outbreaks, some chamois populations recuperated quickly, while others did not recover as expected. In chamois from the first areas, prevalence was high (73.47%) and constant throughout the whole study period and did not differ between chamois born before and after the BDV outbreak; in all, BDV was detected by RT-PCR in six chamois. In the other areas, prevalence was lower (52.79%) and decreased during the study period; as well, prevalence was significantly lower in chamois born after the disease outbreak. No BDV were detected in this population. A comparative virus neutralisation test performed with four BDV strains and one Bovine viral diarrhoea virus (BVDV) strain showed that all the chamois had BDV-specific antibodies. Pestivirus antibodies were detected in all the rest of analyzed species, with low prevalence values in wild ruminants and moderate values in domestic ruminants. No viruses were detected in these species. These results confirm the hypothesis that outbreaks of BDV infection only affect the Pyrenean chamois, although other wild ruminants can occasionally be infected. In conclusion, two different scenarios have appeared since the first border disease outbreaks in Pyrenean chamois: on the one hand frequent BDV circulation with possible negative impact on population dynamics in some areas and on the other, lack of virus circulation and quick recovery of the chamois population.

The border of reproductive control: undocumented immigration as a risk factor for unintended pregnancy in Switzerland.

Unintended pregnancies reflect an unmet need for family planning, and are part of health disparities. Using the only database to inquire about pregnancy intention among women in Switzerland, this study examined the relationship between immigrant documentation and unintended pregnancy (UP). Among pregnant women presenting to a Swiss hospital, we compared pregnancy intention between documented and undocumented women. We used logistic regression to examine whether undocumented status was associated with UP after adjusting for other significant predictors. Undocumented women had more unintended pregnancies (75.2 vs. 20.6 %, p = 0.00). Undocumented status was associated with UP after adjustment (OR 6.23, 95 % CI 1.83-21.2), as was a history of psychological problems (OR 4.09, 95 % CI 1.32-12.7). Contraception non-use was notably associated with lower odds of UP (OR 0.01, 95 % CI 0.004-0.04). Undocumented status was significantly associated with UP, even after adjusting for well-recognized risk factors. This highlights the tremendous risk of undocumented status on UP among women in Switzerland.

Delivery of European Cross-Border Health Care and the Relevance and Effects of EU Regulations and Judicial Processes with Reference to Delivery of Drugs and Blood Donor Information Material.

Valtion rajat ylittävät terveyspalvelut Euroopan unionissa sekä Euroopan unionin säädösten merkitys ja vaikutus erityisesti lääkejakeluun ja verenluovuttajille jaettavaan tiedotusaineistoon Valtion rajat ylittävä terveydenhuolto on suuren kiinnostuksen kohteena Euroopan unionissa. Resurssien hyödyntäminen parhaalla mahdollisella tavalla ja tiedon keskittäminen ovat tarpeen terveydenhuollon kustannusten alati noustessa. Terveydenhuoltopalvelut kuuluvat Euroopan sisämarkkinoiden vapaan liikkuvuuden piiriin. Euroopan unionilla ei ole kuitenkaan toimivaltaa säädellä terveydenhuoltojärjestelmiä, vaan sen mahdollisuudet ovat enimmäkseen kansanterveyden edistämisessä ja suojelussa, myös muilla toimialueilla kuin terveydenhuollossa. Tutkimuksen tavoitteena oli tutkia Euroopan unionin säädösten vaikutusta terveydenhuoltosektoriin, erityisesti valtion rajat ylittäviin terveydenhuoltopalveluihin. Erityiskohteena olivat lääkemääräyksen toimittaminen toisen Euroopan unionin jäsenmaan apteekista, resepti-lääkkeiden maahantuonti omaan henkilökohtaiseen käyttöön, sähköisen lääkemääräyksen käyttö kansallisesti ja mahdollisuudet sen käyttöön eri jäsenmaiden välillä, online-apteekkien soveltuvuus Euroopan unionin sisämarkkinoille sekä verenluovuttajille jaettavan tiedotusaineiston yhtenäistämistarve Euroopan unionin alueella. Tutkimuksen osa-alueiden aineisto koottiin vuosina 1999–2003, jolloin Euroopan unioniin kuului 15 jäsenmaata. Apteekit toimittivat useimmiten myös ei-kansalliset, toisessa Euroopan unionin jäsenmaassa annetut lääkemääräykset. Kaikki jäsenmaat rajoittivat lääkemääräyksen vaativien lääkkeiden maahantuontia. Rajoituksia oli maahantuontimäärissä ja -tavoissa. Lisäksi sairasvakuutuskorvausten saaminen ulkomailla lunastetuista reseptilääkkeistä oli hankalaa. Sähköiset lääkemääräykset olivat käytössä vain kahdessa maassa, mutta useissa maissa suunniteltiin niiden kokeilua. Standardit ja käyttöjärjestelmät olivat erilaisia eri maissa. Euroopan unionin alueelle on perustettu online-apteekkeja, joiden toiminta on kuitenkin vaatimatonta. Verenluovuttajille annettava tiedotusaineisto ei missään maassa täyttänyt veridirektiivin vaatimuksia. Tutkimuksen tulokset osoittivat kansallisten käytäntöjen eroavaisuuksien rajoittavan valtion rajat ylittäviä terveydenhuoltopalveluita. Vaikka Euroopan unionin tavoitteena ei ole yhtenäistää terveydenhuoltojärjestelmiä, on tarpeen arvioida uudelleen unionin ja jäsenmaiden välistä työnjakoa. Kansalliset terveydenhuoltojärjestelmät eivät ole erillään Euroopan sisämarkkinoista, jotka merkittävästi vaikuttavat terveydenhuoltoon.

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.

Cross-Border Place Branding : The Case of Geneva Highlighting Multidimensionality of Places and the Potential Role of Politico-Institutional Aspects

Place branding is not a new phenomenon. The emphasis placed on place branding has recently become particularly strong and explicit to both practitioners and scholars, in the current context of a growing mobility of capital and people. On the one hand, there is a need for practitioners to better understand place brands and better implement place branding strategies. In this respect, this domain of study can be currently seen as 'practitioner led', and in this regard many contributions assess specific cases in order to find success factors and best practices for place branding. On the other hand, at a more analytical level, recent studies show the complexity of the concept of place branding and argue that place branding works as a process including various stakeholders, in which culture and identity play a crucial role. In the literature, tourists, companies and residents represent the main target groups of place branding. The issues regarding tourists and companies have been examined since long by place promoters, location branders, economists or other scholars. However, the analysis of residents' role in place branding has been overlooked until recently and represents a new interest for researchers. The present research aims to further develop the concept of place branding, both theoretically and empirically. First of all, the paper presents a theoretical overview of place branding, from general basic questions (definition of place, brand and place brand) to specific current debates of the literature. Subsequently, the empirical part consists in a case study of the Grand Genève (Great Geneva).

Cross-border post-acquisition integration performed by a Nordic information & telecommunication technology company in the transition economy context of the Czech Republic

Diplomityön tarkoituksena oli arvioida akvisition jälkeistä integraatioprosessia. Integraation tarkoitus on mukauttaa ostettu yritys toimivaksi osaksi konsernia. Työn empiirisenä ongelmana oli yleisesti tunnustettu integraatiojohtamisen kompleksisuus. Samoin myöskin akateemisesta kirjallisuudesta puuttui koherentti malli, jolla arvioida integraatiota. Tutkimuskohteena oli akvisitio, jossa suomalainen tietotekniikkan suuryritys osti osake-enemmistön tsekkiläisestä keskisuuresta ohjelmistoyrityksestä. Tutkimuksessa generoitiin integraatiojohtamisen malli tietopohjaiseen organisaatioon. Mallin mukaan integraatio koostuu kolmesta eriävästä, mutta toisiaan tukevasta alueesta: organisaatiokulttuurin yhdentyminen, tietopääoman tasaaminen ja konsernin sisäisten prosessien yhdenmukaistaminen. Näistä kaksi kaksi jälkimmäistä ovat johdettavissa, mutta kulttuurin yhdentymiseen integraatiojohtamisella voidaan vaikuttaa vain katalysoivasti. Organisaatiokulttuuri levittäytyy vain osallisten vuorovaikuksien kautta. Lisäksi tutkimus osoitti, miten akvisitio on revolutionaarinen vaihe yrityksen kehityksessä. Integraation ensimmäinen ajanjakso on revolutionaarista. Tällöin suurimmat ja näkyvimmät johdettavat muutokset pyritään saamaan aikaan, jotta integraatiossa edettäisiin evolutionaariseen kehitykseen. Revolutionaarisen intergaation vetojuhtana toimii integraatiojohto, kun taas evolutionaarinen integraatio etenee osallisten (organisaation jäsenten) itsensä toiminnan ja vuorovaikutusten kautta.

Prevalence of Acute Coronary Syndrome in Patients Suspected for Pulmonary Embolism or Acute Aortic Syndrome: Rationale for the Triple Rule-out Concept.

BACKGROUND: The aims of the study were to evaluate the prevalence of acute coronary syndrome (ACS) among patients presenting with atypical chest pain who are evaluated for acute aortic syndrome (AAS) or pulmonary embolism (PE) with computed tomoangiography (CTA) and discuss the rationale for the use of triple rule-out (TRO) protocol for triaging these patients. METHODS: This study is a retrospective analysis of patients presenting with atypical chest pain and evaluated with thoracic (CTA), for suspicion of AAS/PE. Two physicians reviewed patient files for demographic characteristics, initial CT and final clinical diagnosis. Patients were classified according to CTA finding into AAS, PE and other diagnoses and according to final clinical diagnosis into AAS, PE, ACS and other diagnoses. RESULTS: Four hundred and sixty-seven patients were evaluated: 396 (84.8%) patients for clinical suspicion of PE and 71 (15.2%) patients for suspicion of AAS. The prevalence of ACS and AAS was low among the PE patients: 5.5% and 0.5% respectively (P = 0.0001), while the prevalence of ACS and PE was 18.3% and 5.6% among AAS patients (P = 0.14 and P = 0.34 respectively). CONCLUSION: The prevalence of ACS and AAS among patients suspected clinically of having PE is limited while the prevalence of ACS and PE among patients suspected clinically of having AAS is significant. Accordingly patients suspected for PE could be evaluated with dedicated PE CTA while those suspected for AAS should still be triaged using TRO protocol.

A Lead-In with Silibinin Prior to Triple-Therapy Translates into Favorable Treatment Outcomes in Difficult-To-Treat HIV/Hepatitis C Coinfected Patients.

BACKGROUND: The efficacy of first-generation protease inhibitor based triple-therapy against hepatitis C virus (HCV) infection is limited in HIV/HCV-coinfected patients with advanced liver fibrosis and non-response to previous peginterferon-ribavirin. These patients have a low chance of achieving a sustained virologic response (SVR) using first generation triple-therapy, with a success rate of only 20%. We investigated the efficacy and safety of lead-in therapy with intravenous silibinin followed by triple-therapy in this difficult-to-treat patient group. METHODOLOGY: Inclusion criteria were HIV/HCV coinfection with advanced liver fibrosis and documented previous treatment failure on peginterferon-ribavirin. The intervention was a lead-in therapy with intravenous silibinin 20 mg/kg/day for 14 days, followed by triple-therapy (peginterferon-ribavirin and telaprevir) for 12 weeks, and peginterferon-ribavirin alone for 36 weeks. Outcome measurements were HCV-RNA after silibinin lead-in and during triple-therapy, SVR data at week 12, and safety and tolerability of silibinin. RESULTS: We examined sixteen HIV/HCV-coinfected patients with previous peginterferon-ribavirin failure, of whom 14 had a fibrosis grade METAVIR ≥F3. All were on successful antiretroviral therapy. Median (IQR) HCV-RNA decline after silibinin therapy was 2.65 (2.1-2.8) log10 copies/mL. Fifteen of sixteen patients (94%) had undetectable HCV RNA at weeks 4 and 12, eleven patients (69%) showed end-of-treatment response (i.e., undetectable HCV-RNA at week 48), and ten patients (63%) reached SVR at week 12 (SVR 12). Six of the sixteen patients (37%) did not reach SVR 12: One patient had rapid virologic response (RVR) (i.e., undetectable HCV-RNA at week 4) but stopped treatment at week 8 due to major depression. Five patients had RVR, but experienced viral breakthroughs at week 21, 22, 25, or 32, or a relapse at week 52. The HIV RNA remained below the limit of detection in all patients during the complete treatment period. No serious adverse events and no significant drug-drug interactions were associated with silibinin. CONCLUSION: A lead-in with silibinin before triple-therapy was safe and highly effective in difficult-to-treat HIV/HCV coinfected patients, with a pronounced HCV-RNA decline during the lead-in phase, which translates into 63% SVR. An add-on of intravenous silibinin to standard of care HCV treatment is worth further exploration in selected difficult-to-treat patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01816490.

A prospective, randomized, triple-blind comparison of articaine and bupivacaine for maxillary infiltrations

Objectives: To compare the clinical anesthetic efficacy of 0.5% bupivacaine and 4% articaine (both with 1:200.000 adrenaline) for anterior maxillary infiltration in healthy volunteers. Material and methods: A triple-blind split-mouth randomized clinical trial was carried out in 20 volunteers. A supraperiosteal buccal injection of 0.9 ml of either solution at the apex of the lateral incisor was done in 2 appointments separated 2 weeks apart. The following outcome variables were measured: latency time, anesthetic efficacy (dental pulp, keratinized gingiva, alveolar mucosa and upper lip mucosa and tissue) and the duration of anesthetic effect. Hemodynamic parameters were monitored during the procedure. Results: Latency time recorded was similar for both anesthetic solutions (p>0.05). No statistically significant differences were found in terms of anesthetic efficacy for dental pulp, keratinized gingiva or alveolar mucosa. Articaine had a significant higher proportion of successful anesthesia at 10 minutes after infiltration in lip mucosa and lip skin (p=0.039). The duration of anesthesia was 336 minutes for bupivacaine and 167 minutes for articaine. (p<0.001). No significant hemodynamic alterations were noted during the procedure. Conclusions: Articaine and bupivacaine exhibited similar anesthetic efficacy for maxillary infiltrations. The duration of anesthesia was longer with the bupivacaine solution, but lip anesthesia was better with articaine