O albendazol (ABZ) é um antiparasitário amplamente utilizado na medicina veterinária para tratar infecções causadas por parasitas helmínticos, devido ao seu baixo custo de aquisição, alta eficácia e facilidade de administração. Apesar, de sua eficácia ser mundialmente conhecida, seu uso não é regulamentado em espécies aquícolas. Diante da demanda nacional por uma maior variedade de medicamentos veterinários regulamentados para uso na aquicultura, o presente projeto visou estimar o período de carência para o ABZ. Para tanto, foi necessário: (i) incorporar o ABZ na ração através da técnica de revestimento polimérico em equipamento de leito fluidizado; (ii) desenvolver e avaliar os métodos analíticos para a determinação do ABZ na ração e do ABZ e seus metabólitos em filé de pacu empregando cromatografia líquida de alta eficiência acoplada à espectrometria de massas (LC-MS/MS) e (iii) realizar um ensaio com pacu para avaliar a depleção do ABZ e seus metabólitos no filé desses peixes. O revestimento da ração com 1,5% de etilcelulose permitiu incorporar o ABZ na ração sem alterar a estrutura física da mesma, o que torna o processo vantajoso, visto que, a ração mantém suas características de flutuabilidade. Além disso, o processo foi homogêneo e diminuiu a lixiviação do fármaco para a água, garantindo a segurança da dose administrada e do meio ambiente. O ABZ foi isolado da ração por extração líquido-líquido. O ABZ e seus metabólitos foram extraídos do filé de pacu pelo método de QuEChERS modificado. Para os dois métodos desenvolvidos, a separação cromatográfica foi realizada em coluna de fase reversa octadecil híbrida. Os métodos foram avaliados mediante os seguintes parâmetros: seletividade, curva analítica, linearidade, precisão e exatidão. Para o método do filé de peixe avaliou-se também o CC? e o CC?. Todos os parâmetros avaliados se encontram de acordo com os guias de validação, o que torna os métodos adequados para os objetivos propostos no presente trabalho. Para avaliar a depleção do ABZ e seus metabólitos no filé de pacu, os peixes receberam o fármaco via ração em dose única de 10 mg de ABZ (kg peso vivo)-1. As curvas de depleção residual do ABZ e seus metabólitos se ajustaram ao modelo exponencial de primeira ordem. Tomando como referência as recomendações da EMA, o período de carência foi estimado em sete dias. / Albendazole (ABZ) is an antiparasitic widely used in veterinary medicine to treat infections caused by parasites anthelmintic, due to its low cost, high efficiency and ease of administration. Regardless of its world widely known effectiveness, its use is not regulated in aquaculture species. Faced with national demand for a greater variety of regulated veterinary drugs for use in aquaculture, this project aimed to estimate the withdrawal time for the ABZ. Therefore, it was necessary to (i) incorporate ABZ the feed through the polymeric coating by spouted bed technique; (Ii) develop and evaluate analytical methods for determining the ABZ in feed and ABZ and its metabolites in pacu fillet using high-performance liquid chromatography coupled to mass spectrometry (LC-MS / MS) and (iii) conduct a test with pacu to evaluate the depletion of ABZ and its metabolites in the fillet of these fish. The ration with 1.5% coating of ethylcellulose allowed incorporate ABZ the feed without altering the physical structure of the same, which makes the process advantageous, since the feed maintains its buoyancy characteristics. Furthermore, the process was homogeneous and reduced leaching of the drug into the water, ensuring the safety of the administered dose and the environment. The ABZ ration was isolated by liquid-liquid extraction. The ABZ and its metabolites were extracted from pacu fillet the modified QuEChERS method. For both developed methods, chromatographic separation was performed in a hybrid octadecyl reverse phase column. The methods were evaluated by the following parameters: selectivity, analytical curve, linearity, precision and accuracy. For fish fillet method also assessed whether it CC? and CC?. All parameters are according to the validation guides, which makes the appropriate methods for the objectives proposed in this paper. To evaluate the depletion of ABZ and its metabolites in pacu fillet, the fish were dosed via single dose in feed 10 mg ABZ (kg body weight)-1. The curves of residual depletion ABZ and its metabolites adjusted to the exponential model of the first order. With reference to the recommendations of the EMA, the withdrawal time was estimated at seven days

Le rôle du changement d’associé dans les sociétés de capitaux a gagné en importance ces dernières années et est ainsi devenu l’un des aspects essentiels du droit des sociétés. Tant en droit allemand qu’en droit français, une cession de droits sociaux peut présenter un certain nombre de difficultés juridiques. La thèse est destinée à apporter, à travers une analyse juridique comparative, une vue globale des possibilités de changement d’associé dans une société au regard des conditions à respecter ainsi que des procédures à suivre en cas de cessions de droits sociaux. L’ensemble des aspects est étudié en tenant compte des différences majeures existant entre le droit allemand et le droit français en la matière, de leurs origines et leurs causes ainsi que des avantages et inconvénients en résultant pour les associés dans chacun des deux systèmes juridiques, afin d’aboutir à une analyse comparative critique. / The role of shareholders changes in joint-stock companies has grown in importance in recent years and has thus become an essential aspect of company law. Both in German and French law, a sale of shares agreement may require solving a substantial number of legal difficulties. Through a comparative law analysis, the thesis aims to provide a global vision of the possibilities of changes to the shareholder structure regarding conditions to be met as well as procedures to be followed in cases of sales of shares. All aspects are examined taking into account the major differences existing between German and French law in this field, from their origins and causes as well as the resulting advantages and drawbacks for shareholders within each of the studied legal systems in order to lead to a comparative and critical analysis.

Submitted by Sara Ribeiro (sara.ribeiro@ucb.br) on 2018-08-08T14:11:40Z No. of bitstreams: 1 ArilsonFernandesMendoncadeSousaTese2018.pdf: 5768876 bytes, checksum: 66d7e7ce78b9d2a4b54e615ac9d3282d (MD5) / Approved for entry into archive by Sara Ribeiro (sara.ribeiro@ucb.br) on 2018-08-08T14:11:52Z (GMT) No. of bitstreams: 1 ArilsonFernandesMendoncadeSousaTese2018.pdf: 5768876 bytes, checksum: 66d7e7ce78b9d2a4b54e615ac9d3282d (MD5) / Made available in DSpace on 2018-08-08T14:11:52Z (GMT). No. of bitstreams: 1 ArilsonFernandesMendoncadeSousaTese2018.pdf: 5768876 bytes, checksum: 66d7e7ce78b9d2a4b54e615ac9d3282d (MD5) Previous issue date: 2018-05-25 / Only two weeks of sprint interval training (SIT) has been shown to be associated with positive changes in aerobic capacity and cardiac autonomic control. Both aerobic capacity and autonomic control have been shown to be positively associated with improved attention. However, to date, the relationship between this type of training and attention has not been investigated yet. The aim of the present study was to investigate the influence of two weeks of SIT on aerobic capacity, cardiac autonomic control and attention components in healthy university students; Also, to verify if the training fidelity would influence these adaptations. One hundred and nine participants were divided into experimental (EG) and control (CG) groups. EG performed a SIT program consisting of 6 sessions of maximal 4 × 30 s all-out efforts on a cycle ergometer, interspersed with active 4-minute rests. The criterion for fidelity was to reach> 90% of the estimated maximum heart rate (HR) during sprint sessions. After analysis, EG was divided into fidelity groups HIGH (n = 26) and LOW (n = 46), respectively. The attention components were evaluated through the Attention Network Test (ANT). The aerobic capacity (VO2max) was estimated according to Astrand's nomogram while the sum of the skinfolds: pectoral, triceps, subscapular, medial axillary, abdomen, suprailiac and thigh was verified. Autonomic HR control was assessed by HR variability (HRV) and HR complexity at rest and during ANT, before and after six sessions of SIT. Both HIGH and LOW significantly increased aerobic capacity, vagal modulation before and during ANT and executive control, and decreased body fat after SIT (p <0.05). However, only HIGH participants showed an increase in HR complexity and accuracy in ANT responses when compared to LOW (p <0.05). Two weeks of SIT improved executive control, body fat, aerobic capacity and autonomic control in university students, with better results reported for the HIGH group. / Apenas duas semanas de treinamento intervalado de esforços supra máximos (TIsm) tem mostrado estar associado com modificações positivas na capacidade aeróbia e controle autonômico cardíaco. Tanto a capacidade aeróbia, como o controlo autonômico demonstram estar associados positivamente com melhoria da atenção. Entretanto, até o presente momento a relação entre este tipo de treinamento e atenção não foi investigada. O objetivo do presente estudo foi investigar a influência de um programa de TIsm na capacidade aeróbia, controle autonômico cardíaco e componentes da atenção em jovens universitários saudáveis; ainda, verificar se a fidelidade do treinamento influenciaria essas adaptações. Cento e nove participantes foram divididos em grupo experimental (GE) e controle (GC). O GE realizou um programa TIsm que consistiu em 6 sessões de TIsm de 4 × 30 s em um cicloergômetro, intercaladas com descansos ativos de 4 min. O critério para fidelidade foi atingir> 90% da frequência cardíaca máxima estimada (FC) durante as sessões de TIsm. Após as análises, o GE foi dividido em grupos de fidelidade alta, GEA (n = 26) e baixa, GEB (n = 46), respectivamente. Os componentes da atenção foram avaliados por meio do Teste de Rede de Atenção (ANT). A capacidade aeróbia (VO2max) foi estimada segundo o nomograma de Astrand enquanto o somatório de dobras cutâneas: peitoral, tríceps, subescapular, axilar média, abdômen, supra-ilíaca e coxa foi realizada. O controle autonômico da FC foi avaliado por meio da VFC e complexidade da FC em repouso e durante o ANT, antes e depois de seis sessões de TIsm. Ambos GEA e GEB aumentaram significativamente a capacidade aeróbia, modulação vagal antes e durante a realização do ANT e o controle executivo e diminuição da gordura corporal após o TIsm (p <0,05). No entanto, apenas os participantes do GEA apresentaram um aumento na complexidade da FC e acurácia nas respostas do ANT quando comparados ao GEB (p <0,05). Duas semanas de TIsm melhoraram o controle executivo, a gordura corporal, a capacidade aeróbia e o controle autonômico em estudantes universitários, com melhores resultados relatados para o grupo com GEA fidelidade.

Il s’agit d’une étude de droit des actes juridiques internationaux (engagements conventionnels et unilatéraux), portant sur un mécanisme largement utilisé dans la pratique conventionnelle mais très peu étudié en doctrine, celui de la suspension, distingué des mécanismes, plus radicaux mais finalement moins intéressants peut-être, d’extinction des engagements. Pour la première fois, est proposée une définition de la suspension, préalablement distinguée des notions voisines avec lesquelles elle a souvent été confondue (dispense, exception d’inexécution, force majeure, contre-mesures, réserve, etc… et surtout, dénonciation et retrait). La définition proposée fait état des caractéristiques de la suspension telle qu’elle se donne à voir dans les clauses conventionnelles, la pratique diplomatique et la jurisprudence, et prend appui sur la « théorie de l’engagement ». L’étude vise également à clarifier le régime de la suspension, duquel Fitzmaurice disait qu’il soulevait de « graves difficultés de classification et de plan ». L’examen de la pratique révèle en effet que ce régime n’est pas unique mais dual, originalité qui ne manquera pas de frapper la curiosité du lecteur, et dont la mise à jour permet une meilleure compréhension du phénomène de suspension. / This study focuses on a mechanism frequently used in legal practice, but, surprisingly, often ignored in international doctrine: suspension. The mechanism of suspension is to be distinguished from more radical, but arguably less interesting mechanisms, such as revocation. Suspension will be analysed within the context of both conventional and unilateral international law commitments. For the first time, a general definition of suspension will be proposed, which sets it apart from the many similar notions with which it has been confused, such as dispense, exception of inexecution, force majeure, countermeasures, reservations, …, and last but not least, denunciation and withdrawal. The proposed definition also aims to identify characteristics that are unique to suspension, as shown in treaty clauses, in diplomatic practice and case law, and as supported by « commitment theory ». The study will also clarify the legal regime of suspension, which, according to Fitzmaurice, involves « serious difficulties of classification and content ». Indeed, a closer look at suspension in practical terms reveals that there are not one, but two legal regimes of suspension. This eye-opening conclusion will not fail to engage the reader’s interest and will contribute to our further understanding of the phenomenon of suspension.

This diploma thesis deals with the content of the consumer contract and its regulation from the perspective of consumers. The aim of this thesis is to analyse this particular regulation, decide whether it is sufficient, where can be seen some deficiencies and whether the regulations fulfil its function, that is to protect the weaker party. The thesis is divided into five fundamental parts. The first one is concerned with the introductory issues, such as the consumer itself, consumer protection, why is the consumer actually protected, the principles on which is the protection based. The second part looks into the unfair terms in consumer contracts. The emphasis is placed on problematic provisions with respect to the Court of Justice case-law as well as the national case-law. An independent head is devoted to the possibility of the contractual penalty in terms of trade. The third section deals with contractual information requirements. It summarizes the European regulation. It also compares the preceding regulation with the new one in order to find the current tendencies. The contractual information requirements are viewed critically, based on specialized comments and analysis. The national regulation is divided into the general regulation and consumer regulation considering the difference between...

The thesis Legal Aspects of Withdrawal from the EU is divided into two parts. The theoretical part sums up the legislation of the withdrawal according to article 5O of the Lisbon Treaty. There is also an example of withdrawal from the EU before the article 50 has been even applied. The section dedicated to the practical results attained from the research was completed by analysing existing preferential agreements, which the UK has owing to EU, as any other member state. Then the same analysis has been carried out with existing preferential agreements, that the UK concluded with third countries. There has been done a forecast of the trade balance and its effect on GDP for the next two years according to the prediction of the Bank of England.

Há leis que instituem programas de parcelamento tributário, concedendo benefícios fiscais e exigindo contrapartidas por parte dos contribuintes, a fim de encerrar os litígios fiscais pendentes e de promover a arrecadação tributária. As exigências mais comuns são a confissão irrevogável e irretratável dos débitos parcelados, a desistência de processos administrativos e judiciais que discutam esses débitos e a renúncia às alegações de direito sobre as quais se fundamentam esses processos. Nesse contexto, o objetivo deste trabalho é verificar a validade e a eficácia dessas cláusulas, a partir de sua conformidade com o sistema constitucional tributário. As condições para adesão aos programas de parcelamento tributário serão analisadas por meio da investigação dos efeitos da manifestação de vontade do sujeito passivo na instituição da obrigação tributária à luz da legalidade e por meio da averiguação da compatibilidade das imposições legais com os direitos fundamentais e com as normas estruturantes do Estado de Direito. Para tanto, analisam-se as leis federais, estaduais e municipais que instituíram os principais programas de parcelamento tributário, com o objetivo de identificar os benefícios fiscais concedidos pelo Poder Público e os requisitos impostos aos contribuintes que quiserem aderir aos programas. Em seguida, passa-se ao exame da legalidade tributária e do papel que a manifestação de vontade do sujeito passivo pode assumir frente a essa norma estruturante do Estado de Direito. A partir das conclusões alcançadas na investigação sobre o papel da manifestação de vontade do sujeito passivo no Direito Tributário, estuda-se a validade e os efeitos da cláusula de confissão irrevogável e irretratável do débito parcelado. Por fim, analisam-se as cláusulas de desistência e de renúncia tendo em vista os limites às restrições de direitos fundamentais no Estado de Direito. Ao final, pretende-se encontrar uma forma de compatibilizar as exigências para ingresso no programa de parcelamento fiscal com o caráter ex lege da obrigação tributária e com os direitos fundamentais dos contribuintes. / Some statutes establish tax installment programs, granting tax reductions and requiring counterparts from taxpayers, in order to terminate tax disputes and promote tax collection. The most common requirements are irrevocable and irreversible confession of the debt inserted in the tax installment program, withdrawal of administrative and judicial procedures against this debt, and waiver of the rights that substantiate these procedures. In this context, the aim of this dissertation is to verify the validity and effectiveness of these clauses, from the point of view of their compliance with the Brazilian constitutional tax system. The conditions to adhere to the tax installment programs will be analyzed by investigating the effects of taxpayers consent in the institution of tax obligation, considering the legality principle, and the compatibility of the legal requirements with fundamental individual rights and the Rule of Law principles. To achieve this objective, federal, state and municipal statutes which established tax installment programs will be analyzed, in order to identify the tax reductions usually granted and the requirements imposed to the taxpayers who want to subscribe to these programs. Subsequently, the tax legality principle will be scrutinized and the role of taxpayers consent will be analyzed considering this Rule of Laws principle. From the conclusions reached in the investigation of the role of taxpayers consent in Tax Law, the validity and effectiveness of the irrevocable and irreversible confession clause will be studied. Finally, the withdrawal and waiver clauses will be analyzed in view of the limits imposed to restriction of fundamental individual rights in the Rule of Law. At the end point, this essay aims to find a way to reconcile the requirements imposed for the subscription to tax installment programs with the tax obligations ex lege character and with taxpayers fundamental rights.

Aim: To examine prospectively over a period of 4 years the profile of cannabis dependence and the risk of specific dependence criteria in a community sample of adolescents. Methods: A representative community sample of 2446 young adults aged 14–24 years at baseline was followed up over a period of 4 years. Frequency of use measures and of criteria for DSM-IV dependence were assessed by standardized diagnostic interview measures (CIDI). To explore the nature of this association, frequency of use and concomitant use of other psychoactive substances was considered. Results: 30% of the sample were cannabis users. Among all users 35% met at least one dependence criterion. Most frequently reported dependence criteria among all users were withdrawal (17%), tolerance (15%), loss of control (14%) and continued use despite a health problem (13%). Even without concomitant use of other illicit drugs, 22% of low frequency users and 81% of high frequency users met at least one dependence criterion. Symptom patterns were similar in high and low frequency users. The occurrence of a dependence syndrome or of specific dependence criteria could not be attributed to the use of other illicit drugs or to comorbid nicotine and alcohol dependence. Conclusions: Regular cannabis use in adolescence is associated with the development of a dependence syndrome. This association cannot be explained by the concomitant use of other illicit substances or by comorbid nicotine and alcohol dependence.

Die vorliegende Arbeit beschäftigt sich mit zwei verschiedenen Therapieformen des Alkoholentzugs. Es geht um den Vergleich einer rein somatischen, sechs bis siebentätigen Kurzzeitentgiftung einerseits mit der ca. dreiwöchigen Qualifizierten Entgiftung andererseits. Im Verlauf der letzten Jahre belegten zahlreiche Untersuchungen die Überlegenheit der Qualifizierten Entgiftung (QE) gegenüber der Kurzzeitentgiftung (KE). Allerdings gab es bisher kaum Studien, die zeigen, welche Faktoren eine Teilnahme an der QE begünstigen. Ziel der vorliegenden Arbeit war es daher, patienten- und umweltbezogene Merkmale zu untersuchen, die mit der Qualifizierten Entgiftung assoziiert sind. Zu diesem Zweck erfolgte die retrospektive Auswertung der Krankenakten von 155 Patienten (KE: 99, QE: 56). Anhand eines selbsterstellten Auswertungsbogens wurden 55 Items erhoben. Davon gingen 47 in die Auswertung ein und wurden zunächst hinsichtlich ihres Einflusses auf die gewählte Therapieart untersucht. Anschließend wurden diese Items bezüglich geschlechts- und altersspezifischer Unterschiede beleuchtet. Nach Abschluss der univariaten Analyse erfolgte eine multivariate Analyse, um den unabhängigen Einfluss der Variablen zu prüfen. Da die Untersuchung als retrospektive Aktenauswertung erfolgte, sind die Ergebnisse vorsichtig zu interpretieren. Dennoch konnten zahlreiche Erkenntnisse gewonnen werden, die einen differenzierteren Umgang mit den Patienten ermöglichen und langfristig genutzt werden können, um mehr Patienten in die Qualifizierte Entgiftung zu integrieren. Angesichts der Tatsache, dass es bisher kaum Veröffentlichungen gibt, die zeigen, welche Faktoren eine Teilnahme an der QE begünstigen, liefert die vorliegende Arbeit wichtige neue Erkenntnisse, die gegebenenfalls in prospektiven Studien näher untersucht werden sollten. Unsere Daten zeigen deutlich, dass die Teilnehmer der QE häufiger männlich waren, meist geplant zur Aufnahme kamen, besser sozial integriert und häufig fremdmotiviert waren sowie eine größerer Eigenmotivation aufwiesen. Außerdem zeigten sie weniger Alkoholfolgesyndrome und befanden sich zum Zeitpunkt der Aufnahme in einem besseren Gesundheitszustand. Desweiteren fiel auf, dass Frauen nur sehr selten geplant an einer Qualifizierten Entgiftung teilnahmen, sondern meist nur eine Kurzzeitentgiftung im Rahmen akuter alkoholbedingter Komplikationen oder psychiatrischer Begleiterkrankungen absolvierten. Zusammenfassend lässt sich sagen, dass es nur selten gelang, notfallmäßig aufgenommene Patienten, v.a. Frauen, zur QE zu motivieren. Dies könnte u.a. daran liegen, dass eine sechs- bis siebentägige Entgiftung nicht genügt, um eine ausreichende Rückbildung kognitiver Defizite zu erreichen und eine Motivation zur QE herbeizuführen. Außerdem ist es speziell für Frauen schwierig, sich aufgrund ihres Rollenverständnisses und ihrer Biografie in gemischtgeschlechtlichen Gruppen mit der Alkoholabhängigkeit auseinanderzusetzen. Für die Zukunft wäre es daher wünschenswert, den zeitlichen Rahmen für die Entgiftung zu erweitern und mehr Therapien anzubieten, die speziell auf die Bedürfnisse alkoholabhängiger Frauen ausgerichtet sind. In unserer Klinik waren die Ergebnisse der vorliegenden Studie Anlass, den Anteil der weiblichen Therapeuten in der Qualifizierten Entgiftung zu erhöhen. Wir hoffen, dadurch mehr Frauen für die Teilnahme an der QE zu motivieren und traumatische Biografien in einem geschützten Rahmen aufzuarbeiten. Inwieweit dies langfristig zu einer verstärkten Teilnahme weiblicher Alkoholabhängiger an der QE führt, sollte in weiterführenden Studien geprüft werden. Außerdem sollte versucht werden, das soziale Netz der Patienten und insbesondere die niedergelassenen Haus- und Fachärzte noch stärker in das Suchthilfesystem einzubinden, um eine Qualifizierte Entgiftung langfristig und effektiv vorbereiten zu können. Insgesamt bleibt festzuhalten, dass eine Qualifizierte Entgiftung möglichst frühzeitig erfolgen sollte. Sind bereits Alkoholfolgeschäden, kognitive Defizite und soziale Isolation eingetreten, fällt es zunehmend schwerer Patienten in eine QE zu integrieren. / This study deals with two different forms of alcohol detoxification therapy. A “simple” somatic detoxification program (KE), lasting six to seven days, was compared with a qualified detoxification program (QE) having a duration of approximately 3 weeks. In recent years research has shown that qualified detoxification programs are more effective than simple somatic detoxification. However, so far there have been few publications showing which factors cause patients to take part in QE. Consequently, the aim of our study was to examine patient-related and environmental factors that are associated with the assignment to qualified detoxification. We completed a retrospective analysis of 155 patients´ charts (KE: 99, QE: 56). With the help of a self-made questionnaire, 55 items were evaluated, of which 47 were included into statistical analysis. First, their influence on the type of chosen therapy was examined. Then the same items were tested on gender-specific and age-related differences. After finishing the univariate analysis a multivariate analysis was completed to investigate the independent influence of the variables. This study was designed as a retrospective data analysis, and the results should be interpreted critically. Nevertheless useful information could be gained, that allows dealing with the patients in a more differentiated way. This knowledge can be used to increase the number of patients taking part in qualified detoxification. Considering the fact that so far there have been very few publications, examining which factors support assignment to QE, our study provides important new data which should be further examined in prospective studies. Our data clearly shows that participants of qualified detoxification were mostly male and that their admission to hospital was planned in advance. Moreover, they had a good social network, better motivation for therapy, and were motivated more often to take part in therapy by their social network. They showed less negative consequences as a result of drinking and were in a better state of health at the time of admission. Another remarkable aspect was that women hardly ever took part in a planned QE. Mostly they only did a KE during treatment for acute alcohol-related complications or psychiatric comorbidities. Patients who had been admitted to the hospital as an emergency, especially women, rarely could be motivated to take part in QE. One reason might be that the time frame of 6 to 7 days for somatic detoxification might not be long enough to allow patients to recover from cognitive deficits and to motivate them to take part in QE. Another issue is that, due to their social role and personal history, dealing with their addiction is difficult for women, especially in mixed-gender groups. For the future it would be desirable to extend the time frame for somatic detoxification and to offer more programs that specifically deal with problems of female alcoholics. In our clinic, the results of this study caused us to increase the number of female therapists in our qualified detoxification program. This way we hope to motivate more women to take part in QE and to be able to deal with their personal problems in a protected atmosphere. Whether this will increase participation of female alcoholics in QE should be further examined by future studies. The social network of the patient, general practitioners, and outpatient specialists should be better integrated into treatment programs to successfully prepare patients for participation in QE programs. We believe that patients should take part in qualified detoxification programs early in the course of their disease. Once adverse effects of alcohol abuse, cognitive deficits, and social isolation have occurred, it becomes increasingly difficult to integrate patients into QE.

Benzodiazepines have been widely prescribed since the 1960s for the management of adverse symptoms related to anxiety, depression, and sleep problems. They were regarded as an efficacious medication when compared with their predecessor, barbiturates. Within 10 years of their introduction, concerns began to be raised regarding their potential to produce dependence and withdrawal symptoms when ceased, including symptoms not present prior to their being prescribed. Subsequent research focussed on establishing effective strategies to ameliorate the adverse symptoms experienced even when the daily intake was slowly reduced. The aim of the work undertaken for this doctorate was to establish whether there was a role for cognitive behaviour therapy (CBT) in benzodiazepine cessation. The initial step in conducting the research for this doctorate was to obtain a detailed understanding of the current state of research on benzodiazepine cessation. Study 1 therefore focussed on establishing the effectiveness of treatment approaches used to assist individuals to cease benzodiazepine use. A Meta-analysis of treatment strategies undertaken in general practice and outpatient settings established that brief intervention resulted in superior cessation rates at post-treatment than routine care. Gradual dose reduction plus CBT was slightly superior to gradual dose reduction alone. However, substitutive pharmacotherapies in combination with gradual dose reduction did not result in a superior outcome to gradual dose reduction alone, and substitutive pharmacotherapy plus abrupt benzodiazepine cessation was less effective than gradual dose reduction. While, providing CBT in conjunction with gradual dose reduction offered a superior outcome than gradual dose reduction alone, current evidence does not identify the CBT strategies that contributed to the superior outcome. The next step in the development of the CBT intervention involved obtaining a deep appreciation of the issues relating to cessation from the perspective of General Practitioners (GPs) and Benzodiazepine Users (BzUs). Accordingly, Study 2 administered semi-structured interviews about benzodiazepine use and its cessation to 28 GPs and 23 BzUs. Responses were analysed using the Consensual Qualitative Research approach, as it enabled comparisons to be made between the views of the two groups of interviewees. The study identified commonality between GPs and BzUs on reasons for commencing use, the role of dependence in continued use, and the importance of lifestyle change in its cessation. BzUs felt there was greater need for GPs to routinely advise patients about non-pharmacological management of their problems and potential adverse consequences of long-term use before prescribing benzodiazepines. Few GPs had assisted a patient to cease use reportedly due to the required time and the expectation of a poor outcome. There was a perception that patients wanted a pharmacological solution to their problems. A critical gap in assessment instruments that are needed for a comprehensive assessment of the outcomes from a treatment trial was identified. In particular, there was no measure of benzodiazepine expectancy or self-efficacy concerning maintenance of benzodiazepine dose reduction. Therefore, Study 3 adapted existing expectancy and self-efficacy measures form other substance domains to verify their applicability to benzodiazepines. Current BzUs (n = 155) were invited to complete two questionnaires either online or via hard copy. Principal component analysis (PCA) of a newly developed Benzodiazepine Expectancy Questionnaire (BEQ) resulted an 18-item, 2-factor scale, while a Benzodiazepine Refusal Self Efficacy Questionnaire (BRSEQ) formed a 16-item, 4-factor scale, Confirmatory factor analysis (CFA) in a second sample (n = 139) confirmed these internal structures, reducing the BEQ to 12 items and the BRSEQ to 14 items respectively. The qualitative study suggested that many GPs would be reluctant to engage in psychological support for benzodiazepine cessation and it was evident that specialist services would be unable to provide substantial support especially in rural and remote areas. Accordingly, it was decided to develop a treatment that was remotely delivered. The initial pilot used a correspondence-based approach, delivered via the postal service. Study 4 comprised a small pilot comparing GP managed gradual dose reduction, plus CBT via mail (M-CBT), which was either delivered immediately (IM-CBT) or after 3 months (DM-CBT). Despite substantial efforts over a 2 year period to recruit GPs and BzUs, only 6 received the allocated intervention. It was decided to trial the intervention as an internet-delivered program to enhance its accessibility to BzUs. Access to the program was promoted through the project website and links from high profile support websites. Study 5 was an uncontrolled trial of internet-based CBT (I-CBT). Access was provided to all newsletters, although, participants were given a suggested sequence for access. Despite placement on the internet and cross-listing on several key websites, the study still only recruited 35 participants (3 of which received the program by mail). Of the 32 undertaking the program via the internet, 21 completed the 3-month assessments and 14 the 6-month assessments. Eight participants reduced their weekly benzodiazepine intake by at least 50%, by 3 months, with five ceasing use at 6 months. A significant increase in self-efficacy, and a decrease in depressive symptoms and dependence were seen. Providing CBT either via mail or the internet assisted some participants to reduce or cease long-term benzodiazepine use. Recruitment to both M-CBT and I-CBT was limited, despite substantial attempts to market the intervention. The studies undertaken for this doctorate make a unique contribution to improving treatment outcomes for people wishing to cease long-term benzodiazepine use. They also provide direction for more extensive studies to definitively establish the nature of effective treatment. The current evidence clearly supports the importance of gradual dose reduction and the role of CBT in further improving treatment outcomes. However, engagement of both BzUs and GPs remains challenging. Remote delivery of CBT via mail or the internet may assist with improving access to CBT, but it does not solve the problem of GP and BzU engagement. An effective system-wide program to address long-term benzodiazepine use will require that incentives for GP involvement (a disincentive for long-term prescription) are in place.