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The purpose of this research study was to determine the effects of Fostering Resilience™ (FR), a new integrative relapse prevention group protocol for improving relapse risk, internalized shame, and psychological well-being in adults with substance use disorders (SUD). This study also sought to identify any relationship among relapse risk, internalized shame, and psychological well-being. It is the first study to investigate the new FR manualized program model compared to treatment as usual (TAU). The FR model was created based upon direct client experience, the supposition of the intrinsic role shame plays in SUD, and the corresponding belief in the essential value of implementing shame reduction techniques for improving treatment outcomes. Participants were 43 adults with SUD (19 FR and 24 TAU) seeking outpatient treatment. All participants received the 8-week intensive outpatient (IOP) treatment, with the FR group receiving 16 sessions of the manualized FR relapse prevention group protocol in lieu of other TAU group options. Assessments were administered pre and postintervention. Results indicated that the FR treatment group produced a significant reduction in relapse risk (p = .002, ES = .825), shame (p = .004, ES = .763), and psychological wellbeing (p = .008, ES = .679) from baseline to post-intervention, while the TAU comparison group produced a non-significant improvement in relapse risk (p = .209, ES = .264), shame (p = 055, ES = .409) and psychological well-being (p = .088, ES = .456). Correlation results indicated highly significant correlations between all the dependent variables. All correlations dropped post-intervention, although remained significant. The strongest relationship was found between shame and relapse risk at baseline: ALL (n = 43, r = .880), FR (n = 19, r = .869), TAU (n = 24, r = .908). This preliminary study establishes support for the new FR model as a beneficial treatment for significantly improving relapse risk, internalized shame, and psychological well-being in adults with SUD. It also provides important knowledge and insight regarding the critical nature of shame and its role relative to relapse risk and psychological well-being in those with SUD. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

<p>Characteristically, in infections that are caused by the zoonotic pathogen <i>Bartonella</i> naturally infected reservoir hosts are asymptomatic, where infected incidental, non-natural, hosts develop symptomatic disease. Cat-scratch disease (CSD) is a well known example. <i>Bartonella </i>infections in humans may be self-limiting or fulminant and affect different organ systems. </p><p>The objectives of the present thesis were to (1) identify and characterise <i>Bartonella </i>infection cases in Sweden, (2) to investigate certain human populations regarding <i>Bartonella </i>infections, and (3) compare natural populations of different <i>Bartonella </i>species.</p><p>Cases with typical and atypical CSD were recognised by using a combination of PCR and serology. Gene sequence comparisons of different genes in <i>B. henselae</i> isolates from the United States and Europe showed that<i> fts</i>Z gene variation is a useful tool for <i>Bartonella</i> genotyping. </p><p>Myocarditis was a common finding among Swedish elite orienteers succumbing to sudden unexpected cardiac death (SUCD). The natural cycle of <i>Bartonella</i> spp., the life style of orienteers, elevated antibody titres to <i>Bartonella</i> antigens, <i>Bartonella</i> DNA amplified from myocardium and the lack of another feasible explanation make <i>Bartonella</i> a plausible aetiological factor.</p><p>The first reported case of <i>Bartonella</i> endocarditis (<i>B. quintana</i>) was identified in an immunocompromised patient who underwent heart valve replacement. The patient had been body louse-infested during his childhood. It is hypothesised that a chronic <i>B. quintana</i> infection was activated by the immunosuppression.</p><p>There was no evidence of an ongoing trench fever (TF) epidemic in a Swedish homeless population, although an increased risk for exposure to <i>Bartonella</i> antigens was demonstrated. The lack of louse infestation might explain the absence of <i>B. quintana</i> bacteremia and low <i>B. quintana</i> antibody titres. </p><p>Comparisons of genetic loci and the whole genomes of environmental <i>B. grahamii</i> isolates from the Uppsala region, Sweden displayed variants that were not related to specific host species but to geographic locality. Natural boundaries seemed to restrict gene flow.</p>

Characteristically, in infections that are caused by the zoonotic pathogen Bartonella naturally infected reservoir hosts are asymptomatic, where infected incidental, non-natural, hosts develop symptomatic disease. Cat-scratch disease (CSD) is a well known example. Bartonella infections in humans may be self-limiting or fulminant and affect different organ systems. The objectives of the present thesis were to (1) identify and characterise Bartonella infection cases in Sweden, (2) to investigate certain human populations regarding Bartonella infections, and (3) compare natural populations of different Bartonella species. Cases with typical and atypical CSD were recognised by using a combination of PCR and serology. Gene sequence comparisons of different genes in B. henselae isolates from the United States and Europe showed that ftsZ gene variation is a useful tool for Bartonella genotyping. Myocarditis was a common finding among Swedish elite orienteers succumbing to sudden unexpected cardiac death (SUCD). The natural cycle of Bartonella spp., the life style of orienteers, elevated antibody titres to Bartonella antigens, Bartonella DNA amplified from myocardium and the lack of another feasible explanation make Bartonella a plausible aetiological factor. The first reported case of Bartonella endocarditis (B. quintana) was identified in an immunocompromised patient who underwent heart valve replacement. The patient had been body louse-infested during his childhood. It is hypothesised that a chronic B. quintana infection was activated by the immunosuppression. There was no evidence of an ongoing trench fever (TF) epidemic in a Swedish homeless population, although an increased risk for exposure to Bartonella antigens was demonstrated. The lack of louse infestation might explain the absence of B. quintana bacteremia and low B. quintana antibody titres. Comparisons of genetic loci and the whole genomes of environmental B. grahamii isolates from the Uppsala region, Sweden displayed variants that were not related to specific host species but to geographic locality. Natural boundaries seemed to restrict gene flow.

Thesis (PhD)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Prospective, longitudinal clinical studies in first-episode schizophrenia have become relatively commonplace over the past two decades or more and have provided a wealth of useful information regarding the clinical presentation, treatment, course and outcome of the illness. However, there remain several unanswered questions. The majority of the studies have been conducted in upper income countries using often costly medication with heterogeneous samples. While the overall outcome of patients showed some progress, there is room for improvement yet. The overall aim of the dissertation was to study the clinical, biological and functional aspects of outcome in first episode schizophrenia in a resource constrained setting. We conducted a prospective, non-comparative, longitudinal study over 12 months assessing the efficacy and tolerability of a cost effective, long-acting injectable antipsychotic (LAI; flupenthixol decanoate) combined with an assertive monitoring program (AMP) among first-episode schizophrenia patients. Efficacy was measured by examining rates of response, remission and relapse, as well as quality of life and social and occupational functioning. Tolerability of our intervention was assessed by measuring extrapyramidal symptoms, and weight and metabolic changes. We also examined the evolution of treatment refractoriness by studying the rates of non-response, and other associated predictor and outcome features. We found high rates of acceptance and adherence to the LAI and AMP. Seventy percent of our patients completed the 12 months of treatment. Treatment response was achieved by 82% of the participants and 60% achieved remission. Although 19% of our patients relapsed, the majority of the relapses were mild and did not require hospitalisation. Patients experienced significant quality of life and social and occupational functioning improvements. We found mild rates of extrapyramidal effects, present in only a third of our cohort. The majority of the extrapyramidal effects were treated with anticholinergics or propranolol. Only 3% of our patients developed transient dyskinesia over the duration of the study. However, our cohort gained considerable weight, with statistically significant increases in BMI (p< .0001) and waist circumference (p=0.0006). Our cohort also experienced significant deleterious changes to their lipid profiles. Of particular concern was the increase in triglycerides (p=0.03) and a significant decrease in high density lipoprotein (p=0.005) leading to a 91% increase in the triglyceride/high density lipoprotein ratio. With regards to emerging treatment refractoriness, 12% of our patients met our pre-defined criteria for non-response. Non-responders were younger and at baseline showed more prominent disorganised symptoms, poorer social and occupational functioning, poorer quality of life for psychological, social and environmental domains, more prominent neurological soft signs (NSS), and lower BMI. At endpoint the non-responders were characterised by higher levels of symptomatology in all domains; poorer functional outcome, poorer quality of life and greater cognitive impairments. They also had more prominent NSS and a lower BMI. The strongest predictors of non-response were prominent baseline NSS and poor early (7 weeks) treatment response. In conclusion, the combination of an LAI with an AMP may be an effective and safe intervention in firstepisode schizophrenia, and may be particularly suitable for resource-constrained settings. The risk of weight gain and metabolic syndrome associated with antipsychotic treatment in first-episode schizophrenia are not restricted to second generation antipsychotics and low-potency first-generation antipsychotics. Ensuring effective treatment for first episode schizophrenia patients is a global problem, and likely to be under-recognised in LMICs. / AFRIKAANSE OPSOMMING: Oor die afgelope twee dekades het toenemend meer longitudinale kliniese studies, wat eerste episode skisofrenie bestudeer, die lig gesien. Die studies het ‘n magdom van waardevolle inligtng oor die kliniese voorkoms, behandeling, verloop en uitkomste van die siekte opgelewer. Die meerderheid van die studies is egter in hoë inkomste ontwikkelde lande gedoen met pasiënte wat duur medikasie gebruik en hoofsaaklik in heterogene steekproewe. Alhoewel dit blyk uit hierdie studies dat daar oor die algemeen vordering gemaak word ten opsigte van die behandeling van pasiënte is daar steeds ‘n gebrek aan voldoende inligting oor die onderwerp veral in minder gegoede, ontwikkelende lande. Die oorhoofse doel van hierdie proefskrif is om binne ‘n hulpbron beperkte konteks die kliniese, biologiese en funksionele aspekte van pasiënt -uitkomste in eerste episode skisofrenie te ondersoek. Ons het ‘n longitudinale studie gedoen waarin ons die effektiwiteit en toleransie van ‘n enkele antipsigotiese medikasie vir 12 maande nagevors het. Die medikasie wat ons ondersoek het, is flupenthixol decanoate en word deur ‘n inspuiting gegee en die medikasie word dan geleidelik deur die liggaam geabsorbeer. As deel van die behandeling het ons pasiënte ook streng gemonitor. Ons het die effektiwiteit van die behandeling gemeet nagelang van hoe pasiënte reageer op die behandeling, hoeveel pasiënte in remissie gaan en terugval, en ook pasiënte se kwaliteit van lewe en hulle sosiale en beroepsfunksionering. Ons het toleransie gemeet nagelang van pasiënte se gewig en metaboliese verandering sowel as die voorkoms van medikasie geïnduseerde newe-effekte. Verder het ons pasiënte wat nie op medikasie gereageer het nie ondersoek sowel as die aspekte wat moontlik hiernee verband hou. Ons het bevind dat die meerderheid van pasiënte hulle medikasie getrou geneem het en ook die streng monitering aanvaar het. Sewentig persent van die pasiënte het hulle 12 maande behandeling voltooi, 82% het op die medikasie gereageer en 60% het in remissie ingegaan. Alhoewel 19% van die pasiënte teruggeval het, was dit nie so ernstig dat ons hulle moes hospitaliseer nie. Pasiënte het beduidende verbetering ten opsigte van hulle kwaliteit van lewe en sosiale en beroepsfunksionering getoon. Ons het slegs ‘n gematigde mate van medikasie geïnduseerde newe-effekte opgemerk en alleenlik by ‘n derde van die kohort. In die meerderheid van gevalle het ons die newe-effekte met anticholinergics of propranolol behandel. Slegs 3% van die pasiënte het gedurende die verloop van 12 maande die kondisie transient dyskinesia ontwikkel. Ongelukkig het ons kohort geweldig baie gewig opgetel en die toename in pasiënte se BMI (p< .0001) en middellyf omtrek (p=0.0006) was statisties beduidend. Ons het ook bevind dat veranderinge in ons kohort se lipied profiele kommerwekkend is veral as in ag geneem word dat die toename in trigliseriede (p = 0,03) en die beduidende afname in die hoë digtheid lipoproteïen (p = 0,005) gelei het tot ‘n 91% verhoging in trigliseriede: hoë digtheid lipoproteïen verhouding.

Ce travail de thèse s’est focalisé sur le développement des approches génériques de spectrométrie de masse (MS) pour la quantification des anticorps monoclonaux (mAbs) et de leurs produits dérivés dans des études précliniques. Premièrement, le développement des protocoles de préparation d’échantillons basée sur la digestion directe à partir de sérum ou comportant une étape d’immuno-précipitation spécifique par anticorps a permis la quantification des mAbs couvrant une large gamme d'étalonnage de cinq ordres de grandeur. En outre, l'emploi de peptides provenant de la région constante du mAb a démontré la polyvalence de telles approches génériques de chromatographie liquide en tandem MS (LC-MS/MS). Deuxièmement, les instruments de MS à haute résolution (HRMS) ont étés évalués dans le cadre de cette thèse en tant qu'alternative aux spectromètres de masse de type triple quadripôle traditionnellement utilisés pour l’analyse bottom-up quantitative. L’avantage majeur de l’intégration des analyseurs de HRMS a été associé à la possibilité de l’analyse quantitative simultanée des mAbs et leurs produits associés directement au niveau de la protéine fournissant un niveau d'informations bien au-delà de celui obtenu avec des approches bottom-up. Par conséquent, l’apport essential de la HRMS pour les analyses qualitative et quantitative des protéines thérapeutiques de type mAbs et produits associés a été démontré dans cette thèse. / This PhD thesis focused on the development of generic mass spectrometry (MS)-based workflows for monoclonal antibody (mAb)-related therapeutic protein quantification in pre-clinical species. First, the development of bottom-up sample preparation protocols either based on direct serum digestion or immuno-capture allowed mAb-related therapeutic protein quantification over five orders of magnitude whereas the employment of peptides from the constant region of the mAb demonstrated the versatility of such generic liquid chromatography tandem MS (LC-MS/MS)-based approaches. Second, high-resolution MS (HRMS) instruments were evaluated as an alternative to triple quadrupole mass analyzers, traditionally utilized for bottom-up mAb quantification by LC-MS/MS. The major benefit of HRMS incorporation into the workflow was associated with the possibility to quantify simultaneously mAb-related therapeutic proteins directly at an intact level, providing an information level far beyond the one obtained with bottom-up LC-MS/MS methodologies. Hence, the pivotal role of HRMS for the qualitative and quantitative analyses of mAb-related therapeutic proteins was further outlined throughout this doctoral work.

Neurodegenerative disorders including Parkinson’s disease (PD), Huntington’s disease (HD) and the most frequent, Alzheimer’s disease (AD), represent one of the most urgent medical needs worldwide. Despite a significantly developed understanding of disease development and pathology, treatments that stop AD progression are not yet available. The recent approval of sodium oligomannate (GV-971) for AD treatment in China emphasized the potential value of natural products for the treatment of neurodegenerative disorders. Many current clinical studies include the administration of a natural compound as a single and combination treatment. The most prominent mechanisms of action are anti-inflammatory and anti-oxidative activities, thus preserving cellular survival. Here, we review current natural products that are either approved or are in testing for a treatment of neurodegeneration in AD. In addition to the most important compounds of plant origin, we also put special emphasis on compounds from algae, given their neuroprotective activity and their underlying mechanisms of neuroprotection.

O objetivo deste trabalho foi realizar diagnóstico para solução de problemas de atraso na entrega das atividades e relatórios de pesquisa, bem como de dificuldade de se definir o objetivo e escopo do projeto, encontrados no departamento de estudos pré-clínicos e clínicos de empresa de saúde animal. Isso porque, antes dos novos produtos veterinários entrarem no mercado, estes devem passar por testes que comprovem sua eficácia e segurança, conforme exigido pelo órgão regulatório. Neste contexto, verifica-se a importância da realização de estudos clínicos conforme planejamento e prazos previamente estabelecidos, pois estes impactam diretamente nos resultados e planejamento estratégico da empresa. Para tanto, foi realizado diagnóstico dos atrasos através de avaliação de cronogramas de projetos finalizados. Como proposta de solução foi elaborado um formulário de planejamento de projetos a partir dos conceitos do PMBOK®. Este foi aplicado no início de cada novo projeto e inserido no fluxograma de processos do departamento. Para avaliação dos resultados da inserção deste formulário foram aplicados aos colaboradores do departamento questionários fechados juntamente a cada preenchimento do formulário. Os dados obtidos destes questionários foram avaliados através da análise de componentes principais. Além disso, foi realizada entrevista semiestruturada com os colaboradores para verificar efetivamente a mudança no cenário do departamento pós-formulário, sendo os dados avaliados conforme método de análise de discurso. Como resultados foi verificado que ocorreram atrasos em pelo menos 50% das atividades presentes nos 22 cronogramas de projetos avaliados, isso devido principalmente ao planejamento inadequado, de acordo com os relatos dos colaboradores. Com a aplicação do formulário e análise dos dados dos questionários e das entrevistas foi possível verificar que a utilização do formulário tem grande importância na definição dos objetivos do projeto, definição de escopo, e consequente definição das atividades indicadas para cada estudo, ou seja, auxilia no planejamento do estudo. Além disso, proporciona aos colaboradores a reflexão e visão crítica dos projetos, assim como deixa documentado tudo aquilo que foi pensado evitando retrabalhos posteriores. / The objective of this study was to perform a diagnosis to solve problems of delay in activities and research reports\' delivery, as well as the difficulty to define project\'s objective and scope, found in the pre-clinical and clinical studies department of animal health company. This happens because new veterinary products must undergo tests that prove their efficacy and safety, as required by the regulatory agencies before being marketed. In this context, it is important to carry out clinical studies according to the planning and deadlines previously established, as these have a direct impact on the results and strategic planning of the company. For this purpose, the delays were diagnosed through the evaluation of completed project schedules. As a proposal for solution, a project planning form was developed based on PMBOK® concepts. This was applied at the beginning of each new project and inserted into the department\'s process flowchart. To evaluate insertions\' results of this form a closed questionnaire was applied to employees of the department with each filling out form. The data obtained from these questionnaires were analyzed through principal components analysis. In addition, a semi-structured interview was conducted with the employees to effectively verify the change in the post-form department scenario and the data were evaluated according to the discourse analysis method. As results it was verified that there were delays in at least 50% of the activities present in the 22 schedules of evaluated projects, mainly due to inadequate planning, according to the collaborators reports. With form\'s application and data\'s analysis of questionnaires and interviews it was possible to verify that the use of the form has great importance in the definition of project\'s objectives, definition of scope and consequent activities\' definition indicated for each study. In other words, it assists in the planning of the study. In addition, it provides the employees with the reflection and critical vision of projects, as well as documenting everything that was thought avoiding subsequent rework.

Os estudos clínicos são importantes para a sociedade, contribuem para o avanço da ciência, geram novos conhecimentos, trazem benefícios, melhoria da qualidade de vida e o bem-estar das pessoas. Devem ser realizados de acordo com os princípios éticos e vários agentes devem estar envolvidos: as autoridades regulatórias, o patrocinador, o pesquisador, o participante de pesquisa e o comitê de ética em pesquisa. Os regulamentos e guias internacionais e nacionais relacionados aos estudos clínicos, entre eles a Diretriz de Boas Práticas Clínicas foram implantados principalmente, para proteger e garantir a segurança e integridade dos participantes de pesquisa. No decorrer dos estudos clínicos podem ocorrer eventos adversos, portanto a plena monitorização é fundamental, pois torna o estudo mais seguro para o participante de pesquisa. Este trabalho teve como objetivo elaborar um manual direcionado a pesquisadores visando orientar a notificação de eventos adversos aos órgãos pertinentes. O estudo foi realizado em quatro etapas. Na primeira etapa realizou-se uma revisão da literatura sobre eventos adversos em estudos clínicos. Na segunda etapa, elaborou-se um manual piloto. Na terceira etapa, o material foi qualificado por um Painel de Especialistas formado por cinco pesquisadores do Hospital Universitário Cassiano Antonio Moraes, que analisaram o conteúdo e responderam a um questionário de onze questões. Na quarta etapa, analisou-se as respostas dos questionários e com as sugestões do Painel de Especialistas aprimorou-se o manual e obteve-se a versão denominada Manual de Procedimentos para Notificação de Eventos Adversos em Estudos Clínicos. Após a apreciação final do produto pela banca do mestrado profissional, o manual será disponibilizado em formato eletrônico, para que vários pesquisadores tenham acesso, em especial os pesquisadores que atuam no Hospital Universitário Cassiano Antonio Moraes e nos hospitais vinculados a rede da Empresa Brasileira de Serviços Hospitalares (EBSERH). / Clinical studies are important to society. They contribute to the advance of science, generate new knowledge, bring benefits, improve the quality of life and the well-being of people. They must be carried out in accordance with ethical principles and several agents should be involved: the regulatory authorities, the sponsor, the researcher, the research participant and the research ethics committee. International and national regulations and guidelines related to clinical studies, including the Clinical Good Practice Guideline, were primarily implemented to protect and ensure the safety and integrity of the research participants. Adverse events can occur during clinical studies; it means that, full monitoring is critical in order to lead the study safer for the research participant. The aim of this work is to elaborate a manual directed at researchers to guide them on the notification of adverse events process to the government organizations. The study was divided in four steps. In the first step, a bibliographic review on adverse events in clinical studies was done. In the second step, a pilot manual was developed. In the third step, the analyzed material was qualified by a Panel of Experts composed of five University Hospital Cassiano Antonio Moraes’ researchers who analyzed the content and answered a questionnaire of eleven questions. In the fourth step, the analyzed questionnaire as well as the Panel of Expert’s suggestions were used for improving the manual, reaching the version called the Manual of Procedures for Notification of Adverse Events in Clinical Studies. After the final evaluation of the product by the master's degree examining board, the manual will be available in electronic format, so that several researchers will have access, especially researchers working in University Hospital Cassiano Antonio Moraes and hospitals linked to the network of the Brazilian Hospital Services Company (EBSERH).