Orientador: Renato Herman Sundfeld / Banca: Ticiane Cestari Fagundes / Banca: Anderson Catelan / Banca: André Luiz Fraga Briso / Banca: Márcio Grama Hoeppner / Resumo: O objetivo desse estudo foi avaliar através das análises clínica e clínica/digital o comportamento de 90 restaurações, realizadas em lesões cervicais não cariosas, após 12 e 24 meses de suas realizações. Foram formados 3 grupos de estudo com 30 dentes cada, de acordo com os materiais e técnicas empregadas. Os dentes pertencentes ao grupo I receberam, após o condicionamento com ácido fosfórico 35% em esmalte e dentina, o sistema adesivo convencional Peak LC Bond (Ultradent Products, Inc., South Jordan, USA); os do grupo II receberam a aplicação do sistema adesivo autocondicionante Clearfil Protect Bond (Kuraray Medical Inc., Kurashiki, Okayama, Japão); os do grupo III, previamente à aplicação do sistema adesivo autocondicionante Clearfil Protect Bond (Kuraray Medical Inc., Kurashiki, Okayama, Japão), receberam o condicionamento com ácido fosfórico apenas em esmalte. Todos os dentes foram restaurados com a resina composta Amelogen Plus (Ultradent Products, Inc., South Jordan, USA). Após o acabamento e polimento, bem como aos 12 e 24 meses, as restaurações foram fotografadas para posterior análise clínica/digital em computador de alta resolução. De acordo com critérios previamente estabelecidos, dois examinadores devidamente calibrados realizaram as análises clínica e clínica/digital das restaurações, nos tempos inicial, 12 e 24 meses de suas realizações. Para a análise clínica das restaurações foram considerados as variáveis retenção, adaptação marginal, descoloração marginal, presença de lesão de cárie e sensibilidade, enquanto que para a clínica/digital, retenção e descoloração marginal. Para análise estatística foram aplicados os testes de Kruskal-Wallis, de Wilcoxon, de Friedman e de Dunn. Aos 12 e 24 meses de análise clínica e clínica/digital não foram observadas diferenças estatisticamente significativas para as variáveis analisadas ... / Abstract: The aim of this study was to evaluate the performance of 90 restorations performed in noncarious cervical lesions through clinical and clinica/digital analysis after 12 and 24 months. Three groups were obtained with 30 teeth each, according to the materials and techniques. The teeth of group I received, after etching with 35% phosphoric acid on enamel and dentin, the total-etch adhesive system Peak LC Bond (Ultradent Products, Inc., South Jordan, USA); the teeth of group II received the self-etching adhesive system Clearfil Protect Bond (Kuraray Medical Inc., Kurashiki, Okayama, Japão), and the teeth of group III, prior to application of the self-etching adhesive system Clearfil Protect Bond (Kuraray Medical Inc., Kurashiki, Okayama, Japão), received the phosphoric acid etching only in enamel. All teeth were restored with composite resin Amelogen Plus (Ultradent Products, Inc., South Jordan, USA). Two calibrated examiners performed the clinical and clinical/digital analysis of the restorations at baseline, 12 and 24 months. For clinical analysis were considered the factors: retention, marginal adaptation, marginal discoloration, presence of caries and sensitivity; while for the clinical/digital analysis only retention and marginal discoloration. At 12 and 24 months of clinical and clinical/digital analysis, there were no statistically significant differences for the variables analyzed among the study groups, as well as within a group in said analysis time. The dental sensitivity significantly decreased and was totally eliminated after 12 and 24 months of clinical analysis, respectively. In the statistical analysis were applied the Kruskal-Wallis, Wilcoxon, Friedman and Dunn tests. We conclude according the clinical and clinical/digital analysis that non-carious cervical lesions restorations, performed with total-etch and self-etching adhesive systems, showed satisfactory and similar clinical performance at 12 and 24 months of analysis. / Doutor

abstract: With the number of internationally-run clinical drug trials increasing, the double standards between those in developed nations and those in developing nations are being scrutinized under the ethical microscope. Many argue that several pharmaceutical companies and researchers are exploiting developing nation participants. Two issues of concern are the use of a placebo control when an effective alternative treatment exists and the lack of drug availability to the country that hosted the clinical trial should the experimental drug prove effective. Though intuitively this seems like an instance of exploitation, philosophically, exploitation theories cannot adequately account for the wrongdoing in these cases. My project has two parts. First, after explaining why the theories of Alan Wertheimer, John Lawrence Hill, and Ruth Sample fail to explain the exploitation in clinical drug research, I provide an alternative account of exploitation that can explain why the double standard in clinical research is harmful. Rather than craft a single theory encompassing all instances of exploitation, I offer an account of a type, or subset, of exploitation that I refer to as comparative exploitation. The double standards in clinical research fall under the category of comparative exploitation. Furthermore, while many critics maintain that cases of comparative exploitation, including clinical research, are mutually beneficial, they are actually harmful to its victims. I explain the harm of comparative exploitation using Ben Bradley's counterfactual account of harm and Larry May's theory of sharing responsibility. The second part of my project focuses on the "standard of care" argument, which most defenders use to justify the double standard in clinical research. I elaborate on Ruth Macklin's position that advocates of the "standard of care" position make three faulty assumptions: placebo-controlled trials are the gold standard, the only relevant question responsive to the host country's health needs is "Is the experimental product being studied better than the 'nothing' now available to the population?", and the only way of obtaining affordable products is to test cheap alternatives to replace the expensive ones. In the end, I advocate moving towards a universalizing of standards in order to avoid exploitation. / Dissertation/Thesis / Ph.D. Philosophy 2013

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Os anestÃsicos locais sÃo as drogas mais amplamente utilizadas na prÃtica odontolÃgica. O presente estudo teve como objetivo reportar a eficÃcia clÃnica e a seguranÃa terapÃutica da MepivacaÃna 2% com Epinefrina 1:100.000 (MEPI-E) e MepivacaÃna 2% com Norepinefrina 1:100.000 (MEPI-N) em infiltraÃÃo anestÃsica de dentes caninos superiores em voluntÃrios saudÃveis. Realizou-se um estudo do tipo ensaio clÃnico, prospectivo, randomizado, cruzado, triplo cego. Trinta pacientes foram randomizados e receberam 0,6 mL de ambas as soluÃÃes anestÃsicas, por meio de anestesia terminal infiltrativa, em caninos superiores. Foi avaliado o grau de dor durante a infiltraÃÃo anestÃsica por meio da escala visual analÃgica de dor (EVA). O tempo de induÃÃo anestÃsica foi mensurado pelo teste elÃtrico pulpar mensurando assim, o tempo necessÃrio para a efetivaÃÃo do bloqueio. Os dentes foram submetidos a testes elÃtricos em ciclos periÃdicos e avaliados por 60 minutos com a finalidade de verificar a eficÃcia anestÃsica em tecido dentÃrio. O teste de picada foi utilizado para mensurar a eficÃcia clÃnica em tecido mole, nos seguintes sÃtios: gengiva inserida vestibular, mucosa alveolar superior, mucosa labial superior e pele. TambÃm foi verificada difusÃo vestÃbulo-palatina da soluÃÃo anestÃsica. PressÃo arterial sistÃlica e diastÃlica, frequÃncia cardÃaca, saturaÃÃo de oxigÃnio e glicemia serviram como parÃmetros sistÃmicos de avaliaÃÃo da seguranÃa terapÃutica. Estabeleceu-se o nÃvel de significÃncia em 0,05 (5%), foram utilizados os software GraphPad Prism e o software SPSSÂ. Foram analisados um total de 60 punÃÃes anestÃsicas em 30 voluntÃrios do estudo. O grupo MEPI-N apresentou menor nÃvel de dor e desconforto durante a infiltraÃÃo anestÃsica, com diferenÃa estatisticamente significante (P = 0,0106) quando comparado ao grupo MEPI-E. 86,7% dos pacientes quando anestesiados com MEPI-N se apresentaram negativos ao teste elÃtrico num tempo ≤ 30 segundos, contra 43,3% do grupo MEPI-E (P = 0,002). Na avaliaÃÃo da eficÃcia anestÃsica pulpar, resultados estatisticamente significantes foram observados nos tempos de 40, 50 e 60 minutos de avaliaÃÃo (P = 0,031, P = 0,021, P = 0,039 respectivamente) mostrando maior potÃncia ao grupo MEPI-N, na anÃlise da eficÃcia anestÃsica em lÃbio superior nos tempos 30, 35 e 40 minutos (P = 0,031) a superioridade tambÃm foi atribuÃda a soluÃÃo MEPI-N. NÃo houve diferenÃa estatÃstica na anÃlise intergrupos sob os parÃmetros de seguranÃa terapÃutica. NÃo foi observada significÃncia estatÃstica na anÃlise intergrupo em relaÃÃo aos parÃmetros sistÃmicos. Na anÃlise intragrupo observou-se que a pressÃo arterial sistÃlica e diastÃlica, a frequÃncia cardÃaca foram significantemente menores que a basal para alguns tempos em ambos os grupos. A mÃdia glicÃmica aos 30 minutos foi superior e estatisticamente significante ao basal. Resultados apontam que bloqueios anestÃsicos com MepivacaÃna 2% com Norepinefrina 1:100.000 sÃo capazes de conferir um melhor padrÃo anestÃsico sem contudo resultar em alteraÃÃes sistÃmicas. / Local anesthetics are the most widely drugs used in dental practice. The present study aimed to report the clinical efficacy and safety of therapeutic Mepivacaine 2% with Epinephrine 1:100,000 (MEPI-E) and Mepivacaine 2% with 1:100,000 norepinephrine (MEPI-N) in infiltration anesthesia of upper canine teeth in healthy volunteers. We conducted a clinical trial, prospective, randomized, crossover, triple blind. Thirty patients were randomly and received either 0.6 ml of both anesthetic solution through terminal infiltrative anesthesia in canines. The degree of pain during anesthetic infiltration was made by visual analog scale of pain (VAE). The induction time was measured by measuring electrical test pulp thus the time required for ensuring the locking. The teeth were subjected to electrical tests in periodic cycles and evaluated by 60 minutes in order to verify the effectiveness of anesthesia in dental tissue. The prick test was used to measure the clinical efficacy in soft tissue, at the following sites: buccal gingiva, upper alveolar mucosa, superior labial mucosa and skin. We also observed vestibular-palatal diffusion of the anesthetic. Systolic and diastolic blood pressure, heart rate, oxygen saturation and blood glucose were used as parameters for assessing the systemic therapeutic safety. Established the significance level of 0.05 (5%) were used GraphPad Prism  and SPSS Â. Were analyzed a total of 60 punctures anesthetic in 30 study volunteers. The MEPI-N group showed lower levels of pain and discomfort during the anesthetic infiltration, which was statistically significant (P = 0.0106) when compared to the MEPI-E. 86.7% when anesthetized with MEPI-N the electric test were negative a time ≤ 30 seconds, against 43.3% of MEPI group-E (P = 0.002). In evaluating the anesthetic efficacy pulp, statistically significant results were observed in intervals of 40, 50 and 60 minutes of evaluation (P = 0.031, P = 0.021, P = 0.039 respectively) showing greater power to the MEPI-N group, in analyzing the effectiveness anesthesia in the upper lip at 30, 35 and 40 minutes (P = 0.031) showed superiority was also attributed to MEPI-N solution. There was no statistical difference between groups in the analysis under the parameters of therapeutic safety. There was no statistical significance in the intergroup analysis in relation to systemic parameters. Intragroup analysis showed that the systolic and diastolic blood pressure, heart rate were significantly lower than baseline for some time in both groups. The mean glucose at 30 minutes was higher and statistically significant at baseline. Results indicate that anesthetic blocks with 2% Mepivacaine with 1:100,000 norepinephrine are able to provide a better standard anesthetic but without result in systemic changes.

>Magister Scientiae - MSc / In clinical trials, adherence of the participants to the dosing instructions is a major challenge. Many researchers have identified medication adherence as a topic to further explore in order to obtain good, usable and reproducible results. In order to gain an understanding of on-the-ground issues in clinical research a survey was conducted, isolating the issue of medication adherence among participants as a discussion point. The research was conducted specifically at clinical trial sites that are involved in HIV pre-exposure prophylaxis research. The survey was conducted at clinical trial sites across South Africa among health care workers in the clinical research sector. The principle issue to be identified was the perceptions of staff and researchers with regards to the current approach to adherence measurement and possible suggestions from them on future adherence interventions strategies. This research was conducted as a qualitative analysis from February to March 2014. Eighteen responses were received. Among the respondents were investigators, medical officers, nurses and pharmacists. The results of the survey suggest that healthcare workers have a strong understanding of the importance adherence monitoring and intervention. They have many ideas on which measurement tools work and which don’t, but most importantly feel that the self-report or interview techniques are the most useful. Researchers also feel that much more can be done in order to improve the perception of the clinical research institutes in the eyes of the community and that a more active role should be taken in the community in order to improve the acceptance of the participants to the use of the product.

Type 2 Diabetes Mellitus (Type 2 DM) is present in the populations of almost all the countries in the world and is a significant disease burden in most developed countries. Evidence suggests that populations in Africa develop Type 2 DM at an increasing rate as they reject their traditional lifestyles. Furthermore, newly released figures by the Medical Research Council of South Africa indicate that diabetes is the 10th most common cause for total life years lost in females in South Africa. Exercise is a low cost, non-pharmacological intervention that has been shown to be effective in metabolic control. Exercise is still vastly under-utilised in the management of Type 2 DM, especially in urban black females with Type 2 DM. This study was designed to determine the effectiveness of an exercise intervention to decrease haemoglobin A1c (HbA1c) over period of 12 weeks in Type 2 DM black female subjects, aged 40to 65 years. This study consisted of three phases. Data captured in the first two phases were utilised to plan the exercise intervention. Questionnaires and focus groups were used in the first two phases of the stud. The final phase of the study consisted of a randomized controlled trial. For this phase 157 female subjects who were recruited at the Mamelodi hospital diabetes outpatient clinic, were randomized to either an experimental or a control group. It was found that the subjects had little knowledge about their disease and that they lead a sedentary lifestyle. Subjects felt that Type 2 DM had a negative impact on their lives. Their attitudes bout Type 2 DM showed a dependence on health professionals and they disagreed with the attitude that they should be involved in decision-making about their health care. The results of the focus groups indicated that patients viewed walking and household chores as suitable exercise for them. Personal barriers to exercise were lack of knowledge, tiredness and health-related stress. Subjects expected that exercise would increase the functional capabilities, increase their knowledge and improve their well being. These findings were used to plan the exercise intervention, which consisted of a home-based exercise programme and fortnightly exercise sessions at the Mamelodi hospital. Subjects also had to complete a diary of their physical activities at home. An analysis of co-variance (ANCOVA) was used to compare the experimental and control groups with respect to change in HbA1c and the secondary outcomes such as walking distance and quality of life outcomes. It was found that the exercise intervention was no more efficacious (p=0.05) than a supervised self-relaxation training intervention to decrease HbA1c, over a period of 12 weeks. The exercise group was however able to walk a significantly further distance (p<0.01) than the control group after the 12-week intervention. While not significantly different between groups (p=0.80), the positive well-being improved significantly within both groups (p<0.01). It is possible to improve blood glucose control by means other than medication in urban black female patients with Type 2 DM. The patients are willing to change their sedentary lifestyle to a more active one, but several environmental and personal barriers impact negatively o their attempts to do so. The role of the health care worker is to identify these barriers and to accompany the patient on the road to a healthier lifestyle. However, this population of women may need more assistance and support initially to take self-responsibility for their diabetes self-management eventually. / Thesis (PhD)--University of Pretoria, 2006. / Physiotherapy / unrestricted

COVID-19 is caused by a novel coronavirus which has a high affinity for ACE-2 receptors in respiratory epithelium. The high affinity for ACE-2 allows the virus to infiltrate cells leading to viral assembly, maturation, and release. COVID-19 presents itself with respiratory and cold-like symptoms which may ultimately develop into ARDS. This study analyzed the demographics of inpatients who tested positive at MGH as well as their eligibility and enrollment status for COVID-19 clinical trials. When looking at the study population, MGH and the state of Massachusetts shared similar distributions of hospitalized men and women. MGH had a slightly higher proportion of Non-Hispanic Black hospitalized patients and a lower proportion of Hispanic hospitalized patients compared to the state of MA. MGH also had a higher percent of hospitalized patients 65 and older compared to the state. This study found statistically significant differences among eligibility status and enrollment status across race/ethnicity and age. There were no statistically significant differences among eligibility status or enrollment status across sex. Differences among eligibility and enrollment status among those 65 and older may be due to the large elderly population that utilizes MGH for care. It may also have to do with the fact that those who were under 65 had shorter hospital stays. The differences between eligibility and enrollment status across race/ethnicity may have to do with the hospital’s program dedicated to clinical trial inclusion of Spanish speaking patients. Findings from this study exemplify MGH’s efforts for equitable clinical trial involvement.

The subject of my dissertation is fraud in clinical trials in terms of ethics and law. The aim of my research was to analyze the frequency of fraud in clinical trials of a given sample of data collected, identify the main fraudsters and to analyze the causes that led participants in clinical trials to commit fraud. In the theoretical part of my dissertation I defined the concepts of clinical trials, deception, ethical issues and the relevant legal framework. The practical part contains the results of the data analysis of the incidence and causes of fraud, the main actors of fraud and conception of recommendations, which appears to be essential for the prevention of fraud in clinical trials. The data analysis and participant observation show that during 107 GCP (Good Glinical Practice) audits conducted during the period of 2008-2013 in 22 countries, 14 revelations of fraud in clinical trials were identified, which represents 13.1 %. Most often fraud was committed by investigators, a total of 47.6 % of all observed groups of cheating clinical trial participants. The main causes that led investigators to commit fraud represent a lack of eligible patients, financial gain and personality traits. Based on the results obtained during my research I highlighted in the practical part of my dissertation the ethical...

Idarubicin, a new analogue of daunorubicin, was administered intravenously at a dose of 15 mg/m2 to 31 patients with previously treated patients with unfavorable non-Hodgkin's lymphoma. Clinical characteristics included median age 69 years, performance status 1, and prior chemotherapeutic regimens 1. Twenty of the patients were relapsing after prior therapy and 11 were refractory; 29 had received prior anthracycline or anthracenedione. Responses were observed in 43% of patient (3 CR and 10 PR) with a median duration of 10 + months (2-29+ months). Idarubicin was well tolerated with non-hematologic toxicities (nausea/vomiting, mucositis, and anorexia) seen in <50% of patients. Median hematologic values during the first cycle for this dosage included WBC 1300/mm3 platelets 129,000/mm3, and hemoglobin 10.9 mg/dl. With dose escalation, hematologic toxicity was dose-limiting. Symptomatic cardiac toxicity was observed in one patient who had received maximum dose doxorubicin and radiotherapy. Median values for the cardiac ejection fraction during the full course of therapy for the entire group of patients were 0.62 (initial) and 0.60 (final). Idarubicin in intravenous form is an active drug in previously treated patients with unfavorable non-Hodgkin's lymphoma. Further studies employing idarubicin in non-Hodgkin's lymphoma should be considered. Cardiac function should be followed in trials utilizing anthracycline-type chemotherapeutic agents.

Drug development in the United States has undergone many changes in the past 25 years, but relatively few fully realize the complexities involved in developing a new drug. Once a promising compound is identified, it must undergo preclinical testing, have an Investigational New Drug Application filed with the U.S. Food and Drug Administration (FDA), and proceed through clinical testing. When sufficient information is gained, a marketing application is filed with the FDA, who identifies it as a New Drug Application for drugs or a Biologics License Application for biologics. After FDA review and approval, postmarketing studies are frequently performed. The FDA and Congress have undertaken several initiatives to expand access and to accelerate drug development and review of investigational drugs for life-threatening and/or serious illnesses. Although the ultimate goal is to bring safer and more effective medical products to patients in a timely manner, multiple challenges face those who participate in drug development.

Indiana University-Purdue University Indianapolis (IUPUI) / Subgroup analyses assess the heterogeneity of treatment effects in groups of patients defined by patients’ baseline characteristics. Identifying subgroup of patients with differential treatment effect is crucial for tailored therapeutics and personalized medicine. Model-based variable selection methods are well developed and widely applied to select significant treatment-by-covariate interactions for subgroup analyses. Machine learning and data-driven based methods for subgroup identification have also been developed. In this dissertation, I consider two different types of subgroup identification methods: one is nonparametric machine learning based and the other is model based. In the first part, the problem of subgroup identification was transferred to an optimization problem and a stochastic search technique was implemented to partition the whole population into disjoint subgroups with differential treatment effect. In the second approach, an integrative three-step model-based variable selection method was proposed for subgroup analyses in longitudinal data. Using this three steps variable selection framework, informative features and their interaction with the treatment indicator can be identified for subgroup analysis in longitudinal data. This method can be extended to longitudinal binary or categorical data. Simulation studies and real data examples were used to demonstrate the performance of the proposed methods. / 2022-05-06