BAYESIAN PHASE I DOSE FINDING IN CANCER TRIALS

This dissertation explores phase I dose-finding designs in cancer trials from three perspectives: the alternative Bayesian dose-escalation rules, a design based on a time-to-dose-limiting toxicity (DLT) model, and a design based on a discrete-time multi-state (DTMS) model. We list alternative Bayesian dose-escalation rules and perform a simulation study for the intra-rule and inter-rule comparisons based on two statistical models to identify the most appropriate rule under certain scenarios. We provide evidence that all the Bayesian rules outperform the traditional ``3+3'' design in the allocation of patients and selection of the maximum tolerated dose. The design based on a time-to-DLT model uses patients' DLT information over multiple treatment cycles in estimating the probability of DLT at the end of treatment cycle 1. Dose-escalation decisions are made whenever a cycle-1 DLT occurs, or two months after the previous check point. Compared to the design based on a logistic regression model, the new design shows more safety benefits for trials in which more late-onset toxicities are expected. As a trade-off, the new design requires more patients on average. The design based on a discrete-time multi-state (DTMS) model has three important attributes: (1) Toxicities are categorized over a distribution of severity levels, (2) Early toxicity may inform dose escalation, and (3) No suspension is required between accrual cohorts. The proposed model accounts for the difference in the importance of the toxicity severity levels and for transitions between toxicity levels. We compare the operating characteristics of the proposed design with those from a similar design based on a fully-evaluated model that directly models the maximum observed toxicity level within the patients' entire assessment window. We describe settings in which, under comparable power, the proposed design shortens the trial. The proposed design offers more benefit compared to the alternative design as patient accrual becomes slower.

Peso insuficiente ao nascer e crescimento alcançado na idade pré-escolar, por crianças atendidas em creches filantrópicas do município de Santo André, São Paulo, Brasil

OBJETIVOS: comparar o crescimento alcançado e a prevalência de baixa estatura na idade pré-escolar entre recém-nascidos de peso insuficiente (PNI) e de peso adequado (PNA). MÉTODOS: foram estudadas 323 crianças com PNI e 886 com PNA de famílias de baixa renda de quinze creches filantrópicas de Santo André, São Paulo, Brasil, em 2001 e 2002. As variáveis foram o escore Z de peso e de estatura para a idade, pelo referencial Center for Disease Control (CDC) and National Center for Health Statistics (NCHS) 2000, comparando-se as médias dos dois grupos. Calculou-se a razão de prevalência (RP) de baixa estatura na idade pré-escolar em decorrência do peso insuficiente ao nascer. RESULTADOS: o escore z médio de peso foi -0,09 e 0,39 e o escore z médio de estatura foi de -0,06 e de 0,24 para as crianças de PNI e de PNA, respectivamente. A prevalência de baixa estatura foi de 2,78% para as crianças com PNI e de 0,79% para aquelas com PNA. A RP de baixa estatura na idade pré-escolar para as crianças de PNI foi de 3,5 (IC95% 1,3-9,4). CONCLUSÕES: as crianças com PNI apresentaram crescimento inferior e maior risco de falhas de crescimento até a idade pré-escolar, sugerindo um efeito negativo do peso insuficiente ao nascer sobre o crescimento infantil.

The contribution of cellblock – histogel – in bronchial washing samples

Introduction: The cellblock is a technique that enables the pathologist to study the morphological detail of residual samples and can be used when it is necessary to perform additional diagnostic techniques. Objective: Demonstrate the processing of bronchial washings in liquid based cytology to cellblock using HistoGel in residual samples, evaluating the morphology and preservation of cytological material. Methods: There were used 40 residual samples from bronchial washings in liquid based cytology, after determination of the clinical diagnosis, being made subsequently 40 cellblocks using HistoGel. For each cellblock there was made one histological section for analysis of cell morphology, which was subsequently stained with the routine histological staining. After microscope observation, the morphology was evaluated by 3 experts in the field of pathology, based on the parameters: Cellularity, Preservation and Background. Results: The average final score of 3 evaluators, on a scale of 0 to 100, in assessing the morphology of the 40 samples was 55.6. From the 40 histological sections, 5 of them were considered not viable for evaluation. Conclusions: The results obtained indicate median quality maintenance of morphology. However, it is noted that in only 5 cases it was not possible to determine an evaluation, knowing from the outset that these are residual samples with a very scant cellularity. Thus, it is possible to say that the processing of bronchial washings to cellblock using HistoGel contributes to a concentration of the cytological material, allowing its evaluation and subsequent diagnosis. Additional diagnostic techniques are shown equally viable in these cellblocks.

Antero-Medialisation of the Tibial Tubercle for Patellar Instability

We reviewed 19 patients (24 knees) with patellofemoral instability treated surgically with antero-medialisation of the tibial tubercle and lateral retinacular release. Twenty-two knees had recurrent patellar dislocation and two patellar subluxation. Lateral retinacular release was performed arthroscopically in 15 knees. Average follow-up was 52 (16-86) months. There was one postoperative haemarthrosis and one failed fixation, which needed surgical revision. The average Lysholm score improved from 63.3 to 98 and only one knee had persistent patello-femoral pain postoperatively. The patellar tilt angle improved from 9.4 degrees to 5.5 degrees . There were no redislocations. We find that the surgical technique produces a consistent correction of patellar instability, but long-term studies are needed to confirm whether it can prevent arthritic degeneration.

Critical analysis: Portuguese 9th grade exam results and socioeconomic factors

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Economics from the NOVA – School of Business and Economics

Effect of school based physical activity programme (KISS) on fitness and adiposity in primary schoolchildren: cluster randomised controlled trial.

To assess the effectiveness of a school based physical activity programme during one school year on physical and psychological health in young schoolchildren. Cluster randomised controlled trial. 28 classes from 15 elementary schools in Switzerland randomly selected and assigned in a 4:3 ratio to an intervention (n=16) or control arm (n=12) after stratification for grade (first and fifth grade), from August 2005 to June 2006. 540 children, of whom 502 consented and presented at baseline. Children in the intervention arm (n=297) received a multi-component physical activity programme that included structuring the three existing physical education lessons each week and adding two additional lessons a week, daily short activity breaks, and physical activity homework. Children (n=205) and parents in the control group were not informed of an intervention group. For most outcome measures, the assessors were blinded. Primary outcome measures included body fat (sum of four skinfolds), aerobic fitness (shuttle run test), physical activity (accelerometry), and quality of life (questionnaires). Secondary outcome measures included body mass index and cardiovascular risk score (average z score of waist circumference, mean blood pressure, blood glucose, inverted high density lipoprotein cholesterol, and triglycerides). 498 children completed the baseline and follow-up assessments (mean age 6.9 (SD 0.3) years for first grade, 11.1 (0.5) years for fifth grade). After adjustment for grade, sex, baseline values, and clustering within classes, children in the intervention arm compared with controls showed more negative changes in the z score of the sum of four skinfolds (-0.12, 95 % confidence interval -0.21 to -0.03; P=0.009). Likewise, their z scores for aerobic fitness increased more favourably (0.17, 0.01 to 0.32; P=0.04), as did those for moderate-vigorous physical activity in school (1.19, 0.78 to 1.60; P<0.001), all day moderate-vigorous physical activity (0.44, 0.05 to 0.82; P=0.03), and total physical activity in school (0.92, 0.35 to 1.50; P=0.003). Z scores for overall daily physical activity (0.21, -0.21 to 0.63) and physical quality of life (0.42, -1.23 to 2.06) as well as psychological quality of life (0.59, -0.85 to 2.03) did not change significantly. A school based multi-component physical activity intervention including compulsory elements improved physical activity and fitness and reduced adiposity in children. Trial registration Current Controlled Trials ISRCTN15360785.

Efficiency diagnostic and advantages of procalcitonin and C-reactive protein in the early diagnosis of sepsis.

The goal of our study is to assess the diagnostic profi tability of procalcitonin (PCT) in septic shock and another biomarker as C-reactive protein (CRP). Results: Fifty-four septic patients were assessed, 66% were males; mean age, 63 years. Eighty-eight percent was diagnosed as septic shock and 11% severe sepsis. Seventy-six percent were medical patients. Positive blood cultures in 42.5%. Sepsis origin: respiratory 46%, neurological 5%, digestive 37% and urinary 3%. Average SOFA score was 10.4. Conclusions: PCT and CRP have the same efficiency in early sepsis diagnosis. The PCT and CRP effi ciency diagnostic together is signifi cant but small. We suggest using both with the doubt of sepsis.

State of Iowa Inmates at Mid-Year, 2001

This report was compiled at the request of the Department of Corrections. The statewide analysis of Iowa’s prison population at mid-year (June 30) 2001 includes the following information: · Type of Most Serious Offense (e.g., arson, assault, burglary, etc.) · Offense Class of Most Serious Offense · Sex · Race/Ethnicity · Age (median, or middle value) · Inmate Custody Level (minimum, medium, maximum security) · Educational Level (average) · Reading Score (average)

Estudi sobre la qualitat de vida de les persones amb demència ateses a la Unitat d'avaluació de deteriorament cognitiu de l'Hospital de la Santa Creu

OBJECTIU: determinar la qualitat de vida de les persones amb demència ateses en una unitat avaluadora de deteriorament cognitiu. MÈTODE: estudi descriptiu transversal amb una mostra consecutiva no probabilística, formada per 42 persones amb demència tipus Alzheimer lleu o moderada i els seus cuidadors. La Qualitat de Vida (QV) es va avaluar amb el qüestionari QoL-AD (Quality of Life Alzheimer’s Disease) en les versions per al pacient (QoL-ADp) i per al cuidador (QoL-ADc). RESULTATS: la mitjana de puntuació del QoL-ADp va ser de 35,38 punts (DE = 5,24) i del QoL-Adc, de 30,60 (DE 5,33). La diferència entre aquests resultats és significativa (p&0,001). Els pacients amb simptomatologia depressiva i els seus cuidadors van puntuar significativament més baix el QoL-AD (p&0,001). En les freqüències per ítems del QoL-ADp s’observa que: més del 75% van valorar com a bona/excel·lent les condicions de vida, família, matrimoni/relació estreta, vida social, situació financera i vida en general; el 61% valoraren bona/excel·lent la capacitat per realitzar tasques a casa; prop del 50% pensava que l’estat d’ànim, l’energia, la salut física, la capacitat per fer coses per diversió i la visió de si mateixos era dolenta/regular, i el 85,7% opinava que la seva memòria era dolenta/regular. CONCLUSIONS: els resultats obtinguts en el QoL-AD no difereixen dels obtinguts en altres investigacions. Suggereixen que les intervencions que genera l’avaluació de la QV en la pràctica clínica inclouen aspectes centrats pròpiament en la malaltia i aspectes vinculats amb les relacions socials.

Scoring system for renal pathology in Fabry disease: report of the international study group of fabry nephropathy (ISGFN).

BACKGROUND: In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function. METHODS: An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported. RESULTS: We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 micromol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m(2) and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1-2 chronic kidney disease with minimal proteinuria. CONCLUSIONS: The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for longitudinal assessment of prognosis and responses to therapy for Fabry nephropathy.

Estudi sobre la qualitat de vida de les persones amb demència ateses a la Unitat d'avaluació de deteriorament cognitiu de l'Hospital de la Santa Creu

OBJECTIU: determinar la qualitat de vida de les persones amb demència ateses en una unitat avaluadora de deteriorament cognitiu. MÈTODE: estudi descriptiu transversal amb una mostra consecutiva no probabilística, formada per 42 persones amb demència tipus Alzheimer lleu o moderada i els seus cuidadors. La Qualitat de Vida (QV) es va avaluar amb el qüestionari QoL-AD (Quality of Life Alzheimer’s Disease) en les versions per al pacient (QoL-ADp) i per al cuidador (QoL-ADc). RESULTATS: la mitjana de puntuació del QoL-ADp va ser de 35,38 punts (DE = 5,24) i del QoL-Adc, de 30,60 (DE 5,33). La diferència entre aquests resultats és significativa (p<0,001). Els pacients amb simptomatologia depressiva i els seus cuidadors van puntuar significativament més baix el QoL-AD (p<0,001). En les freqüències per ítems del QoL-ADp s’observa que: més del 75% van valorar com a bona/excel·lent les condicions de vida, família, matrimoni/relació estreta, vida social, situació financera i vida en general; el 61% valoraren bona/excel·lent la capacitat per realitzar tasques a casa; prop del 50% pensava que l’estat d’ànim, l’energia, la salut física, la capacitat per fer coses per diversió i la visió de si mateixos era dolenta/regular, i el 85,7% opinava que la seva memòria era dolenta/regular. CONCLUSIONS: els resultats obtinguts en el QoL-AD no difereixen dels obtinguts en altres investigacions. Suggereixen que les intervencions que genera l’avaluació de la QV en la pràctica clínica inclouen aspectes centrats pròpiament en la malaltia i aspectes vinculats amb les relacions socials.

Taenia solium transmission in a rural community in Honduras : an examination of risk factors and knowledge

Taenia soliurn taeniasis and cysticercosis are recognized as a major public health problem in Latin America. T. soliurn transmission not only affects the health of the individual, but also social and economic development, perpetuating the cycle of poverty. To determine prevalence rates, population knowledge and risk factors associated with transmission, an epidemiological study was undertaken in the rural community of Jalaca. Two standardized questionnaires were used to collect epidemiological and T. soli urn general knowledge data. Kato-Katz technique and an immunoblot assay (EITB) were used to determine taeniasis and seroprevalence, respectively. In total, 139 individuals belonging to 56 households participated in the study. Household characteristics were consistent with conditions of poverty of rural Honduras: 21.4% had no toilet or latrines, 19.6% had earthen floor, and 51.8% lacked indoor tap water. Pigs were raised in 46.4% of households, of which 70% allowed their pigs roaming freely. A human seroprevalence rate of 18.7% and a taeniasis prevalence rate of 2.4% were found. Only four persons answered correctly 2: 6 out of ten T. soliurn knowledge questions, for an average passing score of 2.9%. In general, a serious gap exists in knowledge regarding how humans acquire the infections, especially neurocysticercosis was identified. After regression analysis, the ability to recognize adult tapeworms and awareness of the clinical importance of taeniasis, were found to be significant risk factors for T. soliurn seropositivity. These results demonstrate a high level of transmission and a low level of kn~,wledge about Taenia soliurn in Jalaca. Consequently, intervention measures integrated with health education are necessary to decrease the burden caused by this parasite.

The relationship between working alliance and treatment outcomes in remedial instruction for older dyslexic children

Research in psychotherapy has demonstrated that a positive working alliance between therapist and client leads to positive treatment outcomes. Though its focus is in the area of psychotherapy, the concept of working alliance holds significant value to the area of education. Current applications of the theory in educational settings have looked at relationships between teacher and students in the broad context of classroom interaction and found significant promise. The present study investigates the application of the theory of working alliance in a sample of older reading disabled children. The study examined the psychometric properties of the Reading Alliance Scale for Children (RASC) and for Teachers (RAST) in relation to student reading ability and motivation. A sample of 254 (66.1 % male, 33.9% female) grade 6-8 students (mean age 12.7 years) were enrolled in a remedial reading program for reading disabled children. The average standard score across multiple reading measures was more than 1 SD below age-level expectations. Students responded to measures of reading achievement and motivation at pretest, after 70 hours (post 70) of remediation and at the end of the program (post 125). All participants completed measures on the working alliance relationship at post 70 and post 125. Results showed that teacher reports were most predictive of outcome compared to student reports of the working alliance relationship. Working alliance was correlated with posttest reading ability and motivation. Male students and Black students obtained the weakest working alliance reports from their teacher. Overall, findings support the view that students' relationships with teachers provide an important component of success in the classroom.

Qualidade de vida na perspectiva de idosos institucionalizados no Município de Natal - RN

A descriptive and exploratory Study, quantitative in nature, with the aim to assess the Quality of Life (QL) of the elderly leaving in a Long Residence Institution (LRI) according to their own perception. It was conducted in six Public Institutions of Long Residence for Seniors, in the municipality of Natal - RN, in the period of July to August 2007. The data was collected using two structured interview forms: the first, containing questions about socio-demographic aspects and the second - the WHOQUOL-OLD, prepared by the World Health Organization to assess elderly s quality of life. The reference population was 266 old persons, and a random sample, of 43, being 28 women and 15 men, who account for 30%. The results indicated there is a predominance of older women (65.1%) and the average age is 76.6 years; the predominant religion is the Catholic - 44.2% and, 32.6% are unmarried without children. As for schooling and precedence, 41.9% are illiterate and 67.4% come from the rural area. The time of residency in the institution goes between 1 to 5 years for 69.8% of the elderly, 37.2% of them residing in the institution for not having another option. Most elderly informed using medicines. 51.3% said they are taking anti-hypertensive. As for the other aspects of QL: sensory aspects, autonomy, past, present and future activities, social participation, death and dying and intimacy, the WHOQOL-OLD, showed an average total score of 52.9% (scale of 0 to 100), with a tendency to neutrality, denoting that the elderly, in this study, evaluated their QL as neither satisfactory or unsatisfactory. Of all the facets of the instrument of QL, the sensory facet secured the highest average scores (68,1%), showing that the elderly are "happy" in the situation in which they find themselves, not showing significant disabilities. The facet of autonomy, which refers to the independence and the ability to make decisions on their own life, received the lowest average scores (40.7%), showing the dissatisfaction of the elderly on this aspect. The evaluation of the elderly on other facets were: social participation (48.2%); activities past, present and future (44.6%) and intimacy (50.6%), all perceived as neither unsatisfactory or satisfactory. On the item death and dying, the elderly people declared themselves satisfied, with average score of 65.5%. The analysis of the reliability of the WHOQOL-OLD by the Cronbach Alpha showed 0.57, considering the 24 items that cover the instrument, showing regular internal reliability of the instrument, in our reality. The result is probably due to differences between the regions south and east and the broader sociocultural diversity. We believe that the elderly in this study, tended to realize their QL as neutral, considering it as neither unsatisfactory or satisfactory, result likely related to the resignation with the destine, characterized, at the time, by the finitude of life, feeling very common among elderly, or perhaps, even for an accommodation, often accompanied by discouragement, present in the daily life of many of them

Evaluation of physicochemical, microbiological and sensorial characteristics of fermented milk beverages with buttermilk addition

This study evaluated three fermented milk beverages to which had been added sugar strawberry puree post-fermentation. The base was composed of 70% of milk, with whey and buttermilk in the concentrations of 30% and 0%, 15% and 15%, and 0% and 30%, respectively. The starter culture developed well with all formulations reaching pH 4.74.9 in 180 min of fermentation. Lactic acid bacteria in the products were above 8 log cfu/mL throughout the study. The beverages presented similar pH, acidity and viscosity. Buttermilk and whey can be interesting ingredients to be added into fermented milk beverages, because the consumers liked all the products equally, which had an average acceptance score exceeding liked moderately.