Predictive Value Of Phase I Trials For Safety In Later Trials And Final Approved Dose: Analysis Of 61 Approved Cancer Drugs.

Phase I trials use a small number of patients to define a maximum tolerated dose (MTD) and the safety of new agents. We compared data from phase I and registration trials to determine whether early trials predicted later safety and final dose. We searched the U.S. Food and Drug Administration (FDA) website for drugs approved in nonpediatric cancers (January 1990-October 2012). The recommended phase II dose (R2PD) and toxicities from phase I were compared with doses and safety in later trials. In 62 of 85 (73%) matched trials, the dose from the later trial was within 20% of the RP2D. In a multivariable analysis, phase I trials of targeted agents were less predictive of the final approved dose (OR, 0.2 for adopting ± 20% of the RP2D for targeted vs. other classes; P = 0.025). Of the 530 clinically relevant toxicities in later trials, 70% (n = 374) were described in phase I. A significant relationship (P = 0.0032) between increasing the number of patients in phase I (up to 60) and the ability to describe future clinically relevant toxicities was observed. Among 28,505 patients in later trials, the death rate that was related to drug was 1.41%. In conclusion, dosing based on phase I trials was associated with a low toxicity-related death rate in later trials. The ability to predict relevant toxicities correlates with the number of patients on the initial phase I trial. The final dose approved was within 20% of the RP2D in 73% of assessed trials.

Censored Linear Regression Models For Irregularly Observed Longitudinal Data Using The Multivariate-t Distribution.

In acquired immunodeficiency syndrome (AIDS) studies it is quite common to observe viral load measurements collected irregularly over time. Moreover, these measurements can be subjected to some upper and/or lower detection limits depending on the quantification assays. A complication arises when these continuous repeated measures have a heavy-tailed behavior. For such data structures, we propose a robust structure for a censored linear model based on the multivariate Student's t-distribution. To compensate for the autocorrelation existing among irregularly observed measures, a damped exponential correlation structure is employed. An efficient expectation maximization type algorithm is developed for computing the maximum likelihood estimates, obtaining as a by-product the standard errors of the fixed effects and the log-likelihood function. The proposed algorithm uses closed-form expressions at the E-step that rely on formulas for the mean and variance of a truncated multivariate Student's t-distribution. The methodology is illustrated through an application to an Human Immunodeficiency Virus-AIDS (HIV-AIDS) study and several simulation studies.

[balloon Laryngoplasty For Acquired Subglottic Stenosis In Children: Predictive Factors For Success].

The treatment of subglottic stenosis in children remains a challenge for the otorhinolaryngologist, and may involve both endoscopic and open surgery. To report the experience of two tertiary facilities in the treatment of acquired subglottic stenosis in children with balloon laryngoplasty, and to identify predictive factors for success of the technique and its complications. Descriptive, prospective study of children diagnosed with acquired subglottic stenosis and submitted to balloon laryngoplasty as primary treatment. Balloon laryngoplasty was performed in 37 children with an average age of 22.5 months; 24 presented chronic subglottic stenosis and 13 acute subglottic stenosis. Success rates were 100% for acute subglottic stenosis and 32% for chronic subglottic stenosis. Success was significantly associated with acute stenosis, initial grade of stenosis, children of a smaller age, and the absence of tracheostomy. Transitory dysphagia was the only complication observed in three children. Balloon laryngoplasty may be considered the first line of treatment for acquired subglottic stenosis. In acute cases, the success rate is 100%, and although the results are less promising in chronic cases, complications are not significant and the possibility of open surgery remains without prejudice.

Comparing Near-infrared Conventional Diffuse Reflectance Spectroscopy And Hyperspectral Imaging For Determination Of The Bulk Properties Of Solid Samples By Multivariate Regression: Determination Of Mooney Viscosity And Plasticity Indices Of Natural Rubber.

Conventional reflectance spectroscopy (NIRS) and hyperspectral imaging (HI) in the near-infrared region (1000-2500 nm) are evaluated and compared, using, as the case study, the determination of relevant properties related to the quality of natural rubber. Mooney viscosity (MV) and plasticity indices (PI) (PI0 - original plasticity, PI30 - plasticity after accelerated aging, and PRI - the plasticity retention index after accelerated aging) of rubber were determined using multivariate regression models. Two hundred and eighty six samples of rubber were measured using conventional and hyperspectral near-infrared imaging reflectance instruments in the range of 1000-2500 nm. The sample set was split into regression (n = 191) and external validation (n = 95) sub-sets. Three instruments were employed for data acquisition: a line scanning hyperspectral camera and two conventional FT-NIR spectrometers. Sample heterogeneity was evaluated using hyperspectral images obtained with a resolution of 150 × 150 μm and principal component analysis. The probed sample area (5 cm(2); 24,000 pixels) to achieve representativeness was found to be equivalent to the average of 6 spectra for a 1 cm diameter probing circular window of one FT-NIR instrument. The other spectrophotometer can probe the whole sample in only one measurement. The results show that the rubber properties can be determined with very similar accuracy and precision by Partial Least Square (PLS) regression models regardless of whether HI-NIR or conventional FT-NIR produce the spectral datasets. The best Root Mean Square Errors of Prediction (RMSEPs) of external validation for MV, PI0, PI30, and PRI were 4.3, 1.8, 3.4, and 5.3%, respectively. Though the quantitative results provided by the three instruments can be considered equivalent, the hyperspectral imaging instrument presents a number of advantages, being about 6 times faster than conventional bulk spectrometers, producing robust spectral data by ensuring sample representativeness, and minimizing the effect of the presence of contaminants.

P16(ink) (4a) Expression As A Potential Marker Of Low-grade Cervical Intraepithelial Neoplasia Progression.

To evaluate p16(INK) (4a) immunoexpression in CIN1 lesions looking for differences between cases that progress to CIN2/3 maintain CIN1 diagnosis, or spontaneously regress. Seventy-four CIN1 biopsies were studied. In the follow-up, a second biopsy was performed and 28.7% showed no lesion (regression), 37.9% maintained CIN1, and 33.4% progressed to CIN2/3. Immunostaining for p16(INK) (4a) was performed in the first biopsy and it was considered positive when there was strong and diffuse staining of the basal and parabasal layers. Pearson's chi-square was used to compare the groups (p ≤ 0.05). The age of the patients was similar. There was no significant difference in p16(INK) (4a) immunoexpression in the groups, however, statistical analyses showed a significant association when only the progression and regression groups were compared (p = 0.042). Considering p16(INK) (4a) positivity and the progression to CIN2/3, the sensitivity, specificity, positive, and negative predictive values in our cohort were 45%, 75%, 47%, and 94%, respectively. We emphasize that CIN1 with p16(INK) (4a) staining was associated with lesion progression, but the sensitivity was not high. However, the negative predictive value was more reliable (94%) and p16(INK) (4a) may represent a useful biomarker that can identify CIN1 lesions that need particular attention, complementing morphology.

Aplicação do escore MELD em pacientes submetidos a transplante de fígado: análise retrospectiva da sobrevida e dos fatores preditivos a curto e longo prazo

BACKGROUND: The model for end-stage liver disease (MELD) was developed to predict short-term mortality in patients with cirrhosis. There are few reports studying the correlation between MELD and long-term posttransplantation survival. AIM: To assess the value of pretransplant MELD in the prediction of posttransplant survival. METHODS: The adult patients (age >18 years) who underwent liver transplantation were examined in a retrospective longitudinal cohort of patients, through the prospective data base. We excluded acute liver failure, retransplantation and reduced or split-livers. The liver donors were evaluated according to: age, sex, weight, creatinine, bilirubin, sodium, aspartate aminotransferase, personal antecedents, brain death cause, steatosis, expanded criteria donor number and index donor risk. The recipients' data were: sex, age, weight, chronic hepatic disease, Child-Turcotte-Pugh points, pretransplant and initial MELD score, pretransplant creatinine clearance, sodium, cold and warm ischemia times, hospital length of stay, blood requirements, and alanine aminotransferase (ALT >1,000 UI/L = liver dysfunction). The Kaplan-Meier method with the log-rank test was used for the univariable analyses of posttransplant patient survival. For the multivariable analyses the Cox proportional hazard regression method with the stepwise procedure was used with stratifying sodium and MELD as variables. ROC curve was used to define area under the curve for MELD and Child-Turcotte-Pugh. RESULTS: A total of 232 patients with 10 years follow up were available. The MELD cutoff was 20 and Child-Turcotte-Pugh cutoff was 11.5. For MELD score > 20, the risk factors for death were: red cell requirements, liver dysfunction and donor's sodium. For the patients with hyponatremia the risk factors were: negative delta-MELD score, red cell requirements, liver dysfunction and donor's sodium. The regression univariated analyses came up with the following risk factors for death: score MELD > 25, blood requirements, recipient creatinine clearance pretransplant and age donor >50. After stepwise analyses, only red cell requirement was predictive. Patients with MELD score < 25 had a 68.86%, 50,44% and 41,50% chance for 1, 5 and 10-year survival and > 25 were 39.13%, 29.81% and 22.36% respectively. Patients without hyponatremia were 65.16%, 50.28% and 41,98% and with hyponatremia 44.44%, 34.28% and 28.57% respectively. Patients with IDR > 1.7 showed 53.7%, 27.71% and 13.85% and index donor risk <1.7 was 63.62%, 51.4% and 44.08%, respectively. Age donor > 50 years showed 38.4%, 26.21% and 13.1% and age donor <50 years showed 65.58%, 26.21% and 13.1%. Association with delta-MELD score did not show any significant difference. Expanded criteria donors were associated with primary non-function and severe liver dysfunction. Predictive factors for death were blood requirements, hyponatremia, liver dysfunction and donor's sodium. CONCLUSION: In conclusion MELD over 25, recipient's hyponatremia, blood requirements, donor's sodium were associated with poor survival.

Estratégias para individualização de resultados em testes de desempenho

Universidade Estadual de Campinas. Faculdade de Educação Física

Reproductive behavior, development and eye regression in the cave armored catfish, Ancistrus cryptophthalmus Reis, 1987 (Siluriformes: Loricariidae), breed in laboratory

The troglobitic armored catfish, Ancistrus cryptophthalmus (Loricariidae, Ancistrinae) is known from four caves in the São Domingos karst area, upper rio Tocantins basin, Central Brazil. These populations differ in general body shape and degree of reduction of eyes and of pigmentation. The small Passa Três population (around 1,000 individuals) presents the most reduced eyes, which are not externally visible in adults. A small group of Passa Três catfish, one male and three females, reproduced spontaneously thrice in laboratory, at the end of summertime in 2000, 2003 and 2004. Herein we describe the reproductive behavior during the 2003 event, as well as the early development of the 2003 and 2004 offsprings, with focus on body growth and ontogenetic regression of eyes. The parental care by the male, which includes defense of the rock shelter where the egg clutch is laid, cleaning and oxygenation of eggs, is typical of many loricariids. On the other hand, the slow development, including delayed eye degeneration, low body growth rates and high estimated longevity (15 years or more) are characteristic of precocial, or K-selected, life cycles. In the absence of comparable data for close epigean relatives (Ancistrus spp.), it is not possible to establish whether these features are an autapomorphic specialization of the troglobitic A. cryptophthalmus or a plesiomorphic trait already present in the epigean ancestor, possibly favoring the adoption of the life in the food-poor cave environment. We briefly discuss the current hypotheses on eye regression in troglobitic vertebrates.

Impact on human health of particulate matter emitted from burnings in the Brazilian Amazon region

OBJECTIVE: To analyze the impact on human health of exposure to particulate matter emitted from burnings in the Brazilian Amazon region. METHODS: This was an ecological study using an environmental exposure indicator presented as the percentage of annual hours (AH%) of PM2.5 above 80 μg/m3. The outcome variables were the rates of hospitalization due to respiratory disease among children, the elderly and the intermediate age group, and due to childbirth. Data were obtained from the National Space Research Institute and the Ministry of Health for all of the microregions of the Brazilian Amazon region, for the years 2004 and 2005. Multiple regression models for the outcome variables in relation to the predictive variable AH% of PM2.5 above 80 μg/m3 were analyzed. The Human Development Index (HDI) and mean number of complete blood counts per 100 inhabitants in the Brazilian Amazon region were the control variables in the regression analyses. RESULTS: The association of the exposure indicator (AH%) was higher for the elderly than for other age groups (β = 0.10). For each 1% increase in the exposure indicator there was an increase of 8% in child hospitalization, 10% in hospitalization of the elderly, and 5% for the intermediate age group, even after controlling for HDI and mean number of complete blood counts. No association was found between the AH% and hospitalization due to childbirth. CONCLUSIONS: The indicator of atmospheric pollution showed an association with occurrences of respiratory diseases in the Brazilian Amazon region, especially in the more vulnerable age groups. This indicator may be used to assess the effects of forest burning on human health.

Impacto da adequação da oferta energética sobre a mortalidade em pacientes de UTI recebendo nutrição enteral

OBJETIVO: Investigar a relação entre adequação da oferta energética e mortalidade na unidade de terapia intensiva em pacientes sob terapia nutricional enteral exclusiva. MÉTODOS: Estudo observacional prospectivo conduzido em uma unidade de terapia intensiva em 2008 e 2009. Foram incluídos pacientes >18 anos que receberam terapia nutricional enteral por >72h. A adequação da oferta de energia foi estimada pela razão administrado/prescrito. Para a investigação da relação entre variáveis preditoras (adequação da oferta energética, escore APACHE II, sexo, idade e tempo de permanência na unidade de terapia intensiva e o desfecho mortalidade na unidade de terapia intensiva, utilizou-se o modelo de regressão logística não condicional. RESULTADOS: Foram incluídos 63 pacientes (média 58 anos, mortalidade 27%), 47,6% dos quais receberam mais de 90% da energia prescrita (adequação média 88,2%). O balanço energético médio foi de -190 kcal/dia. Observou-se associação significativa entre ocorrência de óbito e as variáveis idade e tempo de permanência na unidade de terapia intensiva, após a retirada das variáveis adequação da oferta energética, APACHE II e sexo durante o processo de modelagem. CONCLUSÃO: A adequação da oferta energética não influenciou a taxa de mortalidade na unidade de terapia intensiva. Protocolos de infusão de nutrição enteral seguidos criteriosamente, com adequação administrado/prescrito acima de 70%, parecem ser suficientes para não interferirem na mortalidade. Dessa forma, pode-se questionar a obrigatoriedade de atingir índices próximos a 100%, considerando a elevada frequência com que ocorrem interrupções no fornecimento de dieta enteral devido a intolerância gastrointestinal e jejuns para exames e procedimentos. Pesquisas futuras poderão identificar a meta ideal de adequação da oferta energética que resulte em redução significativa de complicações, mortalidade e custos.

Preditores sócio-demográficos, de estilo de vida e gineco-obstétricos das concentrações séricas ou plasmáticas de homocisteína, ácido fólico e vitaminas B12 e B6 em mulheres de baixa renda de São Paulo, Brasil

O presente estudo investigou fatores sócio-demográficos, de estilo de vida e gineco-obstétricos associados às concentrações séricas ou plasmáticas de homocisteína, ácido fólico, vitaminas B12 e B6 em mulheres de baixa renda de São Paulo, Brasil. Concentrações séricas de ácido fólico e vitamina B12 foram analisadas por fluoroimunoensaio; concentrações plasmáticas de homocisteína e vitamina B6, por cromatografia líquida de alta performance em fase reversa. Variáveis independentes foram inicialmente selecionadas segundo pressupostos teóricos, correlação de Pearson ou teste Kruskal-Wallis (p < 0,20). Concentrações alteradas segundo pontos de corte para homocisteína, ácido fólico, vitaminas B12 e B6 foram observadas em 20%, 6%, 11% e 67% das participantes, respectivamente. Idade foi positivamente correlacionada à vitamina B6 e homocisteína plasmáticas (p < 0,001). Índice de massa corporal foi positivamente correlacionado à vitamina B6 plasmática (p < 0,001). Modelos de regressão linear múltiplos explicaram 10,2%, 5,8%, 14,4% e 9,4% das concentrações de ácido fólico, vitamina B12, vitamina B6 e homocisteína, respectivamente. No presente estudo, variáveis sócio-demográficas, de estilo de vida e gineco-obstétricas apresentaram contribuição importante na variação das concentrações dos indicadores bioquímicos avaliados.

Menopausal status: a possible predictive factor for recurrence in women with cancer of the uterine cervix without pelvic lymph node metastasis

Abstract Objectives to evaluate risk factors for recurrence of carcinoma of the uterine cervix among women who had undergone radical hysterectomy without pelvic lymph node metastasis, while taking into consideration not only the classical histopathological factors but also sociodemographic, clinical and treatment-related factors. Study desin This was an exploratory analysis on 233 women with carcinoma of the uterine cervix (stages IB and IIA) who were treated by means of radical hysterectomy and pelvic lymphadenectomy, with free surgical margins and without lymph node metastases on conventional histopathological examination. Women with histologically normal lymph nodes but with micrometastases in the immunohistochemical analysis (AE1/AE3) were excluded. Disease-free survival for sociodemographic, clinical and histopathological variables was calculated using the Kaplan-Meier method. The Cox proportional hazards model was used to identify the independent risk factors for recurrence. Twenty-seven recurrences were recorded (11.6%), of which 18 were pelvic, four were distant, four were pelvic + distant and one was of unknown location. The five-year disease-free survival rate among the study population was 88.4%. The independent risk factors for recurrence in the multivariate analysis were: postmenopausal status (HR 14.1; 95% CI: 3.7-53.6; P < 0.001), absence of or slight inflammatory reaction (HR 7.9; 95% CI: 1.7-36.5; P = 0.008) and invasion of the deepest third of the cervix (HR 6.1; 95% CI: 1.3-29.1; P = 0.021). Postoperative radiotherapy was identified as a protective factor against recurrence (HR 0.02; 95% CI: 0.001-0.25; P = 0.003). (To continue) Postmenopausal status is a possible independent risk factor for recurrence even when adjusted for classical prognostic factors (such as tumour size, depth of tumour invasion, capillary embolisation) and treatment-related factors (period of treatment and postoperative radiotherapy status)

Chemometric Studies on Natural Products as Potential Inhibitors of the NADH Oxidase from Trypanosoma cruzi Using the VolSurf Approach

Natural products have widespread biological activities, including inhibition of mitochondrial enzyme systems. Some of these activities, for example cytotoxicity, may be the result of alteration of cellular bioenergetics. Based on previous computer-aided drug design (CADD) studies and considering reported data on structure-activity relationships (SAR), an assumption regarding the mechanism of action of natural products against parasitic infections involves the NADH-oxidase inhibition. In this study, chemometric tools, such as: Principal Component Analysis (PCA), Consensus PCA (CPCA), and partial least squares regression (PLS), were applied to a set of forty natural compounds, acting as NADH-oxidase inhibitors. The calculations were performed using the VolSurf+ program. The formalisms employed generated good exploratory and predictive results. The independent variables or descriptors having a hydrophobic profile were strongly correlated to the biological data.

Multi-trait and random regression mature weight heritability and breeding value estimates in Nelore cattle

Mature weight breeding values were estimated using a multi-trait animal model (MM) and a random regression animal model (RRM). Data consisted of 82 064 weight records from 8 145 animals, recorded from birth to eight years of age. Weights at standard ages were considered in the MM. All models included contemporary groups as fixed effects, and age of dam (linear and quadratic effects) and animal age as covariates. In the RRM, mean trends were modelled through a cubic regression on orthogonal polynomials of animal age and genetic maternal and direct and maternal permanent environmental effects were also included as random. Legendre polynomials of orders 4, 3, 6 and 3 were used for animal and maternal genetic and permanent environmental effects, respectively, considering five classes of residual variances. Mature weight (five years) direct heritability estimates were 0.35 (MM) and 0.38 (RRM). Rank correlation between sires' breeding values estimated by MM and RRM was 0.82. However, selecting the top 2% (12) or 10% (62) of the young sires based on the MM predicted breeding values, respectively 71% and 80% of the same sires would be selected if RRM estimates were used instead. The RRM modelled the changes in the (co) variances with age adequately and larger breeding value accuracies can be expected using this model.

Incidence of Pressure Ulcers in the Institutionalized Elderly

PURPOSE: The aim of this study was to analyze the incidence of pressure ulcers (PUs) in elderly people living in long-term care facilities (LTCFs). DESIGN: We completed a prospective, comparison cohort study. SUBJECTS AND SETTING: Ninety-four persons, 60 years or older, participated in the study. Participants resided in 4 not-for-profit LTCFs in 3 cities in the southern region of the Brazilian state of Minas Gerais. METHODS: Participants underwent complete skin examination and Braden Scale rating every 2 days for 3 months. When a PU was detected, a careful examination was done to assess its stage, location, and size. From this moment on, the patient was included in the incidence rate and was excluded from the study. RESULTS: The incidence rate of PUs was 39.4%; 37 (77.1%) developed a single ulcer. The most common locations were the malleolus (27.1%) and the ischium (25.0%). Stage I PU were most frequent (66.7%). Females (62.8%) and whites (68.19%) prevailed, with an average age of 79.06 +/- 9.6 years. Body mass index was 20.93 +/- 4.9, with a predominance of urinary diseases (58.5%) and use of neuroleptics/psychotropics (52.1%); 28.7% had had a previous ulcer. Gender and the occurrence of a previous ulcer were found to predict the development of PU, based on logistic regression analysis (r(2) = 0.311). CONCLUSIONS: The overall incidence of PU was significant, but the incidence of stage II and higher PUs was less than 12% and no elders had stage III or IV ulcers. Factors associated with PU development include female gender, regular use of neuroleptic or psychotropic medications, and a history of pressure ulceration.