A 15-year study on the treatment of undernourished children at a nutrition rehabilitation centre (CREN), Brazil

Objective: To build a life table and determine the factors related to the time of treatment of undernourished children at a nutrition rehabilitation centre (CREN), Sao Paulo, Brazil. Design: Nutritional status was assessed from weight-for-age, height-for-age and BMI-for-age Z-scores, while neuropsychomotor development was classified according to the milestones of childhood development. Life tables, Kaplan-Meier survival curves and Cox multiple regression models were employed in data analysis. Setting: CREN (Centre of Nutritional Recovery and Education), Sao Paulo, Brazil. Subjects: Undernourished children (n 228) from the southern slums of Sao Paulo who had received treatment at CREN under a day-hospital regime between the years 1994 and 2009. Results: The Kaplan-Meier curves of survival analysis showed statistically significant differences in the periods of treatment at CREN between children presenting different degrees of neuropsychomotor development (log-rank = 6.621; P = 0.037). Estimates based on the multivariate Cox model revealed that children aged >= 24 months at the time of admission exhibited a lower probability of nutritional rehabilitation (hazard ratio (HR) = 0.49; P = 0.046) at the end of the period compared with infants aged up 12 months. Children presenting slow development were better rehabilitated in comparison with those exhibiting adequate evolution (HR = 4.48; P = 0.023). No significant effects of sex, degree of undernutrition or birth weight on the probability of nutritional rehabilitation were found. Conclusions: Age and neuropsychomotor developmental status at the time of admission to CREN are critical factors in determining the duration of treatment.

Concordance Probability and Discriminatory Power in Proportional Hazards Regression

The concordance probability is used to evaluate the discriminatory power and the predictive accuracy of nonlinear statistical models. We derive an analytic expression for the concordance probability in the Cox proportional hazards model. The proposed estimator is a function of the regression parameters and the covariate distribution only and does not use the observed event and censoring times. For this reason it is asymptotically unbiased, unlike Harrell's c-index based on informative pairs. The asymptotic distribution of the concordance probability estimate is derived using U-statistic theory and the methodology is applied to a predictive model in lung cancer.

Are beta-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study

BACKGROUND: The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta1-beta2/alpha1 blocker carvedilol compared with placebo. METHODS: Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n = 445) or not (n = 1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations. RESULTS: The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone. CONCLUSION: Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or angiotensin II antagonist) therapy. Therefore, the use of spironolactone in patients with severe CHF does not obviate the necessity of additional treatment that interferes with the adverse effects of sympathetic activation, specifically beta-blockade.

Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study

BACKGROUND: A growing number of case reports have described tenofovir (TDF)-related proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). We assessed TDF-associated changes in cGFR in a large observational HIV cohort. METHODS: We compared treatment-naive patients or patients with treatment interruptions > or = 12 months starting either a TDF-based combination antiretroviral therapy (cART) (n = 363) or a TDF-sparing regime (n = 715). The predefined primary endpoint was the time to a 10 ml/min reduction in cGFR, based on the Cockcroft-Gault equation, confirmed by a follow-up measurement at least 1 month later. In sensitivity analyses, secondary endpoints including calculations based on the modified diet in renal disease (MDRD) formula were considered. Endpoints were modelled using pre-specified covariates in a multiple Cox proportional hazards model. RESULTS: Two-year event-free probabilities were 0.65 (95% confidence interval [CI] 0.58-0.72) and 0.80 (95% CI 0.76-0.83) for patients starting TDF-containing or TDF-sparing cART, respectively. In the multiple Cox model, diabetes mellitus (hazard ratio [HR] = 2.34 [95% CI 1.24-4.42]), higher baseline cGFR (HR = 1.03 [95% CI 1.02-1.04] by 10 ml/min), TDF use (HR = 1.84 [95% CI 1.35-2.51]) and boosted protease inhibitor use (HR = 1.71 [95% CI 1.30-2.24]) significantly increased the risk for reaching the primary endpoint. Sensitivity analyses showed high consistency. CONCLUSION: There is consistent evidence for a significant reduction in cGFR associated with TDF use in HIV-infected patients. Our findings call for a strict monitoring of renal function in long-term TDF users with tests that distinguish between glomerular dysfunction and proximal renal tubulopathy, a known adverse effect of TDF.

Health care index score and risk of death following tuberculosis diagnosis in HIV-positive patients

OBJECTIVES: To assess health care utilisation for patients co-infected with TB and HIV (TB-HIV), and to develop a weighted health care index (HCI) score based on commonly used interventions and compare it with patient outcome. METHODS: A total of 1061 HIV patients diagnosed with TB in four regions, Central/Northern, Southern and Eastern Europe and Argentina, between January 2004 and December 2006 were enrolled in the TB-HIV study. A weighted HCI score (range 0–5), based on independent prognostic factors identified in multivariable Cox models and the final score, included performance of TB drug susceptibility testing (DST), an initial TB regimen containing a rifamycin, isoniazid and pyrazinamide, and start of combination antiretroviral treatment (cART). RESULTS: The mean HCI score was highest in Central/Northern Europe (3.2, 95%CI 3.1–3.3) and lowest in Eastern Europe (1.6, 95%CI 1.5–1.7). The cumulative probability of death 1 year after TB diagnosis decreased from 39% (95%CI 31–48) among patients with an HCI score of 0, to 9% (95%CI 6–13) among those with a score of ≥4. In an adjusted Cox model, a 1-unit increase in the HCI score was associated with 27% reduced mortality (relative hazard 0.73, 95%CI 0.64–0.84). CONCLUSIONS: Our results suggest that DST, standard anti-tuberculosis treatment and early cART may improve outcome for TB-HIV patients. The proposed HCI score provides a tool for future research and monitoring of the management of TB-HIV patients. The highest HCI score may serve as a benchmark to assess TB-HIV management, encouraging continuous health care improvement.

Time to renal disease and end-stage renal disease in PROFILE: a multiethnic lupus cohort.

BACKGROUND: Renal involvement is a serious manifestation of systemic lupus erythematosus (SLE); it may portend a poor prognosis as it may lead to end-stage renal disease (ESRD). The purpose of this study was to determine the factors predicting the development of renal involvement and its progression to ESRD in a multi-ethnic SLE cohort (PROFILE). METHODS AND FINDINGS: PROFILE includes SLE patients from five different United States institutions. We examined at baseline the socioeconomic-demographic, clinical, and genetic variables associated with the development of renal involvement and its progression to ESRD by univariable and multivariable Cox proportional hazards regression analyses. Analyses of onset of renal involvement included only patients with renal involvement after SLE diagnosis (n = 229). Analyses of ESRD included all patients, regardless of whether renal involvement occurred before, at, or after SLE diagnosis (34 of 438 patients). In addition, we performed a multivariable logistic regression analysis of the variables associated with the development of renal involvement at any time during the course of SLE.In the time-dependent multivariable analysis, patients developing renal involvement were more likely to have more American College of Rheumatology criteria for SLE, and to be younger, hypertensive, and of African-American or Hispanic (from Texas) ethnicity. Alternative regression models were consistent with these results. In addition to greater accrued disease damage (renal damage excluded), younger age, and Hispanic ethnicity (from Texas), homozygosity for the valine allele of FcgammaRIIIa (FCGR3A*GG) was a significant predictor of ESRD. Results from the multivariable logistic regression model that included all cases of renal involvement were consistent with those from the Cox model. CONCLUSIONS: Fcgamma receptor genotype is a risk factor for progression of renal disease to ESRD. Since the frequency distribution of FCGR3A alleles does not vary significantly among the ethnic groups studied, the additional factors underlying the ethnic disparities in renal disease progression remain to be elucidated.

Combination of expression levels of miR-21 and miR-126 is associated with cancer-specific survival in clear-cell renal cell carcinoma

BACKGROUND Renal cell carcinoma (RCC) is marked by high mortality rate. To date, no robust risk stratification by clinical or molecular prognosticators of cancer-specific survival (CSS) has been established for early stages. Transcriptional profiling of small non-coding RNA gene products (miRNAs) seems promising for prognostic stratification. The expression of miR-21 and miR-126 was analysed in a large cohort of RCC patients; a combined risk score (CRS)-model was constructed based on expression levels of both miRNAs. METHODS Expression of miR-21 and miR-126 was evaluated by qRT-PCR in tumour and adjacent non-neoplastic tissue in n = 139 clear cell RCC patients. Relation of miR-21 and miR-126 expression with various clinical parameters was assessed. Parameters were analysed by uni- and multivariate COX regression. A factor derived from the z-score resulting from the COX model was determined for both miRs separately and a combined risk score (CRS) was calculated multiplying the relative expression of miR-21 and miR-126 by this factor. The best fitting COX model was selected by relative goodness-of-fit with the Akaike information criterion (AIC). RESULTS RCC with and without miR-21 up- and miR-126 downregulation differed significantly in synchronous metastatic status and CSS. Upregulation of miR-21 and downregulation of miR-126 were independently prognostic. A combined risk score (CRS) based on the expression of both miRs showed high sensitivity and specificity in predicting CSS and prediction was independent from any other clinico-pathological parameter. Association of CRS with CSS was successfully validated in a testing cohort containing patients with high and low risk for progressive disease. CONCLUSIONS A combined expression level of miR-21 and miR-126 accurately predicted CSS in two independent RCC cohorts and seems feasible for clinical application in assessing prognosis.

The effect of cumulating exposure to abacavir on the risk of cardiovascular disease events in patients from the Swiss HIV Cohort Study.

BACKGROUND Patients with HIV exposed to the antiretroviral drug abacavir may have an increased risk of cardiovascular disease (CVD). There is concern that this association arises because of a channelling bias. Even if exposure is a risk, it is not clear how that risk changes as exposure cumulates. METHODS We assess the effect of exposure to abacavir on the risk of CVD events in the Swiss HIV Cohort Study. We use a new marginal structural Cox model to estimate the effect of abacavir as a flexible function of past exposures while accounting for risk factors that potentially lie on a causal pathway between exposure to abacavir and CVD. RESULTS 11,856 patients were followed for a median of 6.6 years; 365 patients had a CVD event (4.6 events per 1000 patient years). In a conventional Cox model, recent - but not cumulative - exposure to abacavir increased the risk of a CVD event. In the new marginal structural Cox model, continued exposure to abacavir during the past four years increased the risk of a CVD event (hazard ratio 2.06, 95% confidence interval 1.43-2.98). The estimated function for the effect of past exposures suggests that exposure during the past 6 to 36 months caused the greatest increase in risk. CONCLUSIONS Abacavir increases the risk of a CVD event: the effect of exposure is not immediate, rather the risk increases as exposure cumulates over the past few years. This gradual increase in risk is not consistent with a rapidly acting mechanism, such as acute inflammation.

Venous thromboembolism in patients with acute leukemia: Prevalence, incidence, recurrence of thrombosis, risk factors, and impact on survival

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most preventable cardiovascular disease and a growing public health problem in the United States. The incidence of VTE remains high with an annual estimate of more than 600,000 symptomatic events. DVT affects an estimated 2 million American each year with a death toll of 300,000 persons per year from DVT-related PE. Leukemia patients are at high risk for both hemorrhage and thrombosis; however, little is known about thrombosis among acute leukemia patients. The ultimate goal of this dissertation was to obtain deep understanding of thrombotic issue among acute leukemia patients. The dissertation was presented in a format of three papers. First paper mainly looked at distribution and risk factors associated with development of VTE among patients with acute leukemia prior to leukemia treatment. Second paper looked at incidence, risk factors, and impact of VTE on survival of patients with acute lymphoblastic leukemia during treatment. Third paper looked at recurrence and risk factors for VTE recurrence among acute leukemia patients with an initial episode of VTE. Descriptive statistics, Chi-squared or Fisher's exact test, median test, Mann-Whitney test, logistic regression analysis, Nonparametric Estimation Kaplan-Meier with a log-rank test or Cox model were used when appropriate. Results from analyses indicated that acute leukemia patients had a high prevalence, incidence, and recurrent rate of VTE. Prior history of VTE, obesity, older age, low platelet account, presence of Philadelphia positive ALL, use of oral contraceptives or hormone replacement therapy, presence of malignancies, and co-morbidities may place leukemia patients at an increased risk for VTE development or recurrence. Interestingly, development of VTE was not associated with a higher risk of death among hospitalized acute leukemia patients.^

Oxygen variance and meridional oxygen supply in the Tropical North East Atlantic oxygen minimum zone

The distribution of the mean oceanic oxygen concentration results from a balance between ventilation and consumption. In the eastern tropical Pacific and Atlantic, this balance creates extended oxygen minimum zones (OMZ) at intermediate depth. Here, we analyze hydrographic and velocity data from shipboard and moored observations, which were taken along the 23°W meridian cutting through the Tropical North East Atlantic (TNEA) OMZ, to study the distribution and generation of oxygen variability. By applying the extended Osborn-Cox model, the respective role of mesoscale stirring and diapycnal mixing in producing enhanced oxygen variability, found at the southern and upper boundary of the OMZ, is quantified. From the well-ventilated equatorial region toward the OMZ core a northward eddy-driven oxygen flux is observed whose divergence corresponds to an oxygen supply of about 2.4 µmol kg-1 year-1 at the OMZ core depth. Above the OMZ core, mesoscale eddies act to redistribute low- and high-oxygen waters associated with westward and eastward currents, respectively. Here, absolute values of the local oxygen supply >10 mmol kg-1 year-1 are found, likely balanced by mean zonal advection. Combining our results with recent studies, a refined oxygen budget for the TNEA OMZ is derived. Eddy-driven meridional oxygen supply contributes more than 50 % of the supply required to balance the estimated oxygen consumption. The oxygen tendency in the OMZ, as given by the multidecadal oxygen decline, is maximum slightly above the OMZ core and represents a substantial imbalance of the oxygen budget reaching about 20 % of the magnitude of the eddy-driven oxygen supply.

Restoration of micro data of John Lossing Buck's survey and analysis of the inverse relationship between yield and farm size in rural China in the 1930's

A large scale Chinese agricultural survey was conducted at the direction of John Lossing Buck from 1929 through 1933. At the end of the 1990’s, some parts of the original micro data of Buck’s survey were discovered at Nanjing Agricultural University. An international joint study was begun to restore micro data of Buck’s survey and construct parts of the micro database on both the crop yield survey and special expenditure survey. This paper includes a summary of the characteristics of farmlands and cropping patterns in crop yield micro data that covered 2,102 farmers in 20 counties of 9 provinces. In order to test the classical hypothesis of whether or not an inverse relationship between land productivity and cultivated area may be observed in developing countries, a Box-Cox transformation test was conducted for functional forms on five main crops of Buck’s crop yield survey. The result of the test shows that the relationship between land productivity and cultivated areas of wheat and barley is linear and somewhat negative; those of rice, rapeseed, and seed cotton appear to be slightly positive. It can be tentatively concluded that the relationship between cultivated area and land productivity are not the same among crops, and the difference of labor intensity and the level of commercialization of each crop may be strongly related to the existence or non-existence of inverse relationships.

A wind tunnel two-dimensional parametric investigation of biplane configurations

This paper presents an experimental and systematic investigation about how geometric parameters on a biplane configuration have an influence on aerodynamic parameters. This experimental investigation has been developed in a two-dimensional approach. Theoretical studies about biplanes configurations have been developed in the past, but there is not enough information about experimental wind tunnel data at low Reynolds number. This two-dimensional study is a first step to further tridimensional investigations about the box wing configuration. The main objective of the study is to find the relationships between the geometrical parameters which present the best aerodynamic behavior: the highest lift, the lowest drag and the lowest slope of the pitching moment. A tridimensional wing-box model will be designed following the pattern of the two dimensional study conclusions. It will respond to the geometrical relationships that have been considered to show the better aerodynamic behavior. This box-wing model will be studied in the aim of comparing the advantages and disadvantages between this biplane configuration and the plane configuration, looking for implementing the box-wing in the UAV?s field. Although the box wing configuration has been used in a small number of existing UAV, prestigious researchers have found it as a field of high aerodynamic and structural potential.

Métodos de adequação e diagnóstico em modelos de sobrevivência dinâmicos

A análise de dados de sobrevivência tem sido tradicionalmente baseada no modelo de regressão de Cox (COX, 1972). No entanto, a suposição de taxas de falha proporcionais assumida para esse modelo pode não ser atendida em diversas situações práticas. Essa restrição do modelo de Cox tem gerado interesse em abordagens alternativas, dentre elas os modelos dinâmicos que permitem efeito das covariáveis variando no tempo. Neste trabalho, foram revisados os principais modelos de sobrevivência dinâmicos com estrutura aditiva e multiplicativa nos contextos não paramétrico e semiparamétrico. Métodos gráficos baseados em resíduos foram apresentados com a finalidade de avaliar a qualidade de ajuste desses modelos. Uma versão tempo-dependente da área sob a curva ROC, denotada por AUC(t), foi proposta com a finalidade de avaliar e comparar a qualidade de predição entre modelos de sobrevivência com estruturas aditiva e multiplicativa. O desempenho da AUC(t) foi avaliado por meio de um estudo de simulação. Dados de três estudos descritos na literatura foram também analisados para ilustrar ou complementar os cenários que foram considerados no estudo de simulação. De modo geral, os resultados obtidos indicaram que os métodos gráficos apresentados para avaliar a adequação dos modelos em conjunto com a AUC(t) se constituem em um conjunto de ferramentas estatísticas úteis para o próposito de avaliar modelos de sobrevivência dinâmicos nos contextos não paramétrico e semiparamétrico. Além disso, a aplicação desse conjunto de ferramentas em alguns conjuntos de dados evidenciou que se, por um lado, os modelos dinâmicos são atrativos por permitirem covariáveis tempo-dependentes, por outro lado podem não ser apropriados para todos os conjuntos de dados, tendo em vista que estimação pode apresentar restrições para alguns deles.

Relative predictive value of intraventricular dysynchrony in determining long-term outcome in patients with known or suspected coronary disease

Improvement of intra-ventricular dysynchrony (IVD) in pts undergoing bi-ventricular pacing is associated with clinical improvementbut little isknownabout the relationship between IVD and prognosis.We sought whether IVD influences long-term outcome in pts with known or suspected coronary disease (CAD). Tissue Doppler imaging was performed in 184 pts (aged 61±10 years, 67% male) prior to dobutamine echo. From velocity curves the interval between QRS onset and max systolic velocity (Ts) was measured in basal septal, lateral, inferior and anterior segments. The maximal difference in Ts between segments (TsMax) was used as a measure of IVD. The standard deviation (TsSD) between all segments and the septal-lateral difference (TsSL) were also calculated. Pts were followed up for a median interval of 5 years and a Cox model used for survival analysis. The medianwall motion index (WMI) was 1.3 (IQR 1.0–1.8) at rest and 1.4 (IQR 1.3–1.9) at stress. The table shows IVD parameters. Forty-one deaths occurred during follow-up. Pts who died during follow-up, compared to survivors, showed greater IVD. WMI at rest (p = 0.03) and peak stress (p = 0.02), TsSD (p = 0.06), TsSL (p = 0.02) and TsMax (p = 0.05) but not QRS width were univariate predictors of mortality. TsSL was the only independent predictor of death (p = 0.01). Therefore, IVD is common in pts with known or suspected CAD. Pts with more IVD have reduced long-term survival, independent of WMI.