Influence of enrollment sequence effect on observed outcomes in the ADDRESS and PROWESS studies of drotrecogin alfa (activated) in patients with severe sepsis

INTRODUCTION: We performed a study to determine whether an enrollment sequence effect noted in the PROWESS (recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis) trial exists in the ADDRESS (Administration of Drotrecogin Alfa [Activated] [DrotAA] in Early Stage Severe Sepsis) trial. METHODS: We evaluated prospectively defined subgroups from two large phase 3 clinical trials: ADDRESS, which included 516 sites in 34 countries, and PROWESS, which included 164 sites in 11 countries. ADDRESS consisted of patients with severe sepsis at low risk of death not indicated for treatment with DrotAA. PROWESS consisted of patients with severe sepsis with one or more organ dysfunctions. DrotAA (24 microg/kg per hour) or placebo was infused for 96 hours. RESULTS: In ADDRESS and PROWESS, there was a statistically significant interaction between the DrotAA treatment effect and the sequence in which patients were enrolled. In both trials, higher mortality was associated with DrotAA use in the subgroup of patients enrolled first at study sites. Compared with placebo, PROWESS mortality was lower with DrotAA treatment for the second and subsequent patients enrolled, whereas in ADDRESS, mortality remained higher for the second patient enrolled but thereafter was lower for DrotAA-treated patients. Comparison of patients enrolled first with subsequent patients enrolled indicated that the characteristics of patients changed. Subsequently enrolled patients were treated earlier, were less likely to suffer nonserious bleeds (ADDRESS), and experienced fewer protocol violations (PROWESS). CONCLUSIONS: Analyses suggest that an enrollment sequence effect was present in the ADDRESS and PROWESS trials. Analysis of this effect on outcomes suggests that it is most apparent in patients at lower risk of death. In PROWESS, this effect appeared to be associated with a reduction of the DrotAA treatment effect for the first patients enrolled at each site. In ADDRESS, this effect may have contributed to early termination of the study. The finding of an enrollment sequence effect in two separate trials suggests that trial designs, site selection and training, data collection and monitoring, and statistical analysis plans may need to be adjusted for these potentially confounding events. TRIAL REGISTRATION: ADDRESS trial registration number: NCT00568737. PROWESS was completed before trial registration was required

SciPy 1.0: fundamental algorithms for scientific computing in Python.

SciPy is an open-source scientific computing library for the Python programming language. Since its initial release in 2001, SciPy has become a de facto standard for leveraging scientific algorithms in Python, with over 600 unique code contributors, thousands of dependent packages, over 100,000 dependent repositories and millions of downloads per year. In this work, we provide an overview of the capabilities and development practices of SciPy 1.0 and highlight some recent technical developments

NITROGÊNIO E POTÁSSIO NA FIXAÇÃO SIMBIÓTICA DE N2 POR SOJA CULTIVADA NO INVERNO NITROGEN AND POTASSIUM IN THE BIOLOGICAL N2 FIXATION BY WINTER SOYBEAN

O efeito do nitrogênio e do potássio sobre a nodulação, fixação simbiótica do nitrogênio, teor de N nos grãos e produtividade de soja, foi avaliado no inverno em experimentos conduzidos nas Estações Experimentais de Mococa, Ribeirão Preto e Votuporanga, do Instituto Agronômico de Campinas, SP, em solos podzólico vermelho-escuro, latossolo roxo e latossolo vermelho-escuro, respectivamente. Doses de nitrogênio na forma de uréia (0, 50 e 100 kg.ha-1 de N), de potássio na forma de cloreto de potássio (0, 30 e 60 kg.ha-1 de K2O) e cultivares de soja (IAC-8 e IAC-14), foram arranjados em fatorial e dispostos no campo, em blocos ao acaso, com três repetições. As sementes foram tratadas com inoculante comercial turfoso na dose de 8 g.kg-1 de semente. No florescimento, plantas foram amostradas para avaliações da nodulação e da atividade da nitrogenase. No final do ciclo, avaliou-se a produtividade e o teor de N dos grãos. Os resultados mostraram que apenas a inoculação não forneceu nitrogênio nas quantidades exigidas para maximizar a produtividade da soja. A adubação nitrogenada prejudicou a nodulação e a fixação simbiótica do nitrogênio mas aumentou a produtividade e o teor de N dos grãos de soja nas três localidades. A adubação potássica não prejudicou a nodulação, a fixação simbiótica do nitrogênio e o teor de N dos grãos. A cultivar IAC-14 apresentou nodulação e produtividade de grãos maiores quando foi adicionado potássio.<br>The objective of these experiments was to study the effect of nitrogen and potassium fertilizations on the response to nodulation, nitrogen fixation, nitrogen seed content and yield of two soybean cultivars planted during the winter season. They were installed on the following soils: Eutric Lixisol (Mococa) and Rhodic Ferralsol (Ribeirão Preto and Votuporanga, SP, Brazil). The treatments consisted of three rates of nitrogen (0, 50 and 100 kg.ha-1 of N) as urea, three of potassium (0, 30 and 60 kg.ha-1 of K2O) as chloride and two soybean cultivars (IAC-8 and IAC-14). The experimental design was a random factorial with four replications. Soybean seeds of all treatments were inoculated with a commercial inoculant. At flowering, plants were sampled to evaluate nodulation and nitrogenase activity. At maturity, plants were harvest and seeds weighed.The results showed that inoculation did not provide the amount of nitrogen required to maximize soybean yield in the winter. The nitrogen treatment reduced nodulation and nitrogen fixation, but increased seed yield at the three localities. Potassium fertilization did not have any significant effect on nodulation, nitrogen fixation and yield of soybeans. Increased however dry matter weight and number of nodules of the cultivar IAC-14