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 μg/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.     

Exceptional early blood pressure control rates: the ACCOMPLISH trial

BACKGROUND: ACCOMPLISH is a "new-generation" hypertension trial assessing single-tablet combination therapy for initial treatment of high-risk hypertension. At baseline, 97% of subjects were treated with anti-hypertensive medication at entry, but only 37% of participants had blood pressure (BP) control (<140/90 mmHg). Single-tablet combination therapy may improve control rates. METHODS: The mean BP change from baseline at the end of 6 months (the time point when subjects should have had all of the drug titrations to achieve BP control) was examined for 10,704 randomized patients. Within-group changes were examined using t-tests. Comparisons between subgroups were made using analysis of variance (ANOVA) and covariance (ANCOVA). RESULTS: Mean (+/-SD) BP fell from 145+/-18/80+/-11 mmHg at randomization to 132+/-16/74+/-10 mmHg. The 6-month BP control rate was 73% in the overall trial (78% in the US), 43% in diabetics and 40% in patients with renal disease. Of the patients uncontrolled, 61% were not on maximal medications, suggesting potential increases in control rates. Serious hypotensive events occurred in 1.8% of participants. CONCLUSION: ACCOMPLISH BP control rates are the highest of any multi-national trial to date. Whereas current guidelines recommend combination therapy only for stage 2 hypertension, in this trial it is expedient and safe for both stage 1 and 2 hypertension.     

Low-grade myxofibrosarcoma: CT and MRI patterns in recurrent disease

OBJECTIVE: Low-grade myxofibrosarcoma often relentlessly recurs after surgical resection, with an unusual infiltrative growth pattern and sometimes without a discrete tumor nodule at pathologic examination. This study was undertaken to determine and show patterns of recurrent low-grade myxofibrosarcoma at CT and MRI. CONCLUSION: Unlike in most other histologic types of low-grade soft-tissue sarcoma, recurrent low-grade myxofibrosarcoma often is infiltrative; shows a tapering, tail-like margin and superficial spreading configuration; and metastasizes to various distant sites, including lungs, pleura, bone, adrenal gland, soft tissue, and mesentery. Knowledge of these unusual characteristics is important in assessing the presence and extent of recurrent low-grade myxofibrosarcoma before surgical reexcision.     

原子吸收分光光度法测定口服甘草锌的血锌浓度及药代动力学研究

甘草锌(1icorzin)是从豆科植物甘草(Glycyrrhiza uralensis Fisch.)根中提取的有效成分与锌盐结合而成的含锌药物(含锌约4～5%,甘草酸约25%)。该药在临床上主要用于补锌,并且对胃肠道的刺激明显小于国内常用的补锌剂硫酸锌。为了解新药甘草锌在人体内     

Epidemiology of pediatric Human Immunodeficiency Virus infection in the United States

Human Immunodeficiency Virus (HIV) infection is a growing problem for children worldwide. As of 31 December 1992, 4249 children with Acquired Immunodeficiency Syndrome (AIDS) under 13 years of age had been reported to the US Centers for Disease Control and Prevention (CDC). HIV is transmitted to children predominantly from their mothers. Nearly all cases of HIV infection acquired from blood transfusions in the United States occurred before donor-screening practices were implemented in March 1985. In 1991, approximately 7000 HIV-infected women gave birth to a liveborn infant in the United States, for a prevalence of 1.7 per 1000 women. Despite recent advances in prophylactic therapy for opportunistic infections, Pneumocystis carinii pneumonia remains the most common AIDS-defming illness in children in the United States. If these cases are to be prevented, children born to HIV-infected mothers will need to be identified early and monitored appropriately for CD4+ cell counts to determine the need for prophylaxis.     

Cerebral venous angiomas imaged by MR

The diagnostic efficacy of magnetic resonance (MR) in the evaluation of cerebral venous angioma was studied. The results of MR and computed tomography (CT) were compared in six cerebral venous angiomas in five patients. MR alone was diagnostically successful in only three of six cases. Venous angiomas appeared as tubular structures of extremely low signal intensity on MR images. Although CT was highly sensitive (100%) in detecting lesions, CT was diagnostically specific in only four of the six cases. Angiography was the only modality able to unquestionably detect all six lesions. By varying the MR pulse sequence, we greatly affected the ability of MR to demonstrate lesions. In the cases where MR helped define the abnormality, T2-weighted MR images were able to clearly demonstrate lesions in five of the six cases whereas T1-weighted images helped detect an abnormality in only two cases. Although MR shows great promise in the evaluation of central nervous system abnormalities, CT remains the best imaging modality for detecting venous angiomas. When CT is not conclusive, angiography can be performed for a definitive diagnosis.     

Neuroprotective function for ramified microglia in hippocampal excitotoxicity

Background  

Most of the known functions of microglia, including neurotoxic and neuroprotective properties, are attributed to morphologically-activated microglia. Resting, ramified microglia are suggested to primarily monitor their environment including synapses. Here, we show an active protective role of ramified microglia in excitotoxicity-induced neurodegeneration.     

Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2014)

Changes to virus taxonomy approved by a vote of all ICTV members in February-March 2014 are reported.