Balance algorithm for cluster randomized trials

<p>Abstract</p> <p>Background</p> <p>Within cluster randomized trials no algorithms exist to generate a full enumeration of a block randomization, balancing for covariates across treatment arms. Furthermore, often for practical reasons multiple blocks are required to fully randomize a study, which may not have been well balanced within blocks.</p> <p>Results</p> <p>We present a convenient and easy to use randomization tool to undertake allocation concealed block randomization. Our algorithm highlights allocations that minimize imbalance between treatment groups across multiple baseline covariates.</p> <p>We demonstrate the algorithm using a cluster randomized trial in primary care (the PRE-EMPT Study) and show that the software incorporates a trade off between independent random allocations that were likely to be imbalanced, and predictable deterministic approaches that would minimise imbalance. We extend the methodology of single block randomization to allocate to multiple blocks conditioning on previous allocations.</p> <p>Conclusion</p> <p>The algorithm is included as Additional file <supplr sid="S1">1</supplr> and we advocate its use for robust randomization within cluster randomized trials.</p> <suppl id="S1"> <title> <p>Additional File 1</p> </title> <text> <p><b>Cluster randomization allocation algorithm version 1.</b> Algorithms scripted in R to provide robust cluster randomization.</p> </text> <file name="1471-2288-8-65-S1.zip"> <p>Click here for file</p> </file> </suppl

Predicting new venture survival and growth: does the fog lift?

This paper investigates whether new venture performance becomes easier to predict as the venture ages: does the fog lift? To address this question we primarily draw upon a theoretical framework, initially formulated in a managerial context by Levinthal (Adm Sci Q 36(3):397–420, 1991) that sees new venture sales as a random walk but survival being determined by the stock of available resources (proxied by size). We derive theoretical predictions that are tested with a 10-year cohort of 6579 UK new ventures in the UK. We observe that our ability to predict firm growth deteriorates in the years after entry—in terms of the selection environment, the ‘fog’ seems to thicken. However, our survival predictions improve with time—implying that the ‘fog’ does lift

SREB, a GATA Transcription Factor That Directs Disparate Fates in Blastomyces dermatitidis Including Morphogenesis and Siderophore Biosynthesis

Blastomyces dermatitidis belongs to a group of human pathogenic fungi that exhibit thermal dimorphism. At 22°C, these fungi grow as mold that produce conidia or infectious particles, whereas at 37°C they convert to budding yeast. The ability to switch between these forms is essential for virulence in mammals and may enable these organisms to survive in the soil. To identify genes that regulate this phase transition, we used Agrobacterium tumefaciens to mutagenize B. dermatitidis conidia and screened transformants for defects in morphogenesis. We found that the GATA transcription factor SREB governs multiple fates in B. dermatitidis: phase transition from yeast to mold, cell growth at 22°C, and biosynthesis of siderophores under iron-replete conditions. Insertional and null mutants fail to convert to mold, do not accumulate significant biomass at 22°C, and are unable to suppress siderophore biosynthesis under iron-replete conditions. The defect in morphogenesis in the SREB mutant was independent of exogenous iron concentration, suggesting that SREB promotes the phase transition by altering the expression of genes that are unrelated to siderophore biosynthesis. Using bioinformatic and gene expression analyses, we identified candidate genes with upstream GATA sites whose expression is altered in the null mutant that may be direct or indirect targets of SREB and promote the phase transition. We conclude that SREB functions as a transcription factor that promotes morphogenesis and regulates siderophore biosynthesis. To our knowledge, this is the first gene identified that promotes the conversion from yeast to mold in the dimorphic fungi, and may shed light on environmental persistence of these pathogens

Früh-postoperative Veränderungen der Beatmungsparameter nach Tracheostomie bei Brandverletzten

Purpose: In patients with major burn injuries mechanical ventilation is often required for longer periods. Tracheostomy (TS) plays an integral role in airway management. We investigated the effect of TS on ventilation parameters within 8 hours after TS.Materials: A retrospective analysis of severely burned patients admitted to the burn unit of a German University Hospital was performed. Ventilation parameters 8 hours before and after TS were registered. Results: A retrospective analysis of 20 patients which received surgical TS was performed. Mean age was 52±19 years. Mean abbreviated burned severity index (ABSI) was 8.3±2.2. A mechanical ventilation was required for 14.3±4.8 days. TS was performed on day 7±4. Inspiratory oxygen concentration (FiO2) (p<0.001), peak inspiratory pressure (p<0.001), positive end-expiratory pressure (p=0.003) and pulmonary resistance (p<0.001) were reduced significantly after TS. The arterial partial pressure of oxygen/FiO2-ratio increased significantly after TS (p<0.001).Conclusions: We demonstrate that TS reduces invasiveness of ventilation in severely burned patients and by this can optimize lung protective ventilation strategy.Einleitung: Schwerbrandverletzte müssen häufig langfristig maschinell beatmet werden. Die Tracheostomie (TS) hat einen hohen Stellenwert in der Langzeitbeatmung. Wir untersuchen, ob eine Veränderung der Beatmungsparameter innerhalb von 8 Stunden nach TS festzustellen ist.Material und Methoden: Retrospektive Analyse an schwerbrandverletzten Patienten einer deutschen Intensiveinheit für Schwerbrandverletzte. Die Beatmungsparameter wurden 8 Stunden vor und 8 Stunden nach der TS ausgewertet. Ergebnisse: 20 Patienten mit einem mittleren Alter von 52±19 Jahren wurden eingeschlossen. Der mittlere ABSI-Wert betrug 8,3±2,2. Die mittlere Beatmungsdauer betrug 14,3±4,8 Tage. Die TS wurde im Mittel am 7. (±4) posttraumatischen Tag durchgeführt. Die inspiratorische Sauerstoffkonzentration (FiO2) (p<0,001), der inspiratorische Spitzendruck (p<0,001), der positive end-exspiratorische Druck (p=0,003) und der pulmonale Widerstand (p<0,001) waren innerhalb von 8 Stunden nach TS signifikant reduziert. Das Verhältnis von arteriellem Sauerstoffpartialdruck und FiO2 stieg innerhalb von 8 Stunden postoperativ signifikant an (p<0,001).Schlussfolgerung: Wir konnten zeigen, dass frühzeitig nach einer TS eine reduzierte Invasivität der maschinellen Beatmung erreicht wird und somit die lungenprotektive Beatmungsstrategie optimiert werden kann

Mesalazine pharmacokinetics and NAT2 phenotype

BACKGROUND: Mesalazine undergoes extensive metabolism by N-acetylation. While there is some evidence for an involvement of N-acetyltransferase (NAT) type 1, a potential role of NAT type 2 (NAT2) in vivo has not been tested. METHODS: In two studies in healthy young Caucasians, NAT2 phenotyping was carried out using a caffeine metabolic ratio in urine 4-6 h postdose. In study A, 1,000 mg mesalazine doses were given thrice daily for 5 days, and urine and blood samples were drawn during the last dosing interval. In study B, a 1,000 mg single dose was given, and samples were taken for 48 h postdose. Pharmacokinetics of mesalazine and N-acetylmesalazine (LC-MS/MS) were calculated by noncompartmental methods. RESULTS: NAT2 phenotype could be allocated unequivocally in 21 slow and 5 rapid acetylators in study A, and in 9 slow and 8 rapid acetylators in study B. Geometric mean (CV%) values in study A for slow [rapid] acetylators were as follows: mesalazine AUC 11.1 microg/mL.h (51%) [12.0 microg/mL.h (52%)], N-acetylmesalazine AUC 27.7 microg/mL.h (32%) [30.5 microg/mL.h (27%)], mesalazine Ae 8.53% (89%) [9.03% (52%)], N-acetylmesalazine Ae 31.4% (46%) [32.2 (41%)]. Values in study B were as follows: mesalazine AUC 3.45 microg/mL.h (113%) [2.36 microg/mL.h (87%)], N-acetylmesalazine AUC 21.3 microg/mL.h (29%) [18.0 microg/mL.h (39%)], mesalazine Ae 0.2% (256%) [0.1% (359%)], N-acetylmesalazine Ae 30.9% (44%) [18.1% (84%)]. Higher AUC and Ae values for mesalazine in steady state study indicate saturation of mesalazine metabolism. Statistics provided no evidence for a true difference in mesalazine pharmacokinetics between slow and rapid acetylators, and no significant correlation between NAT2 activity and any mesalazine pharmacokinetic parameter was found. CONCLUSION: NAT2 has no major role in human metabolism of mesalazine in vivo