Power calculation for cross-sectional stepped-wedge cluster randomized trials with binary outcomes

Power calculation for stepped-wedge cluster randomized trials (SW-CRTs) presents unique challenges, beyond those of standard cluster randomized trials (CRTs), due to the need to consider temporal within cluster correlations and background period effects. To date, power calculation methods specific to SW-CRTs have primarily been developed under a linear model. When the outcome is binary, the use of a linear model corresponds to assessing a prevalence difference; yet trial analysis often employs a non-linear link function. We assess power for cross-sectional SW-CRTs under a logistic model fitted by generalized estimating equations. Firstly, under an exchangeable correlation structure, we show the power based on a logistic model is lower than that from assuming a linear model in the absence of period effects. We then evaluate the impact of background prevalence changes over time on power. To allow the correlation among outcomes in the same cluster to change over time and with treatment status, we generalize the methods to more complex correlation structures. Our simulation studies demonstrate that the proposed power calculation methods perform well with the model-based variance under the true correlation structure and reveal that a working independence structure can result in substantial efficiency loss, while a working exchangeable structure performs well even when the underlying correlation structure deviates from exchangeable. An extension to our methods accounts for variable cluster sizes and reveals unequal cluster sizes have a modest impact on power. We illustrate the approaches by application to a quality of care improvement trial for acute coronary syndrome

Differential expression of skeletal muscle genes following administration of clenbuterol to exercised horses.

BackgroundClenbuterol, a beta2-adrenergic receptor agonist, is used therapeutically to treat respiratory conditions in the horse. However, by virtue of its mechanism of action it has been suggested that clenbuterol may also have repartitioning affects in horses and as such the potential to affect performance. Clenbuterol decreases the percent fat and increases fat-free mass following high dose administration in combination with intense exercise in horses. In the current study, microarray analysis and real-time PCR were used to study the temporal effects of low and high dose chronic clenbuterol administration on differential gene expression of several skeletal muscle myosin heavy chains, genes involved in lipid metabolism and the β2-adrenergic receptor. The effect of clenbuterol administration on differential gene expression has not been previously reported in the horse, therefore the primary objective of the current study was to describe clenbuterol-induced temporal changes in gene expression following chronic oral administration of clenbuterol at both high and low doses.ResultsSteady state clenbuterol concentrations were achieved at approximately 50 h post administration of the first dose for the low dose regimen and at approximately 18-19 days (10 days post administration of 3.2 μg/kg) for the escalating dosing regimen. Following chronic administration of the low dose (0.8 μg/kg BID) of clenbuterol, a total of 114 genes were differentially expressed, however, none of these changes were found to be significant following FDR adjustment of the p-values. A total of 7,093 genes were differentially expressed with 3,623 genes up regulated and 3,470 genes down regulated following chronic high dose administration. Of the genes selected for further study by real-time PCR, down-regulation of genes encoding myosin heavy chains 2 and 7, steroyl CoA desaturase and the β2-adrenergic receptor were noted. For most genes, expression levels returned towards baseline levels following cessation of drug administration.ConclusionThis study showed no evidence of modified gene expression following chronic low dose administration of clenbuterol to horses. However, following chronic administration of high doses of clenbuterol alterations were noted in transcripts encoding various myosin heavy chains, lipid metabolizing enzymes and the β2-adrenergic receptor

Allosteric modulation of beta1 integrin function induces lung repair in animal model of emphysema.

Emphysema is a progressive lung disease characterised by loss of lung parenchyma with associated functional changes including decreased tissue elastance. Here we report beta1 integrin is a novel target for tissue repair and regeneration in emphysema. We show a single dose of a monoclonal antibody against beta1 integrin induced both functional and structural reversal of elastase-induced lung injury in vivo, and we found that similar matrix remodelling changes occurred in human lung tissue. We also identified a potential mechanism of action as this allosteric modulation of beta1 integrin inhibited elastase-induced caspase activation, F-actin aggregate formation and changes in cellular ATP levels. This was accompanied by maintenance of beta1?integrin levels and inhibition of caveolin-1 phosphorylation. We propose that allosteric modulation of beta1 integrin-mediated mechanosensing prevents cell death associated with lung injury and progressive emphysema, thus allowing cells to survive and for repair and regeneration to ensue

Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity.

Falcipain-2 and falcipain-3 are critical hemoglobinases of Plasmodium falciparum, the most virulent human malaria parasite. We have determined the 2.9 A crystal structure of falcipain-2 in complex with the epoxysuccinate E64 and the 2.5 A crystal structure of falcipain-3 in complex with the aldehyde leupeptin. These complexes represent the first crystal structures of plasmodial cysteine proteases with small molecule inhibitors and the first reported crystal structure of falcipain-3. Our structural analyses indicate that the relative shape and flexibility of the S2 pocket are affected by a number of discrete amino acid substitutions. The cumulative effect of subtle differences, including those at "gatekeeper" positions, may explain the observed kinetic differences between these two closely related enzymes

Allosteric Modulation of Beta1 Integrin Function Induces Lung Tissue Repair

The cellular cytoskeleton, adhesion receptors, extracellular matrix composition, and their spatial distribution are together fundamental in a cell's balanced mechanical sensing of its environment. We show that, in lung injury, extracellular matrix-integrin interactions are altered and this leads to signalling alteration and mechanical missensing. The missensing, secondary to matrix alteration and cell surface receptor alterations, leads to increased cellular stiffness, injury, and death. We have identified a monoclonal antibody against β1 integrin which caused matrix remodelling and enhancement of cell survival. The antibody acts as an allosteric dual agonist/antagonist modulator of β1 integrin. Intriguingly, this antibody reversed both functional and structural tissue injury in an animal model of degenerative disease in lung

First Spitzer Space Telescope Observations of Magnetic Cataclysmic Variables: Evidence for Excess Emission at 3--8 microns

We present the first observations of magnetic cataclysmic variables with the Spitzer Space Telescope. We used the Infrared Array Camera to obtain photometry of the polars EF Eri, GG Leo, V347 Pav, and RX J0154.0-5947 at 3.6, 4.5, 5.8, and 8.0 $\mu$m. In all of our targets, we detect excess mid-infrared emission over that expected from the component stars alone. We explore the origin of this IR excess by examining bremsstrahlung, cyclotron emission, circumbinary dust, and L/T brown dwarf secondary stars. Bremsstrahlung and cyclotron emission appear unlikely to be significant contributors to the observed fluxes. At present, the most likely candidate for the excess emission is dust that is probably located in a circumbinary disk with an inner temperature near 800 K. However, a simple dust disk plus any reasonable low mass or brown dwarf-like secondary star is unable to fully explain the observed flux densities in the 3--8 $\mu$m region.Comment: Accepted to ApJ Letter

Using metaphor to illuminate quality in early childhood education

This paper reports on a study in which educators from four early childhood centres used metaphor to discuss their provision of high-quality early childhood education. Qualitative mining of focus group data confirmed ‘quality’ to be complex, multi-dimensional and value-laden. Findings contribute to understandings of quality in early childhood education through four key themes: ‘quality’ as a synergetic flow; the facilitative stance and impact of leaders in the enactment of leadership; children as active contributors to quality; and the role of love. Metaphor is shown to be a valuable tool that can highlight tangible and intangible quality contributors, how these contributors link together and the contextual specificity from which quality in individual early childhood education settings emanates

Protocol for a mixed-methods investigation of quality improvement in early childhood education and care in Australia

International recognition of the early years as a crucial foundational period has led to the design and implementation of quality rating and improvement systems (QRIS) that define, communicate, and monitor the components of quality in early childhood education and care (ECEC). The aim of these policies is to achieve effective quality assurance and improvement through a system-oriented approach to assessment and evaluation. Informed by ecological systems theory, this paper outlines a three-phase, mixed-methods design for researching a national sample of child care centres that showed overall improvement on the Australian National Quality Standard (NQS) assessment and rating (A&R) criteria. The study samples are drawn from a national dataset of centre-based child care services with two or more A&R rounds and an initial rating of Working Towards NQS (N = 1,935). The results of this study will provide insights into the macro-, exo-, meso- and micro-systems level factors and strategies that support quality in ECEC services

Efficacy of miniaturized imacor trans-esophageal echocardiografm (TEE) prove in mechanical circulatory support.

Application of the miniaturized ImaCor Trans-Esophageal Echocardiogram (TEE) probe in Heart Transplant/Mechanical Cardiac Support Patients In the surgical cardiac care unit (SCCU), therapeutic interventions often need to be done at the bedside, necessitating the need for a rapidly employable diagnostic tool for the cardiac intensivist. We report the clinical utility of the miniature ImaCor TEE-probe in guiding management of post heart transplant (H-Txp) and mechanical cardiac support patients (MCS) and describe the economic benefit of such a device. This is an IRB approved retrospective review of MCS/H-Txp patients who had ImaCor TEE monitoring in the SCCU of our institution in 2011. The effect on management was stratified into 3 categories; Major (tamponade/device selection/RV failure), Moderate (weaning support device guidance/ inotrope management/fluid management/hemodynamic instability) and Minor (line placement/useful data). The ImaCor TEE-Probe was utilized in a total of 34 patients, of which 21 were either supported by MCS or were post H-Txp. Of these, 13 were on ECMO, 9 were post-VAD, 3 supported by the Impella device and 4 were post-H-Txp. 6 patients were placed on more than 1 method of MCS and 1 patient was supported by ECMO after a H-Txp. The device had a Major effect on management in 4 patients (19%), Moderate effect in 13 (62%) and a Minor effect in 4 (19%). The cost difference between this new device and the traditional TEE is also significant (900 USD vs 4000 USD). Our institution saved in excess of 150,000 USD with the use of this device instead of traditional TEE. This figure did not include the ability of this probe to be used repeatedly within a 72-hour time frame, and the potential cost of going to the operating theatre for further management. This device has proven to be an invaluable new adjunct in the SCCU by allowing previously unobtainable continuous real time monitoring of the MCS/H-Txp patient. Use of the ImaCor TEE-probe provides the cardiac intensivist with timely important clinical data that improves patient care and is economically advantageous

Mapping the leap: Differences in quality improvement in relation to assessment rating outcomes

Introduction: Australia’s National Quality Standard (NQS) outlines the criteria to assess the quality of early childhood services. A four-point rating scale: (i) Exceeding NQS; (ii) Meeting NQS; (iii) Working Toward NQS; and (iv) Significant Improvement Required is applied to services following a regular assessment and rating process. Settings rated as Working Toward are reassessed within 12 months. Most settings achieved a one-step improvement in this Time 2 reassessment, moving to a Meeting rating but some settings made a two-step improvement, moving to an Exceeding rating. The QIP is a key document used by authorities to assess the quality of a service. Methods: A grounded theory, data driven approach was taken to deepen understanding of quality rating improvements in long day care services in Australia of quality rating improvements by early childhood education and care [ECEC] services in Australia. This study, part of the second phase of a three phase study involved a document analysis of the Time 2 Quality Improvement Plans (QIPs) of a representative sample of Long Day Care (LDC) services (n = 60) from all Australian states and territories to determine what factors may have contributed to these different levels of improvement, with a focus on Quality Area 1 (QA1) (Educational programs and practices) and Quality Area 7 (QA7) (Governance and leadership). The study utilized the semantic analysis tool Leximancer 4.5. Leximancer 4.5 statistically analyses the semantic relationships between concepts in documents by measuring word proximity and correlation. The software creates visual maps of concepts and their connections to each other in texts. Concepts located near one another on the map are more likely to be contextually related. This tool is particularly useful when there are multiple, complex documents to analyze, reducing the potential biases that can arise from documents that use language with which these researchers are very familiar with. Results: The analysis found clear differences between the Time 2 QIPs of services who had made a two-step rating improvement and those who made a one-step improvement. Two-step (Exceeding NQS) category improvers for QA1 placed attention in their QIPs on improvement to the program and overall practice, with an orientation to the role of the educational leader. Two-step (Exceeding NQS) category improvers for QA7 seemed to be more oriented to a systemic view of the processes encompassed by QA7; how the management of the service and information supports the work of educators, with stronger links made between leadership roles (the manager and nominated supervisor) and the work of educators. Discussion: The QIPs demonstrated how the intentional and systemic processes in these quality areas related to practice, management, and leadership