How practical are adaptive designs likely to be for confirmatory trials?

This is a discussion of the following papers appearing in this special issue on adaptive designs: 'Confirmatory Seamless Phase II/III Clinical trials with Hypotheses Selection at Interim: General Concepts' by Frank Bretz, Heinz Schmidli, Franz König, Amy Racine and Willi Maurer; and 'Confirmatory Seamless Phase II/III Clinical Trials with Hypotheses Selection at Interim: Applications and Practical Considerations' by Heinz Schmidli, Frank Bretz, Amy Racine and Willi Maurer.

Sequence variation in the Newcastle disease virus genome.

Full-length genome sequences of five virulent and five avirulent strains of Newcastle disease virus isolated between 1998 and 2002 in Victoria and New South Wales, Australia were determined. Comparisons between these strains revealed that coding sequence variability in the haemagglutinin-neuraminidase (HN), matrix (M) and phosphoprotein (P) gene sequences appeared to be more variable than in the fusion (F), nucleocapsid (N) and RNA dependent-RNA replicase (L) genes. Sequence analysis of a number of other isolates made during the recent virulent NDV outbreaks, also identified the presence of a number of variants with altered F gene cleavage sites, which resulted in altered biological properties of those viruses.

Genome sequence of the thermostable Newcastle disease virus (strain I-2) reveals a possible phenotypic locus.

The complete genome sequence of the Australian I-2 heat-tolerant Newcastle disease virus (NDV) vaccine (master seed stocks) was determined and compared to the sequence of the parent virus from which it had been derived after exposure of the parent stock at 56 degrees C for 30 min. Nucleotide changes were observed at a number of positions with synonymous mutations being greater than those observed for non-synonymous mutations. Sequence data for the HN gene of a parental culture of V4 and two heat-tolerant variants of V4 were obtained.

Supraorbital edema induced by electroconvulsive therapy.

This is a case report of an unusual side effect-unilateral supraorbital edema occurring immediately after electroconvulsive therapy ECT during each treatment occasion-in a depressed patient who was otherwise well. The affected upper eyelid appeared normal before ECT with no history of injury or abnormality. Trauma during ECT, allergic reaction to anesthetic agents, and complications of manual ventilation were found to be unlikely causes.

Perspectives on the use of data mining in pharmaco-vigilance.

In the last 5 years, regulatory agencies and drug monitoring centres have been developing computerised data-mining methods to better identify reporting relationships in spontaneous reporting databases that could signal possible adverse drug reactions. At present, there are no guidelines or standards for the use of these methods in routine pharmaco-vigilance. In 2003, a group of statisticians, pharmaco-epidemiologists and pharmaco-vigilance professionals from the pharmaceutical industry and the US FDA formed the Pharmaceutical Research and Manufacturers of America-FDA Collaborative Working Group on Safety Evaluation Tools to review best practices for the use of these methods.

Drosophila Grainyhead specifies late programmes of neural proliferation by regulating the mitotic activity and Hox-dependent apoptosis of neuroblasts.

The Drosophila central nervous system is generated by stem-cell-like progenitors called neuroblasts. Early in development, neuroblasts switch through a temporal series of transcription factors modulating neuronal fate according to the time of birth. At later stages, it is known that neuroblasts switch on expression of Grainyhead (Grh) and maintain it through many subsequent divisions.

Bayesian analysis of multicentre trial outcomes.

Bayesian methods provide flexibility in the analysis of data from multicentre trials that would be difficult to achieve by other means. This paper illustrates some useful applications of Bayesian methods to the analysis of multicentre trials, with emphasis on insights that would be difficult to obtain using conventional frequentist methods. Two trials provide data for illustration: a large multicentre trial comparing two doses of a drug with placebo with respect to an essentially continuous measurement for which the original analysis revealed a significant treatment by centre effect, and a large multicentre trial with intraclass correlation induced by a categorical outcome of up to four episodes of heartburn reported by individual patients.

Cardiac arrest during neuraxial anesthesia: frequency and predisposing factors associated with survival.

The frequency and predisposing factors associated with cardiac arrest during neuraxial anesthesia remain undefined, and the survival outcome data are contradictory. In this retrospective study, we evaluated the frequency of cardiac arrest, as well as the association of preexisting medical conditions and periarrest events with survival after cardiac arrest during neuraxial anesthesia between 1983 and 2002. To assess whether survival after cardiac arrest differs for patients who arrest during neuraxial versus general anesthesia, data were also obtained for patients who experienced cardiac arrest under general anesthesia during similar surgical procedures during the same time interval.

Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies.

Previous studies have demonstrated that mice lacking a functional folate binding protein 2 gene (Folbp2-/-) were significantly more sensitive to in utero arsenic exposure than were the wild-type mice similarly exposed. When these mice were fed a folate-deficient diet, the embryotoxic effect of arsenate was further exacerbated. Contrary to expectations, studies on 24-h urinary speciation of sodium arsenate did not demonstrate any significant difference in arsenic biotransformation between Folbp2-/- and Folbp2+/+ mice.

Virus strains from a flock exhibiting unusually high mortality due to infectious bursal disease.

Objective: To characterise infectious bursal disease viruses (IBDVs) isolated from commercial broiler flocks exhibiting unusually high mortality due to infectious bursal disease (IBD).

Design: An IBD outbreak occurred in mid 1999 on two broilers farms (A and B) in northern New South Wales amongst chickens 28 to 38 days of age, with a sharp rise in mortality of 2.5%.

Direct crossregulation between retinoic acid receptor {beta} and Hox genes during hindbrain segmentation.

During anteroposterior (AP) patterning of the developing hindbrain, the expression borders of many transcription factors are aligned at interfaces between neural segments called rhombomeres (r). Mechanisms regulating segmental expression have been identified for Hox genes, but for other classes of AP patterning genes there is only limited information. We have analysed the murine retinoic acid receptor beta gene (Rarb) and show that it is induced prior to segmentation, by retinoic-acid (RA) signalling from the mesoderm.

Brainy but not too brainy: starting and stopping neuroblast divisions in Drosophila.

Drosophila neuroblasts are similar to mammalian neural stem cells in that they self-renew and have the potential to generate many different types of neurons and glia. They have already proved useful for uncovering asymmetric division components and now look set to provide insights into how stem cell divisions are initiated and terminated during neural development. In particular, some of the humoral factors and short-range 'niche' signals that modulate neuroblast activity during postembryonic development have been identified.

EGF receptor signaling regulates pulses of cell delamination from the Drosophila ectoderm.

Many different intercellular signaling pathways are known but, for most, it is unclear whether they can generate oscillating cell behaviors. Here we use time-lapse analysis of Drosophila embryogenesis to show that oenocytes delaminate from the ectoderm in discrete bursts of three. This pulsatile process has a 1 hour period, occurs without cell division, and requires a localized EGF receptor (EGFR) response.

Treatment comparisons for a partially categorical outcome applied to a biomarker with assay limit.

The plasma level of HIV-RNA has been shown to be a strong prognostic biomarker for clinical progression and death in HIV infected patients and is widely used as the primary outcome in clinical trials to evaluate antiretroviral treatments. Currently approved assays to measure HIV-RNA levels have a lower limit of reliable quantification (LoQ). Current regulatory guidelines recommend using the proportion of patients achieving HIV-RNA levels below the assay limit at a certain time point (e.

A prognostic index for operable, node-negative breast cancer.

Clinical data and samples from patients diagnosed, more than 10 years previously, with operable node-negative breast cancer (participants in the Scottish Adjuvant Tamoxifen trial), were revisited. Cases with two distinct categories of outcome were selected; more than 10 years disease-free survival ('good outcome') or distant relapse within 6 years of diagnosis ('poor outcome'). An initial set of cases was analysed for a range of putative prognostic markers and a prognostic index, distinguishing the two outcome categories, was calculated.

Genetic diversity of bluetongue viruses in south east Asia.

Bluetongue viruses (BTV) were isolated from sentinel cattle in Malaysia and at two sites in Indonesia. We identified eight serotypes some of which appeared to have a wide distribution throughout this region, while others were only isolated in Malaysia or Australia. Nearly half of the 24 known BTV serotypes have now been identified in Asia.

Industry, government, and academic panel discussion on multiple comparisons in a "real" phase three clinical trial.

A Food and Drug Administration (FDA)/Industry/Academic Panel Discussion on multiplicity aspects of a real Phase III clinical trial was held at the Third International Conference on Multiple Comparisons, August 6, 2002, in Bethesda, Maryland. The goal was to develop some consensus among industry, government, and academic statisticians concerning requirements and methods for multiplicity management in typical clinical trials. The session was tape-recorded; this article mostly comes from an edited transcript.

An outbreak of highly pathogenic avian influenza in Australia in 1997 caused by an H7N4 virus.

In November of 1997 an outbreak of highly pathogenic avian influenza occurred near the town of Tamworth, in northern New South Wales, Australia. The viruses isolated from chickens on two commercial chicken farms were identified as H7N4 viruses, with hemagglutinin cleavage site amino acid sequences of RKRKRG and intravenous pathogenicity indices of 2.52 and 2.

Practical pharmacovigilance analysis strategies.

Purpose: To compare two recently proposed Bayesian methods for quantitative pharmacovigilance with respect to assumptions and results, and to describe some practical strategies for their use.

Methods: The two methods were expressed in common terms to simplify identifying similarities and differences, some extensions to both methods were provided, and the empirical Bayes method was applied to accumulated experience on a new antihypertensive drug to elucidate the pattern of adverse-event reporting. Both methods use the logarithm of the proportional risk ratio as the basic metric for association.

Increased permeability of psoriatic skin to the protein, plasminogen activator inhibitor 2.

The penetration and permeation of the recombinant protein plasminogen activator inhibitor type 2 (PAI-2) in two formulations, one containing a penetration enhancer, into the psoriatic and uninvolved skin of eight patients with plaque-type psoriasis were investigated. Penetration and permeation of PAI-2 were measured by gamma counting and imaging following radiolabelling of a fraction of the applied PAI-2 with (123)I. The feasibility of topical delivery of drug to psoriatic plaques was confirmed by the finding that the permeability of psoriatic plaques to radiolabelled PAI-2 (P=0.