Evaluation of a sequential global test of improved recovery following stroke as applied to the ICTUS trial of citicoline

The International Citicoline Trial in acUte Stroke is a sequential phase III study of the use of the drug citicoline in the treatment of acute ischaemic stroke, which was initiated in 2006 in 56 treatment centres. The primary objective of the trial is to demonstrate improved recovery of patients randomized to citicoline relative to those randomized to placebo after 12 weeks of follow-up. The primary analysis will take the form of a global test combining the dichotomized results of assessments on three well-established scales: the Barthel Index, the modified Rankin scale and the National Institutes of Health Stroke Scale. This approach was previously used in the analysis of the influential National Institute of Neurological Disorders and Stroke trial of recombinant tissue plasminogen activator in stroke. The purpose of this paper is to describe how this trial was designed, and in particular how the simultaneous objectives of taking into account three assessment scales, performing a series of interim analyses and conducting treatment allocation and adjusting the analyses to account for prognostic factors, including more than 50 treatment centres, were addressed. Copyright (C) 2008 John Wiley & Sons, Ltd.

A 25-year review of sequential methodology in clinical studies

This paper explores the theoretical developments and subsequent uptake of sequential methodology in clinical studies in the 25 years since Statistics in Medicine was launched. The review examines the contributions which have been made to all four phases into which clinical trials are traditionally classified and highlights major statistical advancements, together with assessing application of the techniques. The vast majority of work has been in the setting of phase III clinical trials and so emphasis will be placed here. Finally, comments are given indicating how the subject area may develop in the future.

Melt structure and its transformation by sequential crystallization of the two blocks within poly(L-lactide)-block-poly(epsilon-caprolactone) double crystalline diblock copolymers

Sequential crystallization of poly(L-lactide) (PLLA) followed by poly(epsilon-caprolactone) (PCL) in double crystalline PLLA-b-PCL diblock copolymers is studied by differential scanning calorimetry (DSC), polarized optical microscopy (POM), wide-angle X-ray scattering (WAXS) and small-angle X-ray scattering (SAXS). Three samples with different compositions are studied. The sample with the shortest PLLA block (32 wt.-% PLLA) crystallizes from a homogeneous melt, the other two (with 44 and 60% PLLA) from microphase separated structures. The microphase structure of the melt is changed as PLLA crystallizes at 122 degrees C (a temperature at which the PCL block is molten) forming spherulites regardless of composition, even with 32% PLLA. SAXS indicates that a lamellar structure with a different periodicity than that obtained in the melt forms (for melt segregated samples). Where PCL is the majority block, PCL crystallization at 42 degrees C following PLLA crystallization leads to rearrangement of the lamellar structure, as observed by SAXS, possibly due to local melting at the interphases between domains. POM results showed that PCL crystallizes within previously formed PLLA spherulites. WAXS data indicate that the PLLA unit cell is modified by crystallization of PCL, at least for the two majority PCL samples. The PCL minority sample did not crystallize at 42 degrees C (well below the PCL homopolymer crystallization temperature), pointing to the influence of pre-crystallization of PLLA on PCL crystallization, although it did crystallize at lower temperature. Crystallization kinetics were examined by DSC and WAXS, with good agreement in general. The crystallization rate of PLLA decreased with increase in PCL content in the copolymers. The crystallization rate of PCL decreased with increasing PLLA content. The Avrami exponents were in general depressed for both components in the block copolymers compared to the parent homopolymers. Polarized optical micrographs during isothermal crystalli zation of (a) homo-PLLA, (b) homo-PCL, (c) and (d) block copolymer after 30 min at 122 degrees C and after 15 min at 42 degrees C.

Sequential ring-closing metathesis and nitrone cycloaddition on glucose-derived substrates: a divergent approach to analogues of spiroannulated carbanucleosides and conformationally locked nucleosides

The carbohydrate-derived substrate 3-C-allyl-1,2: 5,6-di-O-isopropylidene-alpha-D-allofuranose was judiciously manipulated for preparing suitable synthons, which could be converted to a variety of isoxazolidino-spirocycles and -tricycles through the application of ring-closing metathesis (RCM) and intramolecular nitrone cycloaddition (INC) reactions. Cleavage of the isoxazolidine rings of some of these derivatives by tranfer hydrogenolysis followed by coupling of the generated amino functionalities with 5-amino-4,6-dichloropyrimidine furnished the corresponding chloropyrimidine nucleosides, which were elaborated to spiroannulated carbanucleosides and conformationally locked bicyclo[2.2.1] heptane/ oxa-bicyclo[3.2.1]octane nucleosides. However, use of higher temperature for the cyclization of one of the chloropyrimidines led to the dimethylaminopurine analogue as a sole product, formed via nucleophilic displacement of the chloro group by dimethylamine generated from DMF.

Ligand-centred reactivity of bis(picolyl)amine iridium: sequential deprotonation, oxidation and oxygenation of a "non-innocent" ligand

Treatment of [Ir(bpa)(cod)](+) complex [1](+) with a strong base (e.g., tBuO(-)) led to unexpected double deprotonation to form the anionic [Ir-(bpa-2H)(cod)](-) species [3](-), via the mono-deprotonated neutral amido complex [Ir(bpa-H)(cod)] as an isolable intermediate. A certain degree of aromaticity of the obtained metal-chelate ring may explain the favourable double deprotonation. The rhodium analogue [4](-) was prepared in situ. The new species [M(bpa-2H)(cod)](-) (M = Rh, Ir) are best described as two-electron reduced analogues of the cationic imine complexes [M-I(cod)(Py-CH2-N=CH-Py)](+). One-electron oxidation of [3](-) and [4](-) produced the ligand radical complexes [3]* and [4]*. Oxygenation of [3](-) with O-2 gave the neutral carboxamido complex [Ir(cod)(py-CH2-N-CO-py)] via the ligand radical complex [3]* as a detectable intermediate.

Sex differences in common marmosets (Callithrix jacchus) in response to an unfamiliar food task

There is a growing body of information on sex differences In callitrichid behaviour that includes the animals' performance in food tasks. For example, both reproductive and non-reproductive adult females have been found to be more successful than adult males in solving food tasks. In this study ten adult male and ten adult female common marmosets (Callithrix jacchus), housed individually, were tested with an unfamiliar task that involved the extraction of an embedded food. The task was to open a plastic canister that contained a raisin; the open end was covered with parchment paper. Each marmoset was given 15 trials in three blocks of 5 consecutive days. We measured the latency for each animal to open the lid and get the raisin-by one of five strategies that spontaneously emerged. The females learned the task faster and more efficiently than males; all the females opened the canister on day 1, for instance, in contrast to seven of the males on the same day. Females also progressively decreased the time that they took to open the tube. The final latency on day 15, for instance, was significantly shorter for the females. These results are consistent with relevant literature for callitrichids and cannot be accounted for in terms of differences in mental abilities, strength, hand morphology, or energy requirements. Further investigation is necessary to clarify the reasons for these differences.

A demonstration of attentional bias, using a novel dual task paradigm, towards clinically salient material in recovering alcohol abuse patients?

Background. This study examined whether alcohol abuse patients are characterized either by enhanced schematic processing of alcohol related cues or by an attentional bias towards the processing of alcohol cues. Method. Abstinent alcohol abusers (N = 25) and non-clinical control participants (N = 24) performed a dual task paradigm in which they had to make an odd/even decision to a centrally presented number while performing a peripherally presented lexical decision task. Stimuli on the lexical decision task comprised alcohol words, neutral words and non-words. In addition, participants completed an incidental recall task for the words presented in the lexical decision task. Results. It was found that, in the presence of alcohol related words, the performance of patients on the odd/even decision task was poorer than in the presence of other stimului. In addition, patients displayed slower lexical decision times for alcohol related words. Both groups displayed better recall for alcohol words than for other stimuli. Conclusions. These results are interpreted as supporting neither model of drug cravings. Rather, it is proposed that, in the presence of alcohol stimuli, alcohol abuse patients display a breakdown in the ability to focus attention.

Redintegration and lexicality effects in children: do they depend upon the demands of the memory task?

The effect of long-term knowledge upon performance in short-term memory tasks was examined for children from 5 to 10 years of age. The emergence of a lexicality effect, in which familiar words were recalled more accurately than unfamiliar words, was found to depend upon the nature of the memory task. Lexicality effects were interpreted as reflecting the use of redintegration, or reconstruction processes, in short-term memory. Redintegration increased with age for tasks requiring spoken item recall and decreased with age when position information but not naming was required. In a second experiment, redintegration was found in a recognition task when some of the foils rhymed with the target. Older children were able to profit from a rhyming foil, whereas younger children were confused by it, suggesting that the older children make use of sublexical phonological information in reconstructing the target. It was proposed that redintegrative processes in their mature form support the reconstruction of detailed phonological knowledge of words.

The role of schizotypy and creativity in a group problem-solving task

The well-studied link between psychotic traits and creativity is a subject of much debate. The present study investigated the extent to which schizotypic personality traits - as measured by O-LIFE (Oxford-Liverpool Inventory of Feelings and Experiences) - equip healthy individuals to engage as groups in everyday tasks. From a sample of 69 students, eight groups of four participants - comprised of high, medium, or low-schizotypy individuals - were assembled to work as a team to complete a creative problem-solving task. Predictably, high scorers on the O-LIFE formulated a greater number of strategies to solve the task, indicative of creative divergent thinking. However, for task success (as measured by time taken to complete the problem) an inverted U shaped pattern emerged, whereby high and low-schizotypy groups were consistently faster than medium schizotypy groups. Intriguing data emerged concerning leadership within the groups, and other tangential findings relating to anxiety, competition and motivation were explored. These findings challenge the traditional cliche that psychotic personality traits are linearly related to creative performance, and suggest that the nature of the problem determines which thinking styles are optimally equipped to solve it. (C) 2009 Elsevier Ltd. All rights reserved.

The effect of postnatal depression on mother-infant interaction, infant response to the still-face perturbation, and performance on an instrumental learning task

A representative community sample of primiparous depressed women and a nondepressed control group were assessed while in interaction with their infants at 2 months postpartum. At 3 months, infants were assessed on the Still-face perturbation of face to face interaction, and a subsample completed an Instrumental Learning paradigm. Compared to nondepressed women, depressed mothers' interactions were both less contingent and less affectively attuned to infant behavior. Postnatal depression did not adversely affect the infant's performance in either the Still-face perturbation or the Instrumental Learning assessment. Maternal responsiveness in interactions at 2 months predicted the infant's performance in the Instrumental Learning assessment but not in the Still-face perturbation. The implications of these findings for theories of infant cognitive and emotional development are discussed.

Tests of syntactic comprehension in aphasia: an investigation of task effects

Background: Consistency of performance across tasks that assess syntactic comprehension in aphasia has clinical and theoretical relevance. In this paper we add to the relatively sparse previous work on how sentence comprehension abilities are influenced by the nature of the assessment task. Aims: Our aims are: (1) to compare linguistic performance across sentence-picture matching, enactment, and truth-value judgement tasks; (2) to investigate the impact of pictorial stimuli on syntactic comprehension. Methods Procedures: We tested a group of 10 aphasic speakers (3 with fluent and 7 with non-fluent aphasia) in three tasks (Experiment 1): (i) sentence-picture matching with four pictures, (ii) sentence-picture matching with two pictures, and (iii) enactment. A further task of truth-value judgement was given to a subgroup of those speakers (n=5, Experiment 2). Similar sentence types across all tasks were used and included canonical (actives, subject clefts) and non-canonical (passives, object clefts) sentences. We undertook two types of analyses: (a) we compared canonical and non-canonical sentences in each task; (b) we compared performance between (i) actives and passives, (ii) subject and object clefts in each task. We examined the results of all participants as a group and as case-series. Outcomes Results: Several task effects emerged. Overall, the two-picture sentence-picture matching and enactment tasks were more discriminating than the four-picture condition. Group performance in the truth-value judgement task was similar to two-picture sentence-picture matching and enactment. At the individual level performance across tasks contrasted to some group results. Conclusions: Our findings revealed task effects across participants. We discuss reasons that could explain the diverse profiles of performance and the implications for clinical practice.