Interim analyses and sequential designs in phase III studies

Recruitment of patients to a clinical trial usually occurs over a period of time, resulting in the steady accumulation of data throughout the trial's duration. Yet, according to traditional statistical methods, the sample size of the trial should be determined in advance, and data collected on all subjects before analysis proceeds. For ethical and economic reasons, the technique of sequential testing has been developed to enable the examination of data at a series of interim analyses. The aim is to stop recruitment to the study as soon as there is sufficient evidence to reach a firm conclusion. In this paper we present the advantages and disadvantages of conducting interim analyses in phase III clinical trials, together with the key steps to enable the successful implementation of sequential methods in this setting. Examples are given of completed trials, which have been carried out sequentially, and references to relevant literature and software are provided.

Assessing multilingual lexical incorporation hypotheses through a primed picture-naming task

The incorporation of new representations into the mental lexicon has raised numerous questions about the organisational principles that govern the process. A number of studies have argued that similarity between the new L3 items and existing representations in the L1 and L2 is the main incorporating force (Hall & Ecke, 2003; Herwig, 2001). Experimental evidence obtained through a primed picture-naming task with L1 Polish-L2 English learners of L3 Russian supports Hall and Ecke’s Parasitic Model of L3 vocabulary acquisition, displaying a significant main effect for both priming and proficiency. These results complement current models of vocabulary acquisition and lexical access in multilingual speakers.

Task relevance of emotional information affects anxiety-linked attention bias in visual search

Task relevance affects emotional attention in healthy individuals. Here, we investigate whether the association between anxiety and attention bias is affected by the task relevance of emotion during an attention task. Participants completed two visual search tasks. In the emotion-irrelevant task, participants were asked to indicate whether a discrepant face in a crowd of neutral, middle-aged faces was old or young. Irrelevant to the task, target faces displayed angry, happy, or neutral expressions. In the emotion-relevant task, participants were asked to indicate whether a discrepant face in a crowd of middle-aged neutral faces was happy or angry (target faces also varied in age). Trait anxiety was not associated with attention in the emotion-relevant task. However, in the emotion-irrelevant task, trait anxiety was associated with a bias for angry over happy faces. These findings demonstrate that the task relevance of emotional information affects conclusions about the presence of an anxiety-linked attention bias.

Task design and interaction in collaborative writing: the students’ story

This article investigates student behaviour on collaborative assignments, looking at the relationship between task type and interaction, and considers the implications for task design. Students reported on interactions in a year-long workplace-focussed group communication project, comparing these with interactions on other academy based group assignments. Differences were seen in the amount of brainstorming, the criteria for dividing up work, the intensity of editing, and how conflict was managed. Contributing factors to these differences included the presence or absence of a creative element, the instrumental nature of the task, and the need for a collective approach inherent in the task design.

Voice, appropriation and discourse representation in a student writing task

We investigate the practices by which bilingual university students in Hong Kong appropriate texts in producing utterances, particularly written texts. Following Wertsch and his colleagues we ask: • To what extent do our students appropriate texts in constructing their own discourses? • What linguistic means do they use to do this? • What can these processes tell us about what they now can do with discourse representation; and • What do we need to teach them? This research shows that our students' writing displays considerable intertextuality and interdiscursivity. Responses to this writing in tutorial sessions indicate that they are skilled at orchestrating the multiple voices within their own discourses. The commonly stated concern that our students do not know how to do quotation and citation correctly is somewhat misplaced and researchers need to move the focus away from the mechanisms of citation and attribution to the social practices of textual appropriation.

Impact of lipoprotein lipase gene polymorphism, S447X, on postprandial triacylglycerol and glucose response to sequential meal ingestion

Lipoprotein lipase (LPL) is a key rate-limiting enzyme for the hydrolysis of triacylglycerol (TAG) in chylomicrons and very low-density lipoprotein. Given that postprandial assessment of lipoprotein metabolism may provide a more physiological perspective of disturbances in lipoprotein homeostasis compared to assessment in the fasting state, we have investigated the influence of two commonly studied LPL polymorphisms (rs320, HindIII; rs328, S447X) on postprandial lipaemia, in 261 participants using a standard sequential meal challenge. S447 homozygotes had lower fasting HDL-C (p = 0.015) and a trend for higher fasting TAG (p = 0.057) concentrations relative to the 447X allele carriers. In the postprandial state, there was an association of the S447X polymorphism with postprandial TAG and glucose, where S447 homozygotes had 12% higher TAG area under the curve (AUC) (p = 0.037), 8.4% higher glucose-AUC (p = 0.006) and 22% higher glucose-incremental area under the curve (IAUC) (p = 0.042). A significant gene–gender interaction was observed for fasting TAG (p = 0.004), TAG-AUC (Pinteraction = 0.004) and TAG-IAUC (Pinteraction = 0.016), where associations were only evident in men. In conclusion, our study provides novel findings of an effect of LPL S447X polymorphism on the postprandial glucose and gender-specific impact of the polymorphism on fasting and postprandial TAG concentrations in response to sequential meal challenge in healthy participants

Processing coordinate subject-verb agreement in L1 and L2 Greek

The present study examines the processing of subject-verb (SV) number agreement with coordinate subjects in pre-verbal and post-verbal positions in Greek. Greek is a language with morphological number marked on nominal and verbal elements. Coordinate SV agreement, however, is special in Greek as it is sensitive to the coordinate subject's position: when pre-verbal, the verb is marked for plural while when post-verbal the verb can be in the singular. We conducted two experiments, an acceptability judgment task with adult monolinguals as a pre-study (Experiment 1) and a self-paced reading task as the main study (Experiment 2) in order to obtain acceptance as well as processing data. Forty adult monolingual speakers of Greek participated in Experiment 1 and a hundred and forty one in Experiment 2. Seventy one children participated in Experiment 2: 30 Albanian-Greek sequential bilingual children and 41 Greek monolingual children aged 10–12 years. The adult data in Experiment 1 establish the difference in acceptability between singular VPs in SV and VS constructions reaffirming our hypothesis. Meanwhile, the adult data in Experiment 2 show that plural verbs accelerate processing regardless of subject position. The child online data show that sequential bilingual children have longer reading times (RTs) compared to the age-matched monolingual control group. However, both child groups follow a similar processing pattern in both pre-verbal and post-verbal constructions showing longer RTs immediately after a singular verb when the subject was pre-verbal indicating a grammaticality effect. In the post-verbal coordinate subject sentences, both child groups showed longer RTs on the first subject following the plural verb due to the temporary number mismatch between the verb and the first subject. This effect was resolved in monolingual children but was still present at the end of the sentence for bilingual children indicating difficulties to reanalyze and integrate information. Taken together, these findings demonstrate that (a) 10–12 year-old sequential bilingual children are sensitive to number agreement in SV coordinate constructions parsing sentences in the same way as monolingual children even though their vocabulary abilities are lower than that of age-matched monolingual peers and (b) bilinguals are slower in processing overall.

Speech perception and localization abilities in pediatric bilateral sequential cochlear implant recipients

The primary purpose of this study was to evaluate speech perception and localization abilities in children who have received sequential cochlear implants, with the first implant received before age 4 and the second implant received before age 12. Results indicate performance in the bilateral cochlear implant condition is significantly better than listening with each implant alone for the outcome measures used in this study.

Electronic properties of liquid hydrogen fluoride: A sequential quantum mechanical/Born-Oppenheimer molecular dynamics approach

The electronic properties of liquid hydrogen fluoride (HF) were investigated by carrying out sequential quantum mechanics/Born-Oppenheimer molecular dynamics. The structure of the liquid is in good agreement with recent experimental information. Emphasis was placed on the analysis of polarisation effects, dynamic polarisability and electronic excitations in liquid HF. Our results indicate an increase in liquid phase of the dipole moment (similar to 0.5 D) and isotropic polarisability (5%) relative to their gas-phase values. Our best estimate for the first vertical excitation energy in liquid HF indicates a blue-shift of 0.4 +/- 0.2 eV relative to that of the gas-phase monomer (10.4 eV). (C) 2010 Elsevier B.V. All rights reserved.

NMR Chemical Shielding and Spin-Spin Coupling Constants of Liquid NH(3): A Systematic Investigation using the Sequential QM/MM Method

The NMR spin coupling parameters, (1)J(N,H) and (2)J(H,H), and the chemical shielding, sigma((15)N), of liquid ammonia are studied from a combined and sequential QM/MM methodology. Monte Carlo simulations are performed to generate statistically uncorrelated configurations that are submitted to density functional theory calculations. Two different Lennard-Jones potentials are used in the liquid simulations. Electronic polarization is included in these two potentials via an iterative procedure with and without geometry relaxation, and the influence on the calculated properties are analyzed. B3LYP/aug-cc-pVTZ-J calculations were used to compute the V(N,H) constants in the interval of -67.8 to -63.9 Hz, depending on the theoretical model used. These can be compared with the experimental results of -61.6 Hz. For the (2)J(H,H) coupling the theoretical results vary between -10.6 to -13.01 Hz. The indirect experimental result derived from partially deuterated liquid is -11.1 Hz. Inclusion of explicit hydrogen bonded molecules gives a small but important contribution. The vapor-to-liquid shifts are also considered. This shift is calculated to be negligible for (1)J(N,H) in agreement with experiment. This is rationalized as a cancellation of the geometry relaxation and pure solvent effects. For the chemical shielding, U(15 N) Calculations at the B3LYP/aug-pcS-3 show that the vapor-to-liquid chemical shift requires the explicit use of solvent molecules. Considering only one ammonia molecule in an electrostatic embedding gives a wrong sign for the chemical shift that is corrected only with the use of explicit additional molecules. The best result calculated for the vapor to liquid chemical shift Delta sigma((15)N) is -25.2 ppm, in good agreement with the experimental value of -22.6 ppm.

On the effects of geographical constraints on task execution in complex

In the present work, the effects of spatial constraints on the efficiency of task execution in systems underlain by geographical complex networks are investigated, where the probability of connection decreases with the distance between the nodes. The investigation considers several configurations of the parameters defining the network connectivity, and the Barabasi-Albert network model is also considered for comparisons. The results show that the effect of connectivity is significant only for shorter tasks, the locality of connection simplied by the spatial constraints reduces efficiency, and the addition of edges can improve the efficiency of the execution, although with increasing locality of the connections the improvement is small.

Experimental evidence and model explanation for cell population characteristics modification when applying sequential photodynamic therapy

We present experimental evidence of the existence of cell variability in terms of threshold light dose for Hep G2 (liver cancer cells) cultured. Using a theoretical model to describe the effects caused by successive photodynamic therapy (PDT) sessions, and based on the consequences of a partial response we introduce the threshold dose distribution concept within a tumor. The experimental model consists in a stack of flasks, and simulates subsequent layers of a tissue exposed to PDT application. The result indicates that cells from the same culture could respond in different ways to similar PDT induced-damages. Moreover, the consequence is a partial killing of the cells submitted to PDT, and the death fraction decreased at each in vitro PDT session. To demonstrate the occurrence of cell population modification as a response to PDT, we constructed a simple theoretical model and assumed that the threshold dose distribution for a cell population of a tumor is represented by a modified Gaussian distribution.

Development of a sequential injection-square wave voltammetry method for determination of paraquat in water samples employing the hanging mercury drop electrode

This work describes the development and optimization of a sequential injection method to automate the determination of paraquat by square-wave voltammetry employing a hanging mercury drop electrode. Automation by sequential injection enhanced the sampling throughput, improving the sensitivity and precision of the measurements as a consequence of the highly reproducible and efficient conditions of mass transport of the analyte toward the electrode surface. For instance, 212 analyses can be made per hour if the sample/standard solution is prepared off-line and the sequential injection system is used just to inject the solution towards the flow cell. In-line sample conditioning reduces the sampling frequency to 44 h(-1). Experiments were performed in 0.10 M NaCl, which was the carrier solution, using a frequency of 200 Hz, a pulse height of 25 mV, a potential step of 2 mV, and a flow rate of 100 mu L s(-1). For a concentration range between 0.010 and 0.25 mg L(-1), the current (i(p), mu A) read at the potential corresponding to the peak maximum fitted the following linear equation with the paraquat concentration (mg L(-1)): ip = (-20.5 +/- 0.3) Cparaquat -(0.02 +/- 0.03). The limits of detection and quantification were 2.0 and 7.0 mu g L(-1), respectively. The accuracy of the method was evaluated by recovery studies using spiked water samples that were also analyzed by molecular absorption spectrophotometry after reduction of paraquat with sodium dithionite in an alkaline medium. No evidence of statistically significant differences between the two methods was observed at the 95% confidence level.