A call to restructure the drug development process: Government over-regulation and non-innovative late stage (Phase III) clinical trials are major obstacles to advances in health care

The history of drug/vaccine development has included major advances guided primarily by risk/benefit analyses concerning the innovative agent, not by evidence-based clinical trials (Phase I–IV). Because the approval for new drugs is hindered under the present process, the system requires restructuring. The Phase I/II study period should be more flexible, using the “environment of knowledge” about the new agent, plus risk/benefit assessments. Phase III, as presently constructed, does not add new adverse events data, it provides a narrower profile of drug efficacy than properly done Phase II studies, and placebo-controlled trials continue to raise unresolved ethical and social issues. Phase III studies should be abandoned for most drugs, and substituted with properly powered Phase II doseranging studies plus careful post-marketing surveillance. Phase III should be a penalty for poor drug development, not a regulatory requirement. To accomplish efficient drug development, greater cooperation between pharmaceutical companies and governments in developing clinical trials is needed rather than over-regulation. These changes will synchronize the drug development and regulatory process with the current rapid drug discovery process, reduce drug development time and cost, and improve patient care. The author is Adjunct Professor of Medicine, Weill Medical College of Cornell University, New York, New York, USA.     

Do chickens (Gallus gallus f. domestica) decompose visual figures?

To investigate whether learning to discriminate between visual compound stimuli depends on decomposing them into constituting features, hens were first trained to discriminate four features (red, green, horizontal, vertical) from two dimensions (colour, line orientation). After acquisition, hens were trained with compound stimuli made up from these dimensions in two ways: a separable (line on a coloured background) stimulus and an integral one (coloured line). This compound training included a reversal of reinforcement of only one of the two dimensions (half-reversal). After having achieved the compound stimulus discrimination, a second dimensional training identical to the first was performed. Finally, in the second compound training the other dimension was reversed. Two major results were found: (1) an interaction between the dimension reversed and the type of compound stimulus: in compound training with colour reversal, separable compound stimuli were discriminated worse than integral compounds and vice versa in compound training with line orientation reversed. (2) Performance in the second compound training was worse than in the first one. The first result points to a similar mode of processing for separable and integral compounds, whereas the second result shows that the whole stimulus is psychologically superior to its constituting features. Experiment 2 repeated experiment 1 using line orientation stimuli of reversed line and background brightness. Nevertheless, the results were similar to experiment 1. Results are discussed in the framework of a configural exemplar theory of discrimination that assumes the representation of the whole stimulus situation combined with transfer based on a measure of overall similarity.     

发展性阅读障碍者的快速命名缺陷

快速命名任务是一种需要命名多个高熟悉项目的认知任务,尤其适合用来对成因复杂的发展性阅读障碍进行研究。许多研究者使用不同类型的快速命名任务发现,发展性阅读障碍者的快速命名缺陷在眼动过程表现为中央凹和副中央凹的加工困难,在认知过程中表现为抑制能力较差等。未来的研究中应该注意到快速命名缺陷的复杂性,采用多种方法相结合的方式来探究快速命名缺陷的本质,从而建立系统性的假说。     

Changes in the structure of children's isometric force variability with practice

This study examined the effect of age and practice on the structure of children's force variability to test the information processing hypothesis that a reduction of sensorimotor system noise accounts in large part for age-related reductions in perceptual-motor performance variability. In the study, 6-year-olds, 10-year-olds, and young adults practiced on 5 consecutive days (15 trials/day), maintaining for 15-s trials a constant level of force (5 or 25% of maximum voluntary contraction) against an object using a pinch grip (thumb and index finger). With increasing age, the amount of force error and variability decreased, but the sequential structure of variability increased in irregularity. With practice, children reduced the amount of variability by changing the structure of the force output so as to be more similar to that of their older counterparts. The findings provide further evidence that practice-driven changes in the structure of force output, rather than a decline in the amount of white noise, largely account for age-related reductions in the amount of force variability.     

Why 8-year-olds cannot tell the difference between Steve Martin and Paul Newman: factors contributing to the slow development of sensitivity to the spacing of facial features

Children are nearly as sensitive as adults to some cues to facial identity (e.g., differences in the shape of internal features and the external contour), but children are much less sensitive to small differences in the spacing of facial features. To identify factors that contribute to this pattern, we compared 8-year-olds' sensitivity to spacing cues with that of adults under a variety of conditions. In the first two experiments, participants made same/different judgments about faces differing only in the spacing of facial features, with the variations being kept within natural limits. To measure the effect of attention, we reduced the salience of featural information by blurring faces and occluding features (Experiment 1). To measure the role of encoding speed and memory limitations, we presented pairs of faces simultaneously and for an unlimited time (Experiment 2). To determine whether participants' sensitivity would increase when spacing distortions were so extreme as to make the faces grotesque, we manipulated the spacing of features beyond normal limits and asked participants to rate each face on a "bizarreness" scale (Experiment 3). The results from the three experiments indicate that low salience, poor encoding efficiency, and limited memory can partially account for 8-year-olds' poor performance on face processing tasks that require sensitivity to the spacing of features, a kind of configural processing that underlies adults' expertise. However, even when the task is modified to compensate for these problems, children remain less sensitive than adults to the spacing of features.     

Infants' comprehension of toy replicas as symbols for real objects

Infants' understanding of toy model-real exemplar relations was assessed through preferential looking and habituation tasks. Results from the preferential looking task suggest that 18-month toddlers are just beginning to demonstrate comprehension of symbolic relations between iconic models and their real object counterparts. Performance of 10- and 14-month-old infants in the preferential looking task did not improve when across-domain pairs of videos were used in place of within-domain pairs. Habituation task results indicated that 10-month-olds do not comprehend symbolic relations between miniature toy replicas and their "real" counterparts, but that such understanding begins to emerge by age 14 months. Interactions between symbolic processing and early lexical development are considered, as are methodological implications for the study of infant categorization.     

Algebras of Intervals and a Logic of Conditional Assertions

Intervals in boolean algebras enter into the study of conditional assertions (or events) in two ways: directly, either from intuitive arguments or from Goodman, Nguyen and Walker's representation theorem, as suitable mathematical entities to bear conditional probabilities, or indirectly, via a representation theorem for the family of algebras associated with de Finetti's three-valued logic of conditional assertions/events. Further representation theorems forge a connection with rough sets. The representation theorems and an equivalent of the boolean prime ideal theorem yield an algebraic completeness theorem for the three-valued logic. This in turn leads to a Henkin-style completeness theorem. Adequacy with respect to a family of Kripke models for de Finetti's logic, ukasiewicz's three-valued logic and Priest's Logic of Paradox is demonstrated. The extension to first-order yields a short proof of adequacy for Körner's logic of inexact predicates.     

On Modal μ-Calculus and Non-Well-Founded Set Theory

A finitary characterization for non-well-founded sets with finite transitive closure is established in terms of a greatest fixpoint formula of the modal -calculus. This generalizes the standard result in the literature where a finitary modal characterization is provided only for wellfounded sets with finite transitive closure. The proof relies on the concept of automaton, leading then to new interlinks between automata theory and non-well-founded sets.     

The Suspended Aesthetic: Slavoj Žižek on Eastern European Film

Slavoj iek's writings on Krzysztof Kies´lowski and Andrej Tarkovskij represent direct challenges to the Central and Eastern European tradition of spiritual art and to dominant aesthetic concepts as such. He refuses to separate the solemn films of Kies´lowski and Tarkovskij from popular culture and stresses their import as ethical statements by their directors. Despite this ethical emphasis, iek makes an important contribution to philosophical aesthetics. He implicitly defines art as a suspension of reality which reveals time in its fragility and potentiality. Defining iek's aesthetics in terms of suspension helps to explain his partiality for Kies´lowski and Tarkovskij and bears comparison to the Russian tradition of philosophical aesthetics, in particular Aleksej Losev and Alexander Bakshy.