Sensory theories of developmental dyslexia: three challenges for research.

Recent years have seen the publication of a range of new theories suggesting that the basis of dyslexia might be sensory dysfunction. In this Opinion article, the evidence for and against several prominent sensory theories of dyslexia is closely scrutinized. Contrary to the causal claims being made, my analysis suggests that many proposed sensory deficits might result from the effects of reduced reading experience on the dyslexic brain. I therefore suggest that longitudinal studies of sensory processing, beginning in infancy, are required to successfully identify the neural basis of developmental dyslexia. Such studies could have a powerful impact on remediation.This is the accepted manuscript. The final version is available from NPG at http://www.nature.com/nrn/journal/v16/n1/abs/nrn3836.html

Determining the optimal dose in the development of anticancer agents

Identification of the optimal dose remains a key challenge in drug development. For cytotoxic drugs, the standard approach is based on identifying the maximum tolerated dose (MTD) in phase I trials and incorporating this to subsequent trials. However, this strategy does not take into account important aspects of clinical pharmacology. For targeted agents, the dose-effect relationships from preclinical studies are less obvious, and it is important to change the way these agents are developed to avoid recommending drug doses for different populations without evidence of differential antitumour effects in different diseases. The use of expanded cohorts in phase I trials to better define MTD and refine dose optimization should be further explored together with a focus on efficacy rather than toxicity-based predictions. Another key consideration in dose optimization is related to interindividual pharmacokinetic variability. High variability in intra-individual pharmacokinetics has been observed for many orally-administered drugs, especially those with low bioavailability, which might complicate identification of dose-effect relationships. End-organ dysfunction, interactions with other prescription drugs, herbal supplements, adherence, and food intake can influence pharmacokinetics. It is important these variables are identified during early clinical trials and considered in the development of further phase II and subsequent large-scale phase III studies