The clinical trial: deceitful, disputable, unbelievable, unhelpful, and shameful--what next?
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Biomedical subjects
Publications and source records attributed to R Horton.
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Olfactory receptor (OR) loci frequently cluster and are present on most human chromosomes. They are members of the seven transmembrane receptor (7-TM) superfamily and, as such, are part of one of the largest mammalian multigene families, with an estimated copy number of up to 1000 ORs per haploid genome. As their name implies, ORs are known to be involved in the perception of odors and possibly also in other, nonolfaction-related, functions. Here, we report the characterization of ORs that are part of the MHC-linked OR clusters in human and mouse (partial sequence only). These clusters are of particular interest because of their possible involvement in olfaction-driven mate selection. In total, we describe 50 novel OR loci (36 human, 14 murine), making the human MHC-linked cluster the largest sequenced OR cluster in any organism so far. Comparative and phylogenetic analyses confirm the cluster to be MHC-linked but divergent in both species and allow the identification of at least one ortholog that will be useful for future regulatory and functional studies. Quantitative feature analysis shows clear evidence of duplications of blocks of OR genes and reveals the entire cluster to have a genomic environment that is very different from its neighboring regions. Based on in silico transcript analysis, we also present evidence of extensive long-distance splicing in the 5'-untranslated regions and, for the first time, of alternative splicing within the single coding exon of ORs. Taken together with our previous finding that ORs are also polymorphic, the presented data indicate that the expression, function, and evolution of these interesting genes might be more complex than previously thought.
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Austin Bradford Hill was once a friend to The Lancet, but, as occasionally happens, friends fall out. The great legacy of his association with the journal, however, was Principles of Medical Statistics. As each edition was succeeded by another--the first in 1937, the last in 1991--he seemed to shift his view about the influence of statistical method on clinical practice from one of assured certainty to one of modest advantage. That change paralleled a move away from an emphasis on the importance of internal validity in the randomized trial to one of understanding the inescapably practical significance of generalizability. Writers on medical research have explored notions of external validity in various ways. One view, for example, is to seek a close correlation between the participants in a clinical trial and patients seen in practice. The argument goes that such a correspondence has to be made before any decision can be taken about whether to apply the result of that trial to the clinical setting. Another view, first worked out by the American logician Charles Sanders Peirce, is that one must simply rely on the informed guess, based on a reasonable estimate of the limits of extrapolation. The tensions between and implications of these two different approaches are worked through using the example of coronary stents. A solution is, perhaps, to write explicit rules of interpretation that provide a framework for judging the strength of a claim to applicability. Five questions are posed, which try to lay a foundation for such a framework.
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Information exchange is critical for development of health systems. The information needs of less-developed countries are especially challenging, but many factors inhibit free flow of knowledge. There is much talk about how technical fixes--such as the internet--might fill this information gap. Yet few attempts have been made to ask clinical investigators who work in resource-poor regions for their views on these difficulties and the possible solutions. The messages reported here, from a survey of Lancet editorial advisors, suggest that information, research, and publication capacities are intimately linked. Investigators, publishers, editors, and editorial organisations all have important parts to play in solving this global information poverty.
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