thiostrepton The authors identified other genetic variants t

The authors identified 13 other genetic variants that are promising candidates. None of these additional genetic variants reached the pre-specified level of statistical significance and therefore do not meet the discovery threshold but remain as promising candidates requiring further work and validation. When tested for replication in the collaborators\' genotyped sepsis cohorts, none replicated to the same extent as VPS13A. Among this set, the best candidates included CRISPLD2 (p=5.99×10) and a region on chromosome 13q21.33 (p=3.34×10). Reversing the replication strategy, these investigators tested for replication of top association findings previously reported by Rautanen et al. (). They did not observe directionally similar significant findings for any of the reported SNPs. Again, it must be appreciated that for genetic association studies, the currently reported cohort is quite small and therefore does not have much statistical power to find true associations. The use of previous data to “look-up” potential new discoveries is a very encouraging event. First, replication of the key result is impressive validation and greatly increases the probability that the primary discovery is biologically real and not a statistical fluke. Second, sharing of data is an exciting trend that will certainly improve the veracity of reported results. Another encouraging step was the use of gene-based analysis for replication. Single SNP associations may not identify causal SNPs and may simply be markers in thiostrepton disequilibrium with the underlying causal genetic variants. Sequencing all SNPs within the identified gene is a more powerful approach (). The increased statistical power of this approach () is tempered by the smaller number of patients within this substudy in the current report. Nevertheless, replication of gene association greatly reduces that chance that a SNP association is a false positive result. The current report highlights bad and good features of genetic association studies in sepsis, ARDS, and critical illness. A key bad feature is the relatively low power we currently have to make discoveries because we have not put together sufficiently large genotyped sepsis cohorts. Cohorts in the tens of thousands have successfully identified key genes in, for example, atherosclerosis and asthma. This has led to the development of highly successful new drugs. The very good feature of the current report is that these investigators, and indeed the critical care community, are now starting to coalesce in order to address the important observations arising from genetic association studies. Let\'s put together the first >10,000 patient genetic association study in sepsis and start to make the really exciting discoveries that will transform patient care and outcomes. Support Canadian Institutes of Health Research (136986).
Conflicts of Interest
With the encouraging results of pancreatic islet allotransplantation, increasing attention is being directed towards pig islet xenotransplantation, which would resolve the problem of islet supply (). Free (nonencapsulated) pig islets (either wild-type or genetically-engineered) have maintained normoglycemia in immunosuppressed diabetic nonhuman primates for >1year (). Immunoisolated (encapsulated) pig islets have maintained normoglycemia in non-immunosuppressed diabetic nonhuman primates for up to 6months (). Groth et al. performed the first clinical islet xenotransplantation in 1994 using fetal porcine islet-like cell clusters placed under the kidney capsule (). Although clinical benefit was not demonstrated, evidence was provided by measurement of porcine C-peptide that porcine islets could survive in the human body. The first nationally-regulated clinical trial of intra-peritoneal alginate-poly--ornithine-alginate (APA) encapsulated (neonatal) porcine islet xenotransplantation in nonimmunosuppressed diabetic patients was carried out in New Zealand and was associated with some reduction in hypoglycemic unawareness (). However, there was a lack of correlation between the number of islets transplanted and the clinical outcome; the transplantation of 5000IEq/kg was associated with better results than of 15,000 or 20,000IEq/kg.