Aims To evaluate whether a year long clinical pharmacy program involving development of professional relationships, nurse education on medication issues, and individualized medication reviews could change drug use, mortality and morbidity in nursing home residents. Methods A cluster randomised controlled trial, where an intervention home was matched to three control homes, was used to examine the effect of the clinical pharmacy intervention on resident outcomes. The study involved 905 residents in 13 intervention nursing homes and 2325 residents in 39 control nursing homes in southeast Queensland and north-east New South Wales, Australia. The outcome measures were: continuous drug use data from government prescription subsidy claims, crosssectional drug use data on prescribed and administered medications, deaths and morbidity indices (hospitalization rates, adverse events and disability indices). Results This intervention resulted in a reduction in drug use with no change in morbidity indices or survival. Differences in nursing home characteristics, as de®ned by cluster analysis with SUDAAN 1 , negated intervention-related apparent signi®cant improvements in survival. The use of benzodiazepines, nonsteroidal anti-in¯ammatory drugs, laxatives, histamine H 2 -receptor antagonists and antacids was signi®cantly reduced in the intervention group, whereas the use of digoxin and diuretics remained similar to controls. Overall, drug use in the intervention group was reduced by 14.8% relative to the controls, equivalent to an annual prescription saving of $A64 per resident (approximately £25). Conclusions This intervention improved nursing home resident outcomes related to changes in drug use and drug-related expenditure. The continuing divergence in both drug use and survival at the end of the study suggests that the difference would have been more signi®cant in a larger and longer study, and even more so using additional instruments speci®c for measuring outcomes related to changes in drug use.

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Cystathionine-b-synthase (CBS) deficiency is a human genetic disease causing homocystinuria, thrombosis, mental retardation, and a suite of other devastating manifestations. Early detection coupled with dietary modification greatly reduces pathology, but the response to treatment differs with the allele of CBS. A better understanding of the relationship between allelic variants and protein function will improve both diagnosis and treatment. To this end, we tested the function of 84 CBS alleles previously sequenced from patients with homocystinuria by ortholog replacement in Saccharomyces cerevisiae. Within this clinically associated set, 15% of variant alleles were indistinguishable from the predominant CBS allele in function, suggesting enzymatic activity was retained. An additional 37% of the alleles were partially functional or could be rescued by cofactor supplementation in the growth medium. This large class included alleles rescued by elevated levels of the cofactor vitamin B6, but also alleles rescued by elevated heme, a second CBS cofactor. Measurement of the metabolite levels in CBS-substituted yeast grown with different B6 levels using LC-MS revealed changes in metabolism that propagated beyond the substrate and product of CBS. Production of the critical antioxidant glutathione through the CBS pathway was greatly decreased when CBS function was restricted through genetic, cofactor, or substrate restriction, a metabolic consequence with implications for treatment.T HE first complete human genome sequence seeded the defining challenge of human genetics for the foreseeable future: interpreting the impact of variations in the sequences of individual human genomes. Comparative genome sequencing reveals an average of one single-nucleotide change per 1200 bp between any two individuals. In the absence of strong Mendelian inheritance and linkage, confirming that any human genotype actually caused a phenotype is a significant challenge given the approximately 3 million genetic variants per person. Indeed, 4000 traits of medical interest show evidence for inheritance but lack a clear determinant (Online Mendelian Inheritance in Man 2012). Next-generation sequencing within small pedigrees (Ng et al. 2010a,b;Fan et al. 2011), or a more narrowly defined clinical phenotype (Schubert et al. 1997), can sometimes disentangle the underlying contribution of a gene to disease. In this work we have taken an approach that complements both increased sequencing capacity and expanded phenotypic description. We used surrogate genetics to assay directly the function of allelic variants and then evaluate their potential contribution to phenotypes of clinical importance.Homocystinuria, elevated levels of the sulfur-containing metabolite homocystine in the urine, illustrates several Reference numbers for publicly available data; GenBank: L14577.1 (CBS); dbSNP: rs17849313 (A69P), rs2229413 (P70L), rs11700812 (R369P); SGD: YGR155W (CYS4) and YDR232W (HEM1 challenges inherent to elucidating the molecular bases of human geneti...