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Aims: Aldo-ketoreductases have been implicated in the metabolism of doxorubicin. We sought to assess the influence of AKR1C3 genetic variants on doxorubicin metabolism., Methods: We sequenced AKR1C3 exon 5 and genotyped seven functional single nucleotide polymorphisms in CBR3, ABCB1 and SLC22A16 involved in doxorubicin pharmacology in 151 Asian breast cancer patients treated with doxorubicin-containing chemotherapy, and correlated these genotypes with doxorubicin pharmacokinetics and pharmacodynamics., Results: Two previously reported AKR1C3 intronic variants, IVS4-212 C>G and IVS4+218 G>A, were detected. The AKR1C3 IVS4-212 GG genotype was associated with significantly lower cycle 1 day 15 leucocyte (mean leucocytes 2.49 ± 1.57 × 10(9) vs. 3.85 ± 3.42 × 10(9) l(-1) , P = 0.007) and neutrophil counts (mean neutrophils 0.70 ± 1.01 × 10(9) vs. 1.56 ± 2.80 × 10(9) l(-1) , P = 0.008) and significant improvement of progression-free survival [PFS, mean PFS 49.0 (95% confidence interval 42.2-55.8) vs. 31.0 (95% confidence interval 20.7-41.2) months, P = 0.017] and overall survival [OS; mean OS 64.4 (95% confidence interval 58.3-70.5) vs. 46.3 (95% confidence interval 35.1-57.5) months, P = 0.006] compared with those carrying at least one C allele. There was no significant association between AKR1C3 IVS4-212 C>G and doxorubicin pharmacokinetics. Of the other seven single nucleotide polymorphisms genotyped, CBR3 G11A correlated with doxorubicinol area under the concentration-time curve and OS, ABCB1 G2677T/A correlated with doxorubicin clearance and platelet toxicity, while ABCB1 IVS26+59 T>G correlated with OS. The AKR1C3 IVS4-212 C

Objective: To construct quality measures with measurement validity and meaning for clinicians., Methods: We conducted a prospective cohort study of rates of change in disease-modifying antirheumatic drug (DMARD) and/or systemic corticosteroid drug or dose for 568 patients with rheumatoid arthritis (RA) across 6,159 clinical encounters within 12 months to examine how changes in clinical specifications change adherence., Results: Rates of DMARD change were sensitive to specifications regarding the intensity of disease activity (severe or moderate), duration of specified disease activity, and length of the observation period. Over 12 months, the proportions of 377 patients with severe disease activity observed for 1-month, 2-month, and 3-month time blocks who had a change in DMARD drug or dose were 36%, 57%, and 74%, respectively. Over 12 months, a change in DMARD drug or dose was observed for 44%, 50%, and 68% of 377 patients with severe disease within 3 months, 6 months, and 12 months, respectively, of the patient meeting criteria for severe disease activity. A change in DMARD drug or dose was observed for 21%, 23%, and 34% of 149 patients with moderate disease activity within 3, 6, and 12 months, respectively, of the patient meeting criteria for moderate disease activity., Conclusion: Rates of pharmacologic interventions for patients with moderate and severe RA disease activity vary substantially by intensity and duration of disease activity and by duration of period for observing change. Lack of precision in explicit process criteria could substantially mislead comparisons of quality of care across comparison groups.