Preoperative beta-blocker use and mortality and morbidity following CABG surgery in North America

CONTEXT: beta-Blockade therapy has recently been shown to convey a survival benefit in preoperative noncardiac vascular surgical settings. The effect of preoperative beta-blocker therapy on coronary artery bypass graft surgery (CABG) outcomes has not been assessed. OBJECTIVES: To examine patterns of use of preoperative beta-blockers in patients undergoing isolated CABG and to determine whether use of beta-blockers is associated with lower operative mortality and morbidity. DESIGN, SETTING, AND PATIENTS: Observational study using the Society of Thoracic Surgeons National Adult Cardiac Surgery Database (NCD) to assess beta-blocker use and outcomes among 629 877 patients undergoing isolated CABG between 1996 and 1999 at 497 US and Canadian sites. MAIN OUTCOME MEASURE: Influence of beta-blockers on operative mortality, examined using both direct risk adjustment and a matched-pairs analysis based on propensity for preoperative beta-blocker therapy. RESULTS: From 1996 to 1999, overall use of preoperative beta-blockers increased from 50% to 60% in the NCD (P<.001 for time trend). Major predictors of use included recent myocardial infarction; hypertension; worse angina; younger age; better left ventricular systolic function; and absence of congestive heart failure, chronic lung disease, and diabetes. Patients who received beta-blockers had lower mortality than those who did not (unadjusted 30-day mortality, 2.8% vs 3.4%; odds ratio [OR], 0.80; 95% confidence interval [CI], 0.78-0.82). Preoperative beta-blocker use remained associated with slightly lower mortality after adjusting for patient risk and center effects using both risk adjustment (OR, 0.94; 95% CI, 0.91-0.97) and treatment propensity matching (OR, 0.97; 95% CI, 0.93-1.00). Procedural complications also tended to be lower among treated patients. This treatment advantage was seen among the majority of patient subgroups, including women; elderly persons; and those with chronic lung disease, diabetes, or moderately depressed ventricular function. Among patients with a left ventricular ejection fraction of less than 30%, however, preoperative beta-blocker therapy was associated with a trend toward a higher mortality rate (OR, 1.13; 95% CI, 0.96-1.33; P =.23). CONCLUSIONS: In this large North American observational analysis, preoperative beta-blocker therapy was associated with a small but consistent survival benefit for patients undergoing CABG, except among patients with a left ventricular ejection fraction of less than 30%. This analysis further suggests that preoperative beta-blocker therapy may be a useful process measure for CABG quality improvement assessment.     

Comparison of two indinavir/ritonavir regimens in the treatment of HIV-infected individuals

BACKGROUND: Pharmacokinetic enhancement of protease inhibitors (PIs) with low-dose ritonavir (RTV) for salvage therapy is increasingly common. The purpose of this study was to compare the pharmacokinetics, safety, and tolerability of indinavir (IDV)/RTV at 800/200 mg (arm A) and 400/400 mg (arm B) administered twice daily in HIV-infected subjects failing their first PI-based regimen. METHODS: A phase I/II, randomized, open-label, 24-week study was conducted. Formal 12-hour pharmacokinetic evaluations were performed, and study visits occurred at baseline; at weeks 1, 2, and 4; and every 4 week thereafter for 24 weeks. Clinical symptoms and laboratory assessments were collected. Subjects were allowed to switch arms because of toxicity. RESULTS: Forty-four subjects were enrolled (22 per arm). IDV predose concentration, maximum plasma concentration and area under the curve were significantly higher in arm A. Fifty-five percent and 45% of subjects in arms A and B responded (<200 copies/mL at week 24; P = 0.76), respectively. CD4 cell responses were similar. All subjects had IDV-sensitive virus at baseline and at virologic failure. Tolerability was comparable, but all grade 3 or higher triglyceride increases occurred in arm B and more subjects in arm B switched because of toxicity (5 vs. 1 triglyceride increases). CONCLUSIONS: This is the largest formal pharmacokinetic evaluation of 2 dosage combinations of IDV/RTV in HIV-infected individuals. Pharmacokinetic parameters were consistent with previous results in patients but lower than in seronegative controls. Both regimens exhibited similar tolerability and response rates. High toxicity with a low response suggests that the optimum IDV/RTV combination would include an RTV dose <400 mg and an IDV dose <800 mg in this population.     

Mutations conferring foscarnet resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis

The clinical significance of cytomegalovirus (CMV) foscarnet resistance was studied in patients with acquired immunodeficiency syndrome and CMV retinitis. Sequencing of the CMV pol gene was performed in 30 isolates. Phenotypic resistance was characterized by the DNA hybridization assay (DHA) in 30 isolates and by plaque-reduction assay (PRA) in 18 isolates. Nine isolates had foscarnet resistance mutations, including V787L and E756Q that were confirmed by marker transfer experiments. Seven of 9 isolates with a 50% inhibitory concentration (IC(50)) >600 microM by DHA had genotypic resistance, compared with 2 of 21 with an IC(50) < or =600 microM (P=.0005). By PRA, 5 isolates had an IC(50) >400 microM and genotypic resistance, whereas only 1 of 13 susceptible isolates had genotypic resistance (P=.0007). Sixteen of 18 isolates had concordant PRA and DHA phenotypes. Among 44 patients treated with foscarnet, drug resistance increased the risk of retinitis progression (odds ratio, 14; P=.016). The incidence of foscarnet resistance after 6, 9, and 12 months of therapy was 13%, 24%, and 37%, respectively.     

The protein tyrosine phosphatase N22 gene is associated with juvenile and adult idiopathic inflammatory myopathy independent of the HLA 8.1 haplotype in British Caucasian patients

OBJECTIVE: To examine single-nucleotide polymorphisms (SNPs) of the protein tyrosine phosphatase N22 gene (PTPN22) and to study the relationship between PTPN22 and the HLA region in patients with idiopathic inflammatory myopathies (IIMs). METHODS: PTPN22 SNPs were assessed in a large, cross-sectional, case-control study from the UK involving patients with adult or juvenile IIM, comprising patients with polymyositis (PM) (n=114), dermatomyositis (DM) (n=102), myositis associated with another connective tissue disease (myositis-CTD overlap syndrome) (n=64), or juvenile DM (n=101), in comparison with 748 control subjects. Seventeen PTPN22 SNPs were genotyped using the Sequenom MassArray iPLEX platform. Serotyping for myositis-specific/myositis-associated autoantibodies (MSAs/MAAs) was performed by radioimmunoprecipitation. RESULTS: A significant association was noted between the R620W variant (rs2476601) and IIM (corrected P [Pcorr]=0.0009 versus controls), and specifically with the clinical subgroup of PM (Pcorr=0.003 versus controls). A weaker association was noted with juvenile DM (Pcorr=0.009 versus controls). No significant associations were noted after stratification by serologic subgroups. The association with the R620W variant was independent of alleles forming the HLA 8.1 haplotype. No other PTPN22 SNPs were associated with IIM. The PTPN22 haplotype containing the R620W T allele was the only haplotype significantly associated with IIM. CONCLUSION: The R620W variant is a significant risk factor for IIM, independent of the HLA 8.1 haplotype. Unlike that in the HLA region, risk is not increased in individuals possessing MSAs/MAAs. These results are further evidence that the PTPN22 gene confers autoimmune susceptibility.     

Age-related immune dysfunction in health and in human immunodeficiency virus (HIV) disease: association of age and HIV infection with naive CD8+ cell depletion,reduced expression of CD28 on CD8+ cells,and reduced thymic volumes

Older age is a strong predictor of accelerated human immunodeficiency virus (HIV) disease progression. We investigated the possible immunologic basis of this interaction by comparing older (>/=45 years) and younger (相似文献   

Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial

In an attempt to improve induction chemotherapy for older patients with acute myeloid leukemia (AML),1314 patients were randomized to 1 of 3 induction treatments for 2 courses of DAT (daunorubicin, cytarabine, and thioguanine) 3 + 10, ADE (daunorubicin, cytarabine, and etoposide) 10 + 3 + 5, or MAC (mitoxantrone-cytarabine). The remission rate in the DAT arm was significantly better than ADE (62% vs 50%; P =.002) or MAC (62% vs 55%; P =.04). This benefit was seen in patients younger and older than 70 years. There were no differences between the induction schedules with respect to overall survival at 5 years (12% vs 8% vs 10%). A total of 226 patients were randomized to receive granulocyte colony-stimulating factor (G-CSF) or placebo as supportive care from day 8 after the end of treatment course 1. The remission rate or survival were not improved by G-CSF, although the median number of days to recover neutrophils to 1.0 x 10(9)/L was reduced by 5 days. Patients who entered remission (n = 371) were randomized to stop after a third course (DAT 2 + 7) or after 6 courses, ie, a subsequent COAP (cyclophosphamide, vincristine, cytarabine, and prednisolone), DAT 2 + 5, and COAP. The relapse risk (81% vs 73%), disease-free survival (16% vs 23%), and overall survival at 5 years (23% vs 22%) did not differ between the 3-course or 6-course arms. In addition to a treatment duration randomization, 362 patients were randomized to receive 12-month maintenance treatment with low-dose interferon, but no benefit was seen with respect to relapse risk, disease-free survival, or overall survival.