Identification of a potent MAR element from the human genome and assessment of its activity in stably transfected CHO cells.

Low-level and unstable transgene expression are common issues using the CHO cell expression system. Matrix attachment regions (MARs) enhance transgene expression levels, but additional research is needed to improve their function and to determine their mechanism of action. MAR-6 from CHO chromosomes actively mediates high and consistent gene expression. In this study, we compared the effects of two new MARs and MAR-6 on transgene expression in recombinant CHO cells and found one potent MAR element that can significantly increase transgene expression. Two MARs, including the human CSP-B MAR element and DHFR intron MAR element from CHO cells, were cloned and inserted downstream of the poly(A) site in a eukaryotic vector. The constructs were transfected into CHO cells, and the expression levels and stability of eGFP were detected by flow cytometry. The three MAR sequences can be ranked in terms of overall eGFP expression, in decreasing order, as follows: human CSP-B, DHFR intron MAR element and MAR-6. Additionally, as expected, the three MAR-containing vectors showed higher transfection efficiencies and transient transgene expression in comparison with those of the non-MAR-containing vector. Bioinformatics analysis indicated that the NFAT and VIBP elements within MAR sequences may contribute to the enhancement of eGFP expression. In conclusion, the human CSP-B MAR element can improve transgene expression and its effects may be related to the NFAT and VIBP elements.

The cost implications of the use of telmisartan or ramipril in patients at high risk for vascular events: the ONTARGET study.

BACKGROUND: The recently published ONTARGET trial found that telmisartan was non-inferior to ramipril in reducing CV death, MI, stroke, or heart failure in patients with vascular disease or high-risk diabetes. The cost implications of ramipril and telmisartan monotherapy use based on the ONTARGET study are reported here. METHODS AND RESULTS: Only healthcare system costs were considered. Healthcare resource utilization was collected for each patient during the trial. The authors obtained country-specific unit costs to the different healthcare care resources consumed (i.e., hospitalizations events, procedures, non-study, and study drugs) for all enrolled patients. Purchasing power parities were used to convert country-specific costs into US dollars (US$ 2008). The total undiscounted costs of the study for the telmisartan group was $12,762 per patient and is higher than the ramipril group at $12,007 per patient, an un-discounted difference of $755 (95% confidence interval [CI], $218-$1292); The discounted costs for the telmisartan group was $11,722 compared with $11,019 for the ramipril group; a difference of $703 (95% CI, $209-$1197). The difference in costs is exclusively related to the acquisition cost of telmisartan over generic ramipril. LIMITATIONS: This analysis only considered direct healthcare system costs. Costs accrued outside the hospital were not collected. Combination therapy was excluded since it would likely be more expensive than ramipril alone, with no additional benefit and a risk of some harm. CONCLUSIONS: Based on these results, it is suggested that for the ONTARGET patients, the use of telmisartan instead of ramipril increases costs by 6.3%. These findings suggest that the choice to put patients on telmisartan should be justified based on the patient?s susceptibility to specific adverse events to minimize the cost implications.

Canadian Registry of ICD Implant Testing procedures (CREDIT): current practice, risks, and costs of intraoperative defibrillation testing.

BACKGROUND: There is uncertainty about the proper role of defibrillation testing (DT) at the time of implantable cardioverter defibrillator (ICD) insertion. METHODS: A prospective registry was conducted at 13 sites in Canada between January 2006 and October 2007. OBJECTIVES: To document the details of DT, the reasons for not conducting DT, and the costs and complications associated with DT. RESULTS: DT was conducted at implantation in 230 of 361 patients (64%). DT was more likely to be conducted for new implants compared with impulse generator replacements (71% vs 32%, P = 0.0001), but was similar for primary and secondary prevention indications (64% vs 63%, P = NS). Among patients not having DT, the reason(s) given were: considered unnecessary (44%); considered unsafe, mainly due to persistent atrial fibrillation (37%); lack of an anesthetist (20%); and, patient or physician preference (6%). When performed, DT consisted of a single successful shock > or = 10J below maximum device output in 65% of cases. A 10J safety-margin was met by 97% of patients, requiring system modification in 2.3%. Major perioperative complications occurred in 4.4% of patients having DT versus 6.6% of patients not having DT (P = NS). ICD insertion was $844 more expensive for patients having DT (P = 0.16), largely due to increased costs ($28,017 vs $24,545) among patients having impulse generator replacement (P = 0.02). CONCLUSIONS: DT was not performed in a third of ICD implants, usually due to a perceived lack of need or relative contraindication.

Cost comparison of ablation versus antiarrhythmic drugs as first-line therapy for atrial fibrillation: an economic evaluation of the RAAFT pilot study.

INTRODUCTION: Radiofrequency ablation (RFA) has become an accepted therapy for atrial fibrillation (AF). The objective of this study was to perform an economic evaluation of RFA versus antiarrhythmic drug therapy (AAD) as first-line treatment of symptomatic paroxysmal AF. METHODS: To estimate and compare the costs of RFA versus AAD, a decision analytic model was developed using data on AF recurrence, hospitalization rates, AAD use, and treatment crossover rates derived directly from the Randomized Trial of RFA versus AAD as First-Line Treatment of Symptomatic Atrial Fibrillation (RAAFT). Resource utilization was modeled to reflect Canadian clinical practice in AF management. Unit costs of healthcare interactions were based on available Canadian government resources and published literature. Costs were assessed based on intention-to-treat. Total expected costs were computed to include initial treatment, hospital stay, physician fees, diagnostic tests, and outpatient visits. Sensitivity analyses were performed to account for the uncertainties. The study was conducted from the third party payer's perspective and costs are reported in 2005 Canadian dollars with 3% discount rate used in the analysis. RESULTS: During the 2-month blanking period following therapy selection, total average costs for RFA and AAD were $10,465 and $2,556, respectively; at 1-year follow-up, these were $12,823 and $6,053; and total 2-year cumulative total average costs were $15,303 and $14,392. Sensitivity analyses did not alter the results, suggesting the model is robust. CONCLUSIONS: RFA as first-line treatment strategy in patients with symptomatic paroxysmal AF was cost neutral 2 years after the initial procedure compared to AAD.

Cost comparison of four revascularisation procedures for the treatment of multivessel coronary artery disease.

OBJECTIVE: An economic evaluation was performed, using modelling techniques, to compare 1-year total costs of four revascularisation procedures in patients with multivessel disease: on-pump coronary artery bypass grafting (CABG); off-pump CABG; percutaneous coronary intervention (PCI) with bare-metal stents (BMS); and PCI with drug-eluting stents (DES). METHODS: Clinical data were derived from four randomised clinical trials comparing CABG versus PCI, as well as from literature reviews. Resource use and unit cost estimates were modelled to reflect current Canadian practice. RESULTS: This study demonstrated that 1 year after the initial revascularisation, PCI with BMS is the least costly procedure, followed by off-pump CABG, PCI with DES and on-pump CABG. DES became the most costly procedure if 3.5 or more DES were used or if staged PCI was performed.

A cost comparison of off-pump CABG versus on-pump CABG at one-year: The Canadian off-pump CABG registry.

BACKGROUND: Evidence suggests that off-pump coronary artery bypass graft surgery (CABG) is as safe and effective as on-pump CABG, and the cost of initial hospitalization for off-pump CABG is less expensive than on-pump CABG. However, it is uncertain whether the cost savings are sustained over a longer period of time. OBJECTIVE: To assess in-hospital and one-year direct medical costs of off-pump CABG versus on-pump CABG in the context of the Canadian health care system. METHODS AND RESULTS: From March 2001 to December 2002, 1657 consecutive patients enrolled in the Canadian Off-Pump CABG Registry were compared with 1693 consecutive on-pump patients from Hamilton Health Sciences CABG database. At one year, patients of both groups were followed by telephone interview. An economic analysis was conducted from the perspective of the Ontario Ministry of Health and Long-Term Care, and the data analysis was based on propensity score-matched registry patients (1233 pairs) to ensure the comparability of the two study groups. Clinical event and resource use information was collected from all patients. Unit costs from the Hamilton Health Sciences case-costing system were used to estimate hospital costs; all costs were reported in 2003 Canadian dollars. Sensitivity analyses were performed to account for uncertainties. The cost of initial hospitalization for off-pump CABG was significantly less than on-pump CABG (11,744 dollars versus 13,720 dollars, P < 0.001). Although follow-up costs were similar between the groups, the one-year total cost per patient for off-pump CABG remained significantly less than on-pump CABG (12,063 dollars versus 14,141 dollars, P < 0.001). CONCLUSION: Off-pump CABG offers significant savings during initial hospitalization that are also sustained after one year.

[Analysis on the potential losses of maternal mortality in Sichuan province in 2003].

OBJECTIVE: To explore the years of potential life lost (YPLL), working lost, valued lost from the main causes of maternal mortality. METHODS: We collected the mortality cases and live births by the surveillance network of maternal mortality in Sichuan province in 2003, and calculated YPLL, average years of life lost (AYLL), working years of potential life lost (WYPLL), valued years of potential life lost (VYPLL) caused by the death. RESULTS: In 2003, YPLL, AYLL, WYPLL, VYPLL of the maternal mortality were 4016, 43, 2305 and 2608 respectively. CONCLUSIONS: The ages of the maternal mortality were young, and the potential losses were significant. This not only threatens the life of women, but also is vital losses to the society and economy.

Economic evaluation of the MEDENOX trial: a Canadian perspective. Medical Patients with Enoxaparin.

OBJECTIVE: To perform an economic evaluation of the Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) trial from a Canadian perspective. METHOD: Using a decision tree model, cost effectiveness analysis was carried out to compare the costs and consequences of thromboprophylaxis using enoxaparin 40 mg with placebo in tertiary and community settings. From a third party payer's perspective, the model calculated the expected rate of symptomatic venous thromboembolism (VTE), and the total expected cost of prophylaxis and VTE management, including inpatient and outpatient treatment, professional fees and long term therapy. Data were derived directly from the MEDENOX trial. Costs are direct medical costs in year 2000 Canadian dollars. RESULTS: In a tertiary setting in which the estimated inpatient to outpatient deep vein thrombosis treatment ratio was 10%:90%, the total expected cost per patient was 64 dollars in the enoxaparin group and 62 dollars in the placebo group. The expected symptomatic VTE rates were 0.8% and 3.1% in the enoxaparin and placebo groups, respectively. The incremental cost effectiveness of enoxaparin 40 mg versus placebo was 87 dollars/VTE avoided. In a community hospital setting (with a 50%:50% inpatient to outpatient deep vein thrombosis treatment ratio), the total expected cost per patient was 68 dollars in the enoxaparin group compared with 72 dollars in the placebo group, indicating that prophylaxis with enoxaparin 40 mg was cost saving. The model was sensitive to the inpatient to outpatient ratio. However, within each setting, the results were not sensitive to changes in key variables. CONCLUSION: For patients hospitalized for acute respiratory failure, congestive heart failure or acute infectious disease and who are at moderate risk of developing VTE, thromboprophylaxis with enoxaparin 40 mg daily is a cost effective strategy in both tertiary and community settings.