Specific antibody responses to vaccination with bivalent CM235/SF2 gp120: detection of homologous and heterologous neutralizing antibody to subtype E (CRF01.AE) HIV type 1

HIV-1 CRF.AE-01 (formerly subtype E) infection is highly prevalent in Southeast Asia. Despite success with public health measures, the development of an effective CRF01.AE vaccine is critical to the control of this epidemic. Sera from the open-label arms of the first clinical trial of a bivalent HIV gp120 SF2/CM235 (subtypes B and CRF.AE-01, respectively) vaccine were evaluated for the presence of gp120-specific binding (BAb) and neutralizing antibody (NAb). Twelve pre- and postvaccination sera pairs were tested for CM235 BAb; anti-gp120 CM235 BAb was found in all postvaccination samples. The 12 pre- and postvaccination (1 month after third vaccination) serum pairs were evaluated in several neutralization formats: heterologous T cell line adapted (TCLA) NP03/H9, homologous CM235/PBMC, CM235/dendritic cell, and CM235M4-C4.6/A3R5. A3R5 is a CCR5+ T cell line, and CM235M4-C4.6 is the homologous CM235 virus adapted to growth in A3R5 cells. All volunteers developed BAb, but meaningful NAb was not demonstrable against primary isolate CM235. Using the TCLA CRF01.AE virus NP03 in H9 cells, 9 of 12 persons had NAb with a geometric mean titer (GMT) of 46. The CM235M4-C4.6 virus in A3R5 cells also detected NAb in 9 of 12 persons, with a GMT of 41. CM235M4-C4.6/A3R5 detected NAb in two persons with negligible NAb to NP03/H9 and vice versa. Whether the NAb detected by the CM235M4-C4.6/A3R5 system is qualitatively different from those in more traditional NP03/H9 assays will require further study.     

Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated)

RATIONALE: Patients with severe sepsis frequently receive prophylactic heparin during drotrecogin alfa (activated) (DrotAA) treatment due to risk of venous thromboembolic events (VTEs). Biological plausibility exists for heparin to reduce DrotAA efficacy and/or increase bleeding. OBJECTIVES: Primary: demonstrate in adult patients with severe sepsis receiving DrotAA treatment that 28-day mortality was equivalent for patients treated with concomitant prophylactic heparin compared with placebo; secondary: safety and VTE incidence. METHODS: International, randomized, double-blind, phase 4, equivalence-design trial (n = 1994). Patients were eligible if indicated for and receiving DrotAA treatment under the country's approved label. Study drug (low molecular weight/unfractionated heparin) or placebo (saline) was administered every 12 hours during DrotAA infusion (24 ug/kg/hr for 96 hr). In patients on baseline heparin and randomized to placebo, heparin was stopped. MEASUREMENTS AND MAIN RESULTS: Twenty-eight-day mortality was not equivalent between treatment groups. Heparin mortality was numerically lower (28.3 vs. 31.9%; p = 0.08). In the prospectively defined subgroup of patients exposed to heparin at baseline, patients receiving placebo experienced higher mortality (35.6 vs. 26.9%; p = 0.005). For safety, significant differences were observed during Days 0-6 for any bleeding event (placebo, n = 78; heparin, n = 105; p = 0.049) and ischemic stroke during Days 0-6 (placebo, n = 12; heparin, n = 3; p = 0.02) and Days 0-28 (placebo, n = 17; heparin, n = 5; p = 0.009). The VTE rate was low, with no statistical difference between groups (0-6 d, p = 0.60; 0-28 d, p = 0.26). CONCLUSIONS: Compared with placebo, concomitant prophylactic heparin was not equivalent, did not increase 28-day mortality, and had an acceptable safety profile in patients with severe sepsis receiving DrotAA. Heparin discontinuation should be carefully weighed in patients considered for DrotAA treatment. XPRESS clinical trial registered with www.clinicaltrials.gov (NCT 00049777). The study ID numbers are 6743; F1K-MC-EVBR.     

Patient knowledge of coronary risk profile improves the effectiveness of dyslipidemia therapy: the CHECK-UP study: a randomized controlled trial

BACKGROUND: Despite increasing evidence that treating dyslipidemia reduces cardiovascular events, many patients do not achieve recommended lipid targets. METHODS: To determine whether showing physicians and patients the patient's calculated coronary risk can improve the effectiveness of treating dyslipidemia in a primary care setting, patients were randomized to receive usual care or ongoing feedback regarding their calculated coronary risk and the change in this risk after lifestyle changes, pharmacotherapy, or both to treat dyslipidemia. Outcomes, based on intention-to-treat analysis, included changes in blood lipid levels, coronary risk, and the frequency of reaching lipid targets. RESULTS: Two hundred thirty primary care physicians enrolled 3,053 patients. After 12 months of follow-up, 2,687 patients (88.0%) remained in the study. After adjustment for baseline lipid values, significantly greater mean reductions in low-density lipoprotein cholesterol levels and the total cholesterol to high-density lipoprotein cholesterol ratio were observed in patients receiving risk profiles (51.2 mg/dL [to convert to millimoles per liter, multiply by 0.0259] and 1.5, respectively) vs usual care (48.0 mg/dL and 1.3, respectively), but the differences were small (-3.3 mg/dL; 95% confidence interval [CI], -5.4 to -1.1 mg/dL; and -0.1; 95% CI, -0.2 to -0.1, respectively). Patients in the risk profile group were also more likely to reach lipid targets (odds ratio, 1.26; 95% CI, 1.07 to 1.48). A significant dose-response effect was also noted when the impact of the risk profile was stronger in those with worse profiles. CONCLUSIONS: Discussing coronary risk with the patient is associated with a small but measurable improvement in the efficacy of lipid therapy. The value of incorporating risk assessment in preventive care should be further evaluated.     

Cost-effectiveness of different reading and referral strategies in mammography screening in the Netherlands

In mammography screening with double reading, different strategies can be used when the readers give discordant recommendations for referral. We investigated whether the results of the Dutch breast cancer screening programme can be optimised by replacing the standard referral strategy by consensus. Twenty-six screening radiologists independently and blinded to outcome read a test set consisting of previous screening mammograms of 250 cases (screen-detected and interval cancers) and 250 controls. Their referral recommendations were paired and, in case of discrepancy, re-read according to three referral strategies: (1) decision by one of the readers; (2) arbitration by a third reader; (3) referral if both readers agree (consensus). Data allowed studying other referral strategies, including referral if any reader suggests, as well. Double reading with referral if any reader suggests resulted in a 1.03 times higher sensitivity (76.6%) and a 1.31 times higher referral rate (1.26%) than double reading with consensus. To estimate the cost-effectiveness, the outcomes were used in a microsimulation model. Even if double reading with referral if any reader suggests results in four times as high referral rates and an accompanying increase of biopsies or other invasive procedures, the cost-effectiveness of €4,190 per life-year gained may well be in the range of acceptable cost-effectiveness for Dutch health care programmes. The NETB consists of H.J. de Koning (chair), J. Fracheboud, S.J. Otto, J.H. Groenewoud, G. Draisma, A.E. de Bruijn, Department of Public Health, Erasmus MC, University Medical Center Rotterdam; B.M. van Ineveld, Institute for Medical Technology Assessment, Erasmus MC, University Medical Center Rotterdam; F. van der Horst, National Expert and Training Centre for Breast Cancer Screening, Nijmegen; M.J.M. Broeders, A.L.M. Verbeek, Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, Nijmegen.     

科研项目评估方法的研究

为探讨我国的科研项目评估方法的先进性,本文介绍了国内外科研项目评估的主要方法,阐述了科研项目评估的主要方法的定义、用途及其优缺点,为正确评价各种科研项目评估方法提供参考.