The impact of a quadrivalent human papillomavirus (types 6, 11, 16, 18) virus-like particle vaccine in European women aged 16 to 24

Background  Quadrivalent human papillomavirus (HPV types 6/11/16/18) L1 VLP vaccine is highly effective in preventing HPV 6/11/16/18-related cervical and external genital disease. Herein, we evaluated the impact of the quadrivalent HPV 6/11/16/18 L1 VLP vaccine on prevention of HPV-associated cervico-genital lesions in a broad population of sexually active European women.
Methods  Female subjects ( N = 9265) aged 16–24 with four or fewer lifetime sexual partners were enrolled and randomized to quadrivalent HPV vaccine or placebo. Subjects underwent cervicovaginal sampling for HPV DNA detection. Papanicolaou testing and anti-HPV 6/11/16/18 serology testing was also performed.
Results  Vaccine efficacy against lesions representing immediate cervical cancer precursors (cervical intraepithelial neoplasia grade 2/3 or adenocarcinoma in situ ) related to HPV 6/11/16/18 in the per-protocol population was 100.0%[95% confidence interval (95% CI), 89.8–100.0]. Efficacy against external genital lesions (vulvar or vaginal intraepithelial neoplasia, condyloma, vulvar or vaginal cancer) related to vaccine HPV types in the per-protocol European population was 99.0% (95% CI, 94.4–100.0).
Conclusion  These data demonstrate that quadrivalent HPV 6/11/16/18 vaccination programs in 16- to 24-year-old European women can be beneficial.
NCT0009252, NCT00092534, NCT00092495     

Assessment of baroreflex sensitivity in patients with preserved and impaired left ventricular function by means of the Valsalva manoeuvre and the phenylephrine test

The purpose of the present study was to assess the agreement between measurements of baroreflex sensitivity (BRS) obtained by the Valsalva manoeuvre and by the phenylephrine test in patients with previous myocardial infarction and different degrees of left ventricular dysfunction. Patients with a previous myocardial infarction were enrolled consecutively into two groups according to their left ventricular ejection fraction (LVEF): 40% (n=52). All patients underwent BRS assessment by the phenylephrine technique (Phe-BRS) and by the Valsalva manoeuvre, with the latter using both the overshoot part of phase IV (Ov-VM-BRS) and the whole of phase IV (IV-VM-BRS). The linear association between methods was assessed by correlation analysis and the agreement was evaluated by computing the bias and the limits of agreement. IV-VM-BRS and Ov-VM-BRS could not be computed in 26% and 39% of patients respectively. For both indices a much higher percentage of non-computable Valsalva manoeuvre slopes was found in the group of patients with LVEF 40% the results were: r=0.91 (P<0.001), bias=0.1 ms/mmHg (P=0.84) and limits of agreement from -4.8 to 5 ms/mmHg. When comparing Phe-BRS and IV-VM-BRS, we found r=0.67 (P=0.001), bias=-1.5 ms/mmHg (P=0.06) and limits of agreement from -8.8 to 5.7 ms/mmHg in the group of patients with LVEF 40%. Dichotomizing Ov-VM-BRS, the best cut-off value to identify patients with a Phe-BRS of <3 ms/mmHg was found to be 7 ms/mmHg, giving 100% sensitivity and 69% specificity. In conclusion, estimation of BRS by the Valsalva manoeuvre in post-myocardial infarction patients is limited by a large number of non-measurable results. When computable, measurements are well correlated with those obtained by Phe-BRS, but, because of large limits of agreement, the two methods cannot be used interchangeably. If used as a screening test for risk stratification, the Valsalva manoeuvre could reduce by about one-third the need for phenylephrine injection.     

Use of recombinant human erythropoietin to assist autologous blood donation by anemic rheumatoid arthritis patients undergoing major orthopedic surgery

BACKGROUND: In rheumatoid arthritis (RA) patients undergoing orthopedic surgery, anemia is the major factor in the use of allogeneic blood. STUDY DESIGN AND METHODS: To determine whether recombinant human erythropoietin (rHuEPO) could allow preoperative autologous blood procurement and reduce allogeneic blood exposure, 11 RA patients who were unable preoperatively to deposit blood for autologous use because of their anemia (baseline hematocrit < 34% [0.34]) and who were scheduled for primary total hip replacement or total knee replacement were treated intravenously with 300 U per kg of rHuEPO in combination with intravenous iron saccharate (100 mg), given twice weekly for 3 weeks. The transfusion treatment was compared with that in 12 control patients with comparable baseline hematologic values who underwent the same operation. RESULTS: Control patients could not preoperatively deposit any blood for autologous use, while all but one of the rHuEPO- treated patients deposited 2 or more units (mean, 2.6 +/− 0.6; range, 2- 4) (p < 0.001). The control group received more allogeneic units (2.6 +/− 1.6 vs. 0.8 +/− 0.8) (p = 0.009). Moreover, 50 percent of the rHuEPO-treated patients, as compared with 8 percent of controls, completely avoided allogeneic transfusion. CONCLUSION: Recombinant human erythropoietin is safe and effective in stimulating erythropoiesis, allowing preoperative donation of blood for autologous use, and reducing exposure to allogeneic blood for RA patients who are unable preoperatively to deposit blood because of anemia.     

Relative contribution of ecto-ATPase and ecto-ATPDase pathways to the biphasic effect of ATP on acetylcholine release from myenteric motoneurons

Background and purpose:

The relative contribution of distinct ecto-nucleotidases to the modulation of purinergic signalling may depend on differential tissue distribution and substrate preference.

Experimental approach:

Extracellular ATP catabolism (assessed by high-performance liquid chromatography) and its influence on [³H]acetylcholine ([³H]ACh) release were investigated in the myenteric plexus of rat ileum in vitro.

Key results:

ATP was primarily metabolized via ecto-ATPDase (adenosine 5′-triphosphate diphosphohydrolase) into AMP, which was then dephosphorylated into adenosine by ecto-5′-nucleotidase. Alternative conversion of ATP into ADP by ecto-ATPase (adenosine 5′-triphosphatase) was more relevant at high ATP concentrations. ATP transiently increased basal [³H]ACh outflow in a 2′,3′-O-(2,4,6-trinitrophenyl)adenosine-5′-triphosphate (TNP-ATP)-dependent, tetrodotoxin-independent manner. ATP and ATPγS (adenosine 5′-[γ-thio]triphosphate), but not α,β-methyleneATP, decreased [³H]ACh release induced by electrical stimulation. ADP and ADPβS (adenosine 5′[β-thio]diphosphate) only decreased evoked [³H]ACh release. Inhibition by ADPβS was prevented by MRS 2179 (2′-deoxy-N⁶-methyl adenosine 3′,5′-diphosphate diammonium salt, a selective P2Y₁ antagonist); blockade of ADP inhibition required co-application of MRS 2179 plus adenosine deaminase (which inactivates endogenous adenosine). Blockade of adenosine A₁ receptors with 1,3-dipropyl-8-cyclopentyl xanthine enhanced ADPβS inhibition, indicating that P2Y₁ stimulation is cut short by tonic adenosine A₁ receptor activation. MRS 2179 facilitated evoked [³H]ACh release, an effect reversed by the ecto-ATPase inhibitor, {"type":"entrez-protein","attrs":{"text":"ARL67156","term_id":"1186396857","term_text":"ARL67156"}}ARL67156, which delayed ATP conversion into ADP without affecting adenosine levels.

Conclusions and implications:

ATP transiently facilitated [³H]ACh release from non-stimulated nerve terminals via prejunctional P2X (probably P2X₂) receptors. Hydrolysis of ATP directly into AMP by ecto-ATPDase and subsequent formation of adenosine by ecto-5′-nucleotidase reduced [³H]ACh release via inhibitory adenosine A₁ receptors. Stimulation of inhibitory P2Y₁ receptors by ADP generated alternatively via ecto-ATPase might be relevant in restraining ACh exocytosis when ATP saturates ecto-ATPDase activity.     

Effect of Establishing Guidelines on Appropriate Urinary Catheter Placement

Objectives: Avoiding placement of unnecessary urinary catheters (UCs) in the emergency department (ED) affects UC utilization during hospitalization. The authors sought to evaluate the effect of establishing institutional guidelines for appropriate UC placement coupled with emergency physician (EP) education on UC utilization. Methods: Urinary catheter utilization was measured before and after the establishment of guidelines and EP education. Data collected included the presence of a UC on ED arrival, placement of a UC in the ED, documentation of a physician order for UC placement, reasons for placement, and compliance with the guidelines. Chi‐square analyses were used to study the association between pre‐ and postintervention time periods and catheter use. Results: A total of 377 (15%) patients had UCs; only 151 (47%) UCs initially placed in the ED had a physician order documented. UC placement was appropriately indicated in 75.5% of patients with a documented physician order, but in only 52% of cases without a documented physician order (p < 0.001). The physician intervention was associated with an overall reduction in UC utilization from 16.4% to 13% (p = 0.018). Physicians ordered 40% fewer UCs postintervention compared to preintervention. Preintervention, a physician order for UC placement was found indicated in 72.6% patients, compared to 82.2% patients with UC placed postintervention (p = 0.21). Conclusions: Establishing guidelines for UC placement and physician education in the ED were associated with a marked reduction in utilization. However, addressing appropriate UC utilization may require evaluating other factors such as nursing influence on utilization. ACADEMIC EMERGENCY MEDICINE 2010; 17:337–340 © 2010 by the Society for Academic Emergency Medicine     

Balancing high accrual and ethical recruitment in paediatric oncology: a qualitative study of the 'look and feel' of clinical trial discussions

Background  

High accrual to clinical trials enables new treatment strategies to be tested rapidly, accurately and with generalisability. Ethical standards also must be high so that participation is voluntary and informed. However, this can be difficult to achieve in trials with complex designs and in those which are closely embedded in clinical practice. Optimal recruitment requires a balance of both ethical and accrual considerations. In the context of a trial of stratified treatments for children with acute lymphoblastic leukaemia (UKALL2003) we examined how recruitment looked to an observer and how it felt to the parents, to identify how doctors' communication could promote or inhibit optimal recruitment.