Priorities among effective clinical preventive services: methods

Decision makers want to know which healthcare services matter the most, but there are no well-established, practical methods for providing evidence-based answers to such questions. Led by the National Commission on Prevention Priorities, the authors update the methods for determining the relative health impact and economic value of clinical preventive services. Using new studies, new preventive service recommendations, and improved methods, the authors present a new ranking of clinical preventive services in the companion article. The original ranking and methods were published in this journal in 2001. The current methods report focuses on evidence collection for a priority setting exercise, guidance for which is effectively lacking in the literature. The authors describe their own standards for searching, tracking, and abstracting literature for priority setting. The authors also summarize their methods for making valid comparisons across different services. This report should be useful to those who want to understand additional detail about how the ranking was developed or who want to adapt the methods for their own purposes.     

Clinical pharmacokinetics of carbonated local anesthetics. III: Interscalene brachial block model

To compare serum levels of lidocaine resulting from 1.1% lidocaine carbonate and 1.0% lidocaine hydrochloride, the two salts were administered to ten healthy adult patients undergoing upper extremity surgery under interscalene brachial plexus block. Epinephrine (1:200,000) was added to both the solutions just prior to injection, and, following performance of the blocks, venous blood samples were drawn at 3, 5, 10, 15, 20, 30, 60 and 120 minutes. The concentration of lidocaine tended to rise more rapidly and to achieve higher levels in the first 10 minutes following injection of the carbonated lidocaine. However, no significant differences were found in the parameters of Cmax, Tmax or AUC for the two salts, and the serum levels in both groups at all times were well below the levels known to produce systemic toxicity. Therefore, while previous studies appear to indicate that the carbonate salt enhances diffusion, penetration, and uptake of neural tissues as compared with the hydrochloride salt, the present study indicates that vascular uptake is not similarly affected.     

Incidence and etiology of failed spinal anesthetics in a university hospital: a prospective study

Two recent retrospective reports on the incidence of failed spinal anesthetics that indicated extremely variable results prompted the present prospective study of 200 consecutive spinal anesthetics to determine the incidence and causes of failed spinal anesthetics. Tetracaine was the spinal anesthetic agent utilized in all cases--crystalline tetracaine (Niphanoid) in 71% and a 1% solution in 19% of the cases. The failure rate overall was 4%, with all failures being due to anesthetic factors, both technical and pharmacologic. However, only 25% of the failures were due to errors in technique, and 75% were due to errors in judgment with respect to pharmacologic factors (dosage, use of epinephrine, and/or positioning of the patient). Our data, therefore, differ from those of Levy et al. (Anesth Analg 1985;64:705-10), both in terms of failure rate, which is 25% of theirs, and in terms of causation, with our data indicating errors in judgment to be the causative factor three times as often as errors in technique. Presumably, this difference is due to the greater experience in spinal anesthesia that a resident receives at our institution.     

Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma

This phase III randomized study compared concurrent cisplatin-radiotherapy (CRT) versus radiotherapy (RT) alone in patients with locoregionally advanced nasopharyngeal carcinoma. A total of 350 patients were randomly assigned to receive external RT alone or concurrently with cisplatin at a dosage of 40 mg/m(2) weekly. The primary endpoint was overall survival, and the median follow-up was 5.5 years. The 5-year overall survival was 58.6% (95% confidence interval [CI] = 50.9% to 66.2%) for the RT arm and 70.3% (95% CI = 63.4% to 77.3%) for the CRT arm. In Cox regression analysis adjusted for T stage, age, and overall stage, the difference in overall survival was statistically significantly in favor of concurrent CRT (P = .049, hazard ratio [HR] = 0.71 [95% CI = 0.5 to 1.0]). Subgroup analysis demonstrated that there was no difference between overall survival in the arms for T1/T2 stage (P = .74, HR = 0.93 [95% CI = 0.59 to 1.4]), whereas there was a difference between the arms for T3/T4 stage (P = .013, HR = 0.51 [95% CI = 0.3 to 0.88]), favoring the CRT arm. The regimen of weekly concurrent CRT is a promising standard treatment strategy for locoregionally advanced nasopharyngeal carcinoma patients.     

Endothelial dysfunction in the streptozotocin-induced diabetic apoE-deficient mouse

Endothelial dysfunction plays a role in the development of atherosclerosis and diabetes-associated vascular disease and, in the streptozotocin (STZ)-induced apoE-deficient diabetic mouse, we report that, when compared to the citrate (CIT)-treated nondiabetic apoE-deficient control, acetylcholine (Ach)-mediated endothelium-dependent relaxation was reduced in the small mesenteric arteries (SMA) and the plaque-prone regions of the aorta from the STZ-diabetic mouse. In the SMA the component of Ach-mediated relaxation that was attributed to nitric oxide (NO) from STZ-treated diabetic apoE-deficient mice was enhanced; however, the endothelium-derived hyperpolarizing factor (EDHF)-mediated component was reduced. The EDHF component was assessed by determining the component of the Ach-mediated response that was resistant to the combination of the NO synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester, cyclooxygenase inhibitor, indomethacin, and soluble guanylate cyclase inhibitor, ODQ, and inhibited by the combination of the intermediate conductance KCa (IKCa) inhibitor TRAM-34 and the small-conductance KCa (SKCa) inhibitor apamin. Endothelial NOS was increased but SK2, SK3 and connexin (Cx) 37 mRNA expressions were significantly (P<0.05) decreased in the SMA from STZ-treated apoE-deficient mice compared to the CIT-treated controls. There was no difference in the IKCa expression or in Cx 40, 43 and 45 mRNA levels between STZ- and CIT-treated mice. The microvasculature of STZ-induced apoE-deficient mice developed endothelial dysfunction, which may be linked to a decrease in the contribution of the EDHF component due to a decrease in SK2 and 3 and Cx 37 expression.     

Clinical and immunological impact of HIV envelope V3 sequence variation after starting initial triple antiretroviral therapy

BACKGROUND: The HIV-1 envelope third variable loop (V3 loop) is an important determinant of viral phenotype and co-receptor usage. We wished to determine the impact of specific V3 genotypes associated with viral phenotype and co-receptor usage on response to initial triple antiretroviral therapy. METHODS: Pre-therapy plasma samples from the HOMER cohort of 1191 antiretroviral-naive, HIV-infected adults who initiated triple therapy in British Columbia, Canada between August 1996 and September 1999 were genotyped for V3 loop sequence. V3 sequences were dichotomized by the presence or absence of positively charged residues at codons 11 and/or 25 (an '11/25' genotype). Neural network (NN) and Position Specific Scoring Matrix (PSSM) approaches were used as alternative V3 sequence interpretation methods. The association of V3 genotypes with clinical endpoints was assessed over a median of 43 months of follow up. RESULTS: One-hundred and eighteen (10.9%) of the 1085 isolates successfully genotyped for V3 displayed the 11/25 genotype. In multivariate analyses, this genotype was associated with a more rapid CD4 decline [risk ratio, (RR), 1.38; P = 0.012] and earlier mortality (RR, 1.70; P = 0.027), despite comparable viral load suppression below 500 HIV RNA copies/ml. We observed no influence of the 11/25 genotype on time to viral rebound or the development of drug resistance. PSSM-based sequence categories were similarly predictive of outcomes. NN sequence categories were not associated with any endpoints. CONCLUSION: The 11/25 genotype of the HIV V3 loop is an independent predictor of poor immunological response and more rapid mortality even after starting triple antiretroviral therapy. These results may prove to be useful for the clinical management of HIV-infected individuals.