A Randomized Trial to Assess the Effect of Doravirine on the QTc Interval Using a Single Supratherapeutic Dose in Healthy Adult Volunteers.

INTRODUCTION: Doravirine is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor exhibiting a robust safety and efficacy profile in combination with other antiretrovirals. While existing data do not suggest that doravirine delays cardiac repolarization, the aim of this trial was to evaluate the effects of a supratherapeutic dose of doravirine on the heart-rate corrected QT (QTc) interval in healthy adults. METHODS: A randomized, three-period, crossover, placebo-controlled trial was conducted in healthy adults, 18-55 years of age. Three treatments were administered: single-dose doravirine 1200 mg, placebo, and positive control (single-dose moxifloxacin 400 mg). QT interval measurements were collected at serial time points following treatment administration. Clinically significant placebo-corrected, baseline-adjusted QTc interval prolongation was defined when the upper bound of the two-sided 90% confidence interval (CI) for the mean effect on double delta QTc exceeded 10 ms. Doravirine tolerability and pharmacokinetics were also evaluated. RESULTS: Forty-five subjects were enrolled and 39 completed the study per protocol. Fridericia's QT correction for heart rate was demonstrated to be inadequate; therefore, a population-specific correction was applied (QTcP). Assay sensitivity was confirmed with moxifloxacin. Following doravirine administration, QTc intervals did not exceed the pre-specified significance threshold - upper 90% CIs were ≤5.42 ms across all time points. Categorical analyses identified no outliers or clinically meaningful deviations. Doravirine geometric mean area under the time-concentration curve from dosing until 24 h post-dose (AUC0-24) and maximum plasma concentration (C max) were 119 µM·h and 9240 nM, respectively, which exceeded values expected following therapeutic dose administration of doravirine 100 mg, even in the setting of intrinsic and extrinsic factors that may cause increases in doravirine concentrations. All treatments were generally well tolerated. CONCLUSION: A single oral supratherapeutic dose of doravirine 1200 mg does not cause clinically meaningful QTc interval prolongation in healthy adults.

CIN in pregnancy: antepartum and postpartum cytology and histology.

OBJECTIVE: To determine the rates of antepartum and postpartum cervical intraepithelial neoplasia (CIN) 2 or worse in pregnant women with abnormal cervical cytology. STUDY DESIGN: A prospective, cohort study of 283 pregnant women referred for colposcopy between 1992 and 1999 for the evaluation of abnormal Pap smears. In this analysis, the population was stratified by severity of referral cytology (atypical squamous cells of undetermined significance [ASCUS] or low grade squamous intraepithelial lesion [LSIL] versus high grade squamous intraepithelial lesion [HSIL] and atypical glandular cells of undetermined significance [AGUS]). RESULTS: Sixty-seven women (24%) had ASCUS, 147 (52%) LSIL, 67 (24%) HSIL and 2 (0.7%) AGUS. As compared to women with HSIL or AGUS, women with ASCUS or LSIL were less likely to undergo antepartum biopsy (relative risk [RR] .34, 95% CI .23-.51) and if biopsied, less likely to have CIN 2 or worse (OR .49, 95% CI .24-.99). Women with antepartum ASCUS or LSIL were less likely to have postpartum HSIL (OR .29, 95% CI, .17-.52) and tended to have fewer histologically severe biopsies as compared to women with antepartum HSIL (OR .55, 95% CI .31-1.05). CONCLUSION: Among those biopsied, pregnant women with mildly abnormal cytology (ASCUS or LSIL), as compared to pregnant women with HSIL, were less likely to have either antepartum or postpartum CIN 2 or worse.

A randomized comparison of propofol and methohexital as general anesthetics for vacuum abortion.

The objective of this study was to determine whether propofol and methohexital differ in their efficacy, acceptability, cost and side effects when used as the single anesthetic agent for inducing general anesthesia in first-trimester vacuum abortion. We randomized 400 unpremedicated American Society of Anesthesiologists grade I-II women to receive 1% propofol or 1% methohexital by intravenous bolus infusion during abortion. No ancillary anesthetic or adjunctive drugs were used. Visual analogue scale scores were used to grade preoperative patient anxiety and the quality of the anesthetic experience. All personnel outside the operating suites, except the data analyst, were blinded. Chi2, median, analysis of variance and Student's t-tests were used, as appropriate. There were no statistically significant differences in age, gravidity, parity, spontaneous and induced abortion, body mass index or gestational age. Mean total operating time and total drug dose were similar. Propofol use resulted in a significant reduction in the incidence of postoperative nausea (11.5% vs. 17.5%) or vomiting (3.5% vs. 7.0%) with a combined p (mean difference) = 0.002 (95% confidence interval of the mean difference 1.8%, 17.2%). Both the nursing and patient appraisals of the quality of the anesthetic experience favored propofol, but only the nursing scores reached statistical significance (p < 0.001). The cost differential was more than twofold greater for propofol patients, 9.51 dollars vs. 4.42 dollars. In our population of midwestern patients in a major urban area, propofol use had modest advantages over methohexital when used as single agents as judged by first recovery charge nurses, but patients found them equally acceptable.

A randomized trial of the sleeved cytobrush and the endocervical curette.

OBJECTIVE: To compare endocervical specimens obtained with the endocervical curette to those obtained with the sleeved cytobrush. METHODS: All nonpregnant women undergoing either cervical conization or hysterectomy were eligible for this randomized, split-sample trial. Both endocervical curette and cytobrush sampling were performed on all 62 participants before surgery, with randomization designating the order of the sampling procedures. A pathologist blinded to sampling order reviewed study specimens. The endocervical canals of the surgical specimens were evaluated against endocervical curette and brush samples. Odds ratios (ORs), relative risks (RRs), and risk differences were used to compare the sensitivity and specificity of each procedure in unmatched and matched analyses. RESULTS: There was a significantly higher rate of inadequate specimens in the endocervical curette group (22% versus 2% in the brush group; 95% confidence interval [CI] for the difference: 9%, 31%). Unmatched analysis showed the two tests to be comparable in terms of sensitivity and specificity. Whereas the specificities of both tests were high (100% for the endocervical curette, 88% for the brush; RR 1.13, 95% CI 1.00, 1.28), the sensitivities were poor (44% for the sleeved brush and 32% for the endocervical curette; RR 1.38, 95% CI 0.65, 2.94). Matched analysis showed the sleeved endocervical brush to be a more sensitive sampling method compared with the curette (OR 2.04, 95% CI 0.98, 4.22). Sparse data prevented a matched analysis on the specificity of the two tests. CONCLUSION: Endocervical sampling with the sleeved cytobrush achieves similar sensitivity and specificity to that of traditional endocervical curettage. Given the much greater rate of inadequate specimens when using the endocervical curette, the sleeved cytobrush is a reasonable alternative to this technique.

Development and preclinical evaluation of a Bacillus Calmette-Guérin-MUC1-based novel breast cancer vaccine.

Due to the high incidence of breast cancer and associated mortality rate,the development of an effective vaccine may be beneficial for the prevention or adjuvant treatment of this malignancy. We have constructed a novel breast cancer vaccine, Bacillus Calmette-Guérin (BCG)-hIL2MUC1, that consists of BCG and expresses a truncated form of MUC1 and human interleukin (IL)-2. In vitro analysis of the BCG-hIL2MUC1 construct confirmed coexpression of MUC1 and human IL-2. The ability of BCG-hIL2MUC1 to inhibit breast cancer growth was evaluated in hu-PBL-SCID mice (severe combined immunodeficient mice reconstituted with 50 x 10(6) human peripheral blood lymphocytes) that received three biweekly injections of BCG-hIL2MUC1 (0.5 colony-forming unit). Control animals received PBS, MUC1 peptide (100 microg), or empty vector BCG-261 (0.5 colony-forming unit) vaccination. After immunization, hu-PBL-SCID mice (n = 8 in each group) were xenografted with 4 x 10(6) ZR75-1 human breast cancer cells. Whereas mice receiving the control vaccines developed a tumor, only 87% of BCG-hIL2MUC1-immunized animals developed a palpable tumor with a slower rate of tumor growth (P < 0.001). Histological analysis of the primary tumors in BCG-hIL2MUC1-immunized animals revealed areas of reduced MUC1 expression. CD8-positive human lymphocytes were detected only in tumors grown in BCG-hIL2MUC1-immunized animals. These results imply a critical role of coexpressed IL-2 and MUC1 in eliciting tumor-specific immune response. To our knowledge, this is the first report of BCG engineered to express a tumor-associated antigen. Our results suggest that BCG-hIL2MUC1 immunization inhibited breast cancer growth in hu-PBL-SCID mice. Therefore, BCG-hIL2MUC1 may be a promising candidate as a breast cancer vaccine.

Preterm premature rupture of membranes: risks of recurrent complications in the next pregnancy among a population-based sample of gravid women.

OBJECTIVE: The purpose of this study was to ascertain the predictive value of antecedent preterm premature rupture of membranes for recurrent preterm premature rupture of membranes and preterm delivery rates in the next pregnancy compared with background rates among a population-based sample of women at a single institution. STUDY DESIGN: Records of patients with index singleton pregnancies that were complicated by preterm premature rupture of membranes whose next delivery resulted in a delivery at >or=20 weeks at the same institution were reviewed for the incidence and gestational age of recurrent preterm premature rupture of membranes and preterm delivery. All subjects were patients of physicians whose obstetric practices were based at a single institution. Background rates of preterm premature rupture of membranes and preterm delivery in this population were generated from a systematically selected comparison group composed of the two deliveries after each of the study group's second delivery. RESULTS: The rates of recurrent preterm premature rupture of membranes (16.7%) and preterm delivery (34.2%) in the 114 study group patients were substantially greater (odds ratio, 20.6; 95% CI, 4.7-90.2; and odds ratio, 3.6; 95% CI, 2.1-6.4) than noted background rates (0.96% and 12.5%) but considerably less than the recurrence rates of either preterm premature rupture of membranes or preterm delivery that were reported by others. The gestational age of preterm premature rupture of membranes in the index pregnancy affected neither the magnitude of risk nor the gestational age of recurrent preterm premature rupture of membranes or preterm delivery in the subsequent pregnancy. Stratification of outcome measures into three subgroups that were based on the gestational age of index preterm premature rupture of membranes demonstrated no significant differences in the incidence of preterm premature rupture of membranes or preterm delivery. CONCLUSION: After a pregnancy that was complicated by preterm premature rupture of membranes, the risk for recurrent preterm premature rupture of membranes is increased by 20-fold and for recurrent preterm delivery by almost 4-fold. Gestational age of antecedent preterm premature rupture of membranes is predictive of neither risk nor timing of recurrent complications. Estimates of recurrence risks appear to be moderated by limiting analysis to a population-based sample of gravid women when compared with previous studies.

Down syndrome and cell-free fetal DNA in archived maternal serum.

OBJECTIVE: Increased levels of cell-free fetal DNA (f-DNA) in the maternal circulation are a potential noninvasive marker for fetal Down syndrome. Our objectives were to (1) determine whether f-DNA could be quantified by using archived serum and amniotic fluid, (2) examine whether serum f-DNA levels are elevated in Down syndrome pregnancies in a case-control series matched for gestational age and duration of sample storage, and (3) determine whether f-DNA levels are elevated in the amniotic fluid of Down syndrome fetuses. STUDY DESIGN: Eleven serum and six amniotic fluid samples previously collected and stored at -20 degrees C from gravid women carrying a 47,XY,+21 fetus were each paired with five matched control samples of identical specimen type from gravid women carrying a presumed euploid male fetus. f-DNA concentration was quantified blindly by real-time polymerase chain reaction amplification for a Y-chromosome sequence. Matched rank-sum analysis and analysis of variance were used for analysis. RESULTS: The mean observed rank of 5.0 in the Down syndrome group was significantly higher than expected (P

Combination of bacterial vaginosis and leukorrhea as a predictor of cervical chlamydial or gonococcal infection.

OBJECTIVE: To evaluate whether the combination of bacterial vaginosis and leukorrhea on microscopic evaluation of a saline wet preparation is associated with cervical infection with Chlamydia trachomatis (C. trachomatis) or Neisseria gonorrhea (N. gonorrhea). METHODS: A cross-sectional study of 598 patients was performed. Nonpregnant patients undergoing a saline wet preparation and microbiologic testing for C. trachomatis and N. gonorrhea were eligible. Providers prospectively collected data from saline microscopic analysis. Bacterial vaginosis was documented based on Amsel's criteria, and ligase chain reaction testing of the endocervix was performed for C. trachomatis and N. gonorrhea. RESULTS: On univariate analysis, young age (less than 25 years), unmarried marital status, black race, and the presence of leukorrhea were all associated with increased rates of testing positive for C. trachomatis and N. gonorrhea (P <.05). We stratified patients into three groups: 1) no evidence of bacterial vaginosis or leukorrhea; 2) evidence of either bacterial vaginosis or leukorrhea, but not both; and 3) evidence of both bacterial vaginosis and leukorrhea. Using logistic regression analysis to control for age, marital status, and race, we found an odds ratio of 3.8 (95% confidence interval 1.3, 11.6) for a positive microbiologic test for either C. trachomatis or N. gonorrhea in women with the combination of bacterial vaginosis and leukorrhea. CONCLUSION: In this group of high-risk women seen in an urgent care facility, the presence of both bacterial vaginosis and leukorrhea was associated with an increased risk of cervical infection. Future prospective studies should evaluate whether empiric treatment of high-risk women with these findings is justified and cost-effective.

Microflora changes with the use of a vaginal microbicide.

BACKGROUND: The rate of HIV transmission is increasing more in women than in any other group. There is an urgent need for the development of microbicides with activity against this virus that women can use during intercourse. These products must be convenient, effective, and safe, and ideally they will cause minimal disruption in the normal vaginal ecosystem. GOAL: The objective of this study was to evaluate changes in vaginal microflora, specifically Lactobacillus species, with the use of BufferGel. STUDY DESIGN: A prospective cohort study was performed to evaluate the change in vaginal flora before and after BufferGel use. BufferGel was applied vaginally once or twice daily for 14 days by low-risk abstinent and monogamous women. RESULTS: There was no change in frequency of Lactobacillus species after BufferGel use. However, there was a decrease in H2O2-producing lactobacilli (from 4.9 x 107 to 1.1 x 107 cfu; P = 0.001). The proportion of facultative gram-negative rods present increased from 27% to 65% after BufferGel use, whereas obligately anaerobic microbes decreased from 62% to 38%. CONCLUSION: Use of BufferGel once or twice daily for 14 days resulted in no clinically significant change in Lactobacillus colonization.