Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years.

BACKGROUND: Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. METHODS: Women aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848. FINDINGS: For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred. INTERPRETATION: Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. FUNDING: GlaxoSmithKline Biologicals (Belgium).

Female genital warts: global trends and treatments.

The increasing incidence of human papillomavirus (HPV) infection and HPV-associated conditions such as genital warts in women is a global concern. Genital warts are a clinical manifestation of HPV types 6 and 11, and are estimated to affect 1% of sexually active adults aged between 15 and 49. HPV infection is also strongly associated with cervical cancer, and is prevalent in as many as 99% of cases. The psychological stress of having genital warts is often greater than the morbidity of the disease, and therefore successful treatment is crucial. Current treatments are patient-applied and provider-administered therapies. Imiquimod 5% cream, a patient-applied therapy, is an efficacious treatment with tolerable side-effects and a low recurrence rate, and has the potential to be an effective strategy for the management of genital warts.

Antibiotic prophylaxis at Cesarean delivery.

OBJECTIVE: Our aim was to compare the efficacy of ampicillin, cefotetan, and ampicillin/sulbactam in the prevention of post-Cesarean endomyometritis. METHODS: Consenting patients undergoing Cesarean delivery at the University of Louisville Hospital were enrolled in a prospective, double-blinded randomization to receive either ampicillin/sulbactam (Group 1), cefotetan (Group 2), or ampicillin (Group 3) single dose antibiotic prophylaxis following umbilical cord clamping. The primary outcome variable was the frequency of endomyometritis in the respective groups. RESULTS: Among 301 randomized patients, outcome data was available for 298 patients. Fourteen patients (4.7%), all of whom underwent non-elective Cesarean delivery, developed endomyometritis. The frequency of endomyometritis was not different among groups: Group 1, 4/101 (4%); Group 2, 4/96 (4.2%); and Group 3, 6/101 (5.9%). Wound infections were infrequently observed 4/298 (1.3%) without significant differences among groups. Stepwise discriminative analysis identified only last cervical dilatation as a significant predictor of endomyometritis (P = 0.006). CONCLUSION: Post-Cesarean endomyometritis occurs infrequently following single dose antibiotic prophylaxis after umbilical cord clamping. An advantage of broader spectrum antibiotics over ampicillin was not demonstrated.

Weekly administration of prostaglandin E2 gel compared with expectant management in women with previous cesareans. Prepidil Gel Study Group.

OBJECTIVE: To compare the clinical effectiveness and safety of outpatient administration of intracervical prostaglandin (PG) E2 gel with expectant treatment for women desiring vaginal births after cesareans. METHODS: This was a randomized, multicenter investigation involving term pregnant women who each had one previous low-transverse cesarean and an unfavorable cervix (Bishop score no more than 6), and who was a candidate for vaginal delivery. They were assigned to receive 0.5 mg of PGE2, (Prepidil; Pharmacia-Upjohn, Kalamazoo, MI) intracervically at 39 weeks' gestation, repeated at weekly office visits for up to three doses, or expectant treatment. The main outcome variable was vaginal birth. RESULTS: Of 294 cases, 143 received gel and 151 were treated expectantly. No differences between groups were found for maternal age, race, or Bishop score. Compared with the expectant treatment group, the PGE2 gel group was not more likely to deliver sooner or vaginally (57% versus 55%, P = .68). The onset of labor, duration of labor among those delivering vaginally, and 1- and 5-minute Apgar scores were not different between groups. No uterine ruptures occurred, and adverse effects were equally likely in both groups. CONCLUSION: Although its safety was confirmed for outpatient use, weekly doses of intracervical PGE2 did not improve the likelihood of vaginal births after cesareans.

Epsilon-aminocaproic acid administration and stroke following coronary artery bypass graft surgery.

BACKGROUND: Epsilon-aminocaproic acid is routinely used to reduce bleeding during cardiac surgery. Anecdotal reports of thrombotic complications have led to speculation regarding this drug's safety. We investigated the association between epsilon-aminocaproic acid administration and postoperative stroke. METHODS: Six thousand two hundred ninety-eight patients undergoing isolated coronary artery bypass graft surgery between 1989 and 1995 were studied. Data was obtained from the Duke Cardiovascular Database as well as from an automated intraoperative anesthesia record keeper. Patients identified as having postoperative stroke were reviewed and confirmed by a board certified neurologist blinded to epsilon-aminocaproic acid administration. RESULTS: Postoperative stroke occurred in 97 patients (1.5%). Three thousand one hundred thirty-five (49.8%) patients received epsilon-aminocaproic acid. Increased age was associated with a higher incidence of postoperative stroke (p = 0.0001). In contrast, there was no significant difference (p = 0.7370) in the incidence of stroke between use of epsilon-aminocaproic acid (1.3%) and nonuse (1.7%). Multivariable logistic regression found no significant effect of epsilon-aminocaproic acid use on stroke after accounting for age, date of surgery, and history of diabetes. CONCLUSIONS: This series suggests that epsilon-aminocaproic acid administration does not increase the risk of postoperative stroke.

Transvaginal versus transperineal ultrasonography: a blinded comparison in the assessment of cervical length at midgestation.

OBJECTIVE: The study's objective was to determine the correlation and agreement between transperineal ultrasonography and transvaginal ultrasonography in the assessment of cervical length in gravid patients. STUDY DESIGN: After a pilot, unblinded series of transperineal and transvaginal cervical length measurements in 200 gravid patients, 206 study patients between 14 and 34 weeks' gestation with intact membranes and cervical dilatation of < or = 2 cm underwent transperineal and transvaginal cervical length assessment under a blinded, 2-sonographer protocol. The Pearson correlation coefficient, Lin concordance coefficient, and Bland-Altman plot were used. Acceptable concordance was defined as > 0.82, with an acceptable correlation of > 0.9 and an acceptable difference between the means of < 3 mm. The power of the study to detect this degree of concordance was estimated to be 95% at this sample size. RESULTS: Paired ultrasonographic measurements were obtained for all 206 study patients. Transperineal mean cervical length was 35 +/- 8.6 mm. Transvaginal mean cervical length was 35.9 +/- 8.8 mm. The Pearson correlation coefficient was 0.959, and the Lin concordance coefficient was 0.955, with a 95% confidence lower bound of 0.949. Close agreement between transperineal and transvaginal measurements was observed across the full range of cervical lengths (1-5 cm). The estimated difference between the paired means was 1 mm. The 95% tolerance interval for any given paired observation (Transperineal length - Transvaginal length) was -5.7 to +4 mm. CONCLUSIONS: Cervical length measured by transperineal ultrasonography demonstrates close correlation and agreement with transvaginal measurements. With sonographer experience and optimal technique, approximately 95% of transperineal cervical length observations can be expected to be within 5 mm of a given paired transvaginal measurement. Transperineal ultrasonography may be a preferred method of cervical length assessment for situations in which vaginal placement of instruments should be minimized.

Ambulatory management of multiple gestation.

Ambulatory management of multiple gestation requires careful and continuing care by the obstetrician. The initial evaluation should include a comprehensive history, including use of fertility enhancing drugs and ART, family history, social history; a general physical examination, including a pelvic examination; laboratory evaluation, including complete blood cell count, dipstick urinalysis for protein and glucose, urine culture, blood type, Rh factor and irregular blood antibody determination, serology for rubella, syphilis, hepatitis B surface antigen and varicella (if there is no history). A Papanicolaou smear should be done at the time of the pelvic examination, as should evaluation for bacterial vaginosis. Ultrasound assessment of placentation should be done at 14 weeks' gestation, but vaginal or perineal ultrasound of cervical length should be done at the initial visit. Other testing procedures should include repeat ultrasound evaluation for fetal growth every 4 weeks in a dichorionic placentation and every 3 weeks if monochorionic placentation is present. Triple screen MSAFP at 16-18 weeks' gestation and blood sugar screening at 22-26 weeks should be performed. After the first trimester, the patient should schedule physician visits every 2 weeks or less. Routine medications should include one prenatal vitamin per day, additional folic acid supplementation of 1.0 mg per fetus, supplemental iron preparation, and additional calcium to equal 1500 mg/day. The use of low-dose aspirin to prevent preeclampsia in twin gestations has not been adequately studied. Continuing vigilance by the knowledgeable obstetrician should occur. Multiple gestations should not be cared for by non-physician providers or by family physicians. Referral to a maternal-fetal medicine unit is recommended.

Umbilical cord blood interleukin-6 levels and neonatal morbidity.

OBJECTIVE: To study umbilical cord interleukin-6 levels and the occurrence of neonatal sepsis, congenital pneumonia, necrotizing enterocolitis, and grade II-IV intraventricular hemorrhage. METHODS: Umbilical cord blood was collected from 133 preterm newborns. The study population was divided according to the presence or absence of neonatal complications. Interleukin-6 levels and clinical characteristics were compared by univariate and multivariate analyses. RESULTS: Sixteen neonates had adverse outcomes, and 117 were unaffected. The median interleukin-6 level was significantly higher in affected than in unaffected infants (145 pg/mL versus 0 pg/mL, P = .002). Elevated interleukin-6 levels were associated independently with neonatal morbidity in multiple logistic regression modeling that included gestational age, birth weight, and antenatal steroid exposure. CONCLUSION: Umbilical cord blood interleukin-6 levels are elevated in neonates who subsequently develop sepsis, congenital pneumonia, necrotizing enterocolitis, or grade II-IV intraventricular hemorrhage.

Persistence of penicillin G benzathine in pregnant group B streptococcus carriers.

OBJECTIVE: To determine if streptococcicidal levels of penicillin G benzathine can be detected in maternal serum 4 weeks after treatment with 4.8 million units. METHODS: Thirty-seven pregnant women with positive group B streptococcus vaginal or urine cultures were each given 4.8 million units of penicillin G benzathine. Maternal blood samples were collected after injection and at delivery. Serum penicillin levels were measured by high-pressure liquid chromatography. Follow-up cultures were done when possible. RESULTS: None of the patients had serum penicillin levels below 0.20 microgram/mL 30 days after treatment. Cord blood levels were approximately 50% lower than maternal levels. In all but three subjects, cord blood levels exceeded 0.06 microgram/mL, the minimal inhibitory concentration for group B streptococcus. The three exceptions were patients who delivered more than 100 days after treatment. Group B streptococcus cultures were negative at the time of delivery in 72% of cases. None of the patients with positive cultures were moderately or heavily colonized. CONCLUSION: In pregnant women, penicillin G benzathine levels are high enough to inhibit the growth of group B streptococcus for more than 4 weeks after injection with 4.8 million units. Further studies are needed to evaluate whether this regimen can prevent neonatal colonization and invasive group B streptococcus disease.

Clinical uses of intravenous immunoglobulin in pregnancy.

Intravenous immunoglobulin was licensed for use in the United States in 1981. Currently, there are only a few Food and Drug Administration-labeled indications for intravenous immunoglobulin, but up to 50 "off-label" uses are reported in the literature. The obstetric literature contains numerous reports on intravenous immunoglobulin therapy during pregnancy. This article reviews the properties, pharmacokinetics, mechanisms of action, and side effects of intravenous immunoglobulin, as well as the reported uses of intravenous immunoglobulin during pregnancy.

Left ventricular adaptation to aortic regurgitation in conscious dogs.

OBJECTIVE: Cardiac failure as a result of valvular heart disease remains a major clinical problem that frequently leads to ventricular dysfunction, myocardial failure, and even death. The development of irreversible myocardial damage may be especially insidious in volume overload as a result of aortic or mitral regurgitation. METHODS AND RESULTS: Left ventricular wall volume, ventricular function, and myocardial performance were assessed in 10 chronically instrumented conscious dogs before and after creation of aortic regurgitation. Left ventricular wall volume was measured by serial echocardiography. Left ventricular function was assessed by total cardiac output, stroke work, the slope of the Frank-Starling relationship, and the slope of the end-systolic pressure-volume relationship. Myocardial performance was assessed by the slope of the myocardial power output versus end-diastolic strain relationship. End-diastolic wall stress and volume both increased acutely and remained elevated after creation of aortic regurgitation. Peak systolic wall stress increased initially (1 to 3 weeks) from 336 +/- 30 to 369 +/- 55 mm Hg but returned to control values as left ventricular wall volume increased from 78 +/- 13 to 88 +/- 16 ml after development of compensatory hypertrophy. Left ventricular systolic function remained constant or increased and was maintained initially by increased myocardial performance, which returned to baseline levels after the development of compensatory hypertrophy. CONCLUSIONS: Myocardial performance and ventricular function vary independently in aortic regurgitation. Measures of myocardial performance such as the myocardial power output versus end-diastolic strain relationship may be useful in clinical assessment of aortic regurgitation.

Effects of valve replacement on ventricular mechanics in mitral regurgitation and aortic stenosis.

BACKGROUND: This study in humans assessed changes in left ventricular function early and late after correction of mitral regurgitation (MR) (n = 9) or aortic stenosis (AS) (n = 10). METHODS: Ventricular function was measured with radionuclide and micromanometer-derived pressure-volume loops during preload manipulation, thermodilution cardiac outputs, and echocardiograms. Late radionuclide and echocardiographic data were acquired at 24 hours and 20 months. RESULTS: Perioperative left ventricular performance (stroke work-end-diastolic volume relationship) did not change for patients with MR or AS. Significant changes in afterload occurred: ejection fraction (MR, 0.49 to 0.37; AS, 0.54 to 0.60; both, p = 0.013), mean left ventricular ejection pressure (MR, 73 to 91 mm Hg; AS, 138 to 93 mm Hg; both, p < 0.01), and end-systolic wall stress (MR, 26 to 42 x 10(3) dynes/cm2; AS, 37 to 22 x 10(3) dynes/cm2; both, p < 0.01). Ejection efficiency improved for MR patients (0.69 +/- 0.26 to 1.0 +/- 0.15; p < 0.05). The 20-month data showed improved New York Heart Association functional class, normal resting ejection fraction, and normal exercise response for both groups. CONCLUSIONS: Early after operation, a significant change in left ventricular load was seen with correction of MR and AS. Data obtained late after operation showed improvement consistent with ventricular remodeling.

Expression and shedding of CD44 variant isoforms in patients with gynecologic malignancies.

OBJECTIVES: The presence of CD44 isoforms was evaluated in ascitic fluid and serum samples of patients with gynecologic malignancies. Previously, the shedding of tumor-associated cell surface antigens has been demonstrated in the blood and malignant effusions of gynecologic cancer patients. Thus, the shedding of CD44 was also studied in ascitic fluids and sera of these patients, to address variant isoform expression as a biomarker of gynecologic cancer. METHODS: The expression of CD44 isoforms by ovarian tumor cells was examined by flow cytometry using variant-specific monoclonal antibodies. The release of these isoforms into the peripheral circulation and ascites was assayed by Western immunoblot analysis. RESULTS: Flow cytometric analysis of ovarian tumor cell lines revealed a strong expression of CD44 with significant levels of v4/5 and v6 isoforms. The presence of circulating CD44 isoforms was detectable in the sera of six of eight cancer patients, as well as in 12 of 16 ascitic fluids. Of the CD44-positive specimens, all six positive sera expressed detectable levels of variant CD44. The CD44v6 was present in all of the positive sera samples tested. In the ascites, the "shed" CD44 appeared to be associated predominantly with shed particles (vesicles) of plasma membranes (membrane fragments). Of ten CD44-positive ascites samples, all expressed significant levels of variant CD44. CONCLUSIONS: In addition to mediating metastasis, the differential expression and shedding of CD44 isoforms into the circulation may represent important determinants in the escape of tumors from immune surveillance, and their detection may be a diagnostic or prognostic marker.

Management of microfistula following pulmonary resection.

The symptoms and signs of cough and changes in the air-fluid pattern on chest radiograph are critical as warning signs of bronchopleural fistula. Drainage of the pleural space is a critical first step for all patients to limit endobronchial contamination and prevent drowing. Once nutritional status is optimized and treatment for infection is established, suture reclosure of the bronchial stump with vascularized flap coverage is curative for the acutely presenting fistula, usually fewer than 2 weeks after surgery. Patients who present with bronchopleural fistula at times more remote from resection are unlikely to have direct reclosure of their fistula. These patients may have closure of their fistula by either an anterior, transpericardial approach, thoracotomy with muscle flap to fill the pleural space, or muscle flap coverage of the fistula with a limited thoracoplasty to obliterate the pleural space. Patients who cannot undergo operations of this magnitude may be treated with endoscopically placed tissue adhesives to seal the fistula. These various treatment options are successful in 75% to 100% of cases, and have been responsible for significantly reducing the morbidity and mortality from bronchopleural fistula.

Effect of three concentrations of intracervical prostaglandin E2 gel for cervical ripening.

To evaluate the efficacy and safety of three concentrations of prostaglandin E2 (PGE2) gel for preinduction cervical ripening. Two hundred ninety-one patients with an unfavorable cervix scheduled for induction of labor were eligible to participate in a prospective, randomized, double-blind study of one or two doses of intracervical PGE2 gel. Group 1 received a dose of 0.125 mg/2 ml; group 2 received 0.25 mg/2 ml; and group 3 received 0.5 mg/2 ml. Outcome variables included change in Bishop score, uterine tachysystole, oxytocin use, route of delivery, and maternal and neonatal complications. Two hundred twenty-nine patients were included in the study, 79 in group 1, 70 in group 2, and 80 in group 3. Among the three groups, no statistically significant differences were noted for change in Bishop score, uterine tachysystole, oxytocin use, route of delivery, or incidence of maternal or neonatal complications, Subsequent labors were frequently complicated by fetal heart rate abnormalities (24.3%) and uterine tachysystole (9.6%); 84 (38.9%) patients were delivered by cesarean section. A dose-dependent influence on outcome variables was not identified. Complications from PGE2-ripening within 4 hours of gel application were not dose dependent and occurred infrequently. This study demonstrates that there is no dose in the range tested that assures an absences of tachysystole, limiting the role of outpatient cervical ripening without some period of observation.

Assessment of the Frank-Starling relationship by two-dimensional echocardiography.

The Frank-Starling relationship between left ventricular stroke work and end-diastolic minor-axis cross-sectional area was evaluated as a load-insensitive measure of inotropic state by two-dimensional echocardiography in 10 conscious dogs. Stroke work was calculated as the product of systolic change in cross-sectional area and either (1) beat-to-beat mean arterial pressure or (2) initial systolic blood pressure. Both Frank-Starling relationships were highly linear during preload variation (mean r = 0.96), sensitive to the inotropic state (slope increase with calcium 51% +/- 43% and 62% +/- 53%, respectively), and insensitive to afterload (r < 0.4, slope or x intercept versus afterload). Thus the Frank-Starling relationships derived from two-dimensional echocardiographic images and peripheral arterial pressure may be a useful and practical means of assessing inotropic state with minimally invasive measurements.