Summary Background After the introduction of a quadrivalent human papillomavirus (HPV) vaccination programme in Australia in April, 2007, we measured the prevalence of vaccine-targeted and closely ...related HPV types with the aim of assessing direct protection, cross-protection, and herd immunity. Methods In this repeat cross-sectional study, we recruited women aged 18–24 years who attended Pap screening between October, 2005, and July, 2007, in three major metropolitan areas of Australia to form our prevaccine-implementation sample. For our postvaccine-implementation sample, we recruited women aged 18–24 years who attended Pap screening in the same three metropolitan areas from August, 2010, to November, 2012. We compared the crude prevalence of HPV genotypes in cervical specimens between the prevaccine and the postvaccine implementation groups, with vaccination status validated against the National HPV Vaccination Program Register. We estimated adjusted prevalence ratios using log linear regression. We estimated vaccine effectiveness both for vaccine-targeted HPV types (16, 18, 6, and 11) and non-vaccine but related HPV types (31, 33, and 45). Findings 202 women were recruited into the prevaccine-implementation group, and 1058 were recruited into the postvaccine-implementation group. Crude prevalence of vaccine-targeted HPV genotypes was significantly lower in the postvaccine-implementation sample than in the prevaccine-implementation sample (58 29% of 202 vs 69 7% of 1058; p<0·0001). Compared with the prevaccine-implementation sample, adjusted prevalence ratios for vaccine-targeted HPV genotypes were 0·07 (95% CI 0·04–0·14; p<0·0001) in fully vaccinated women and 0·65 (0·43–0·96; p=0·03) in unvaccinated women, which suggests herd immunity. No significant declines were noted for non-vaccine-targeted HPV genotypes. However, within the postvaccine-implementation sample, adjusted vaccine effectiveness against vaccine-targeted HPV types for fully vaccinated women compared with unvaccinated women was 86% (95% CI 71–93), and was 58% (26–76) against non-vaccine-targeted but related genotypes (HPV 31, 33, and 45). Interpretation 6 years after the initiation of the Australian HPV vaccination programme, we have detected a substantial fall in vaccine-targeted HPV genotypes in vaccinated women; a lower prevalence of vaccine-targeted types in unvaccinated women, suggesting herd immunity; and a possible indication of cross-protection against HPV types related to the vaccine-targeted types in vaccinated women. Funding Australian National Health and Medical Research Council and Cancer Council Victoria.
Abstract Objective: This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single doses of exenatide in adolescent patients with type 2 diabetes mellitus (T2DM). Methods: ...This was a randomized, single-blind, dose-escalation, crossover study in adolescent (age 10–16 years) patients with T2DM who were being treated with diet and exercise or a stable dose of metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea for at least 3 months before screening. Eligible patients were allocated to receive single subcutaneous doses of exenatide 2.5 μg, exenatide 5 μg, and placebo, each followed by a standardized meal, on 3 separate days (maximum interval between first and third doses, 5 weeks). Exenatide 2.5 μg always preceded exenatide 5 μg in each treatment sequence. The primary end points were the pharmacokinetics and safety profile of exenatide; secondary end points included postprandial plasma glucose, serum insulin, and plasma glucagon concentrations. Results: The study enrolled 13 adolescent patients with T2DM (7 females, 6 males; mean SD age, 15 1 years; body mass index, 32.5 5.0 kg/m2 ; glycosylated hemoglobin, 8.2% 1.5%). After administration of exenatide 5 μg, the geometric mean (SE) exenatide AUC0−∞ and Cmax were 339.5 (39.6) pg · h/mL and 85.1 (11.5) pg/mL, respectively (n = 12). The exenatide AUC appeared to be dose dependent, although exenatide was not quantifiable in all patients at the 2.5-μg dose; after administration of exenatide 2.5-μg, the geometric mean AUC0−∞ ) was 159.2 (23.1) pg · h/mL (n = 6) and the geometric mean Cmax was 56.3 (10.1) pg/mL (n = 9). Both exenatide doses were associated with significant reductions in postprandial plasma glucose excursions compared with placebo ( P < 0.01); the incremental mean (SE) AUC15–360min was −3465.6 (1587.3) mg · min/dL for exenatide 2.5 pg, −4422.2 (2434.4) mg · min/dL for exenatide 5 μg, and 3457.4 (1615.5) mg · min/dL for placebo. The 2 exenatide doses were also associated with significant reductions in postprandial plasma glucagon concentrations compared with placebo ( P < 0.01); the respective incremental mean values for AUC15–180min were 125.5 (658.4), −1403.8 (632.1), and 1843.1 (540.6) pg · min/mL. There were no significant differences in serum insulin concentrations between exenatide and placebo. Exenatide was generally well tolerated, with no hypoglycemic events recorded during the study. Conclusions: In these adolescent patients with T2DM, administration of single 2.5- and 5-μg doses of exenatide were associated with dose-dependent increases in plasma exenatide concentrations and improved postprandial glucose concentrations compared with placebo. Both doses appeared to be well tolerated. ClinicalTrials.gov Identifier: NCT00254254.
When patients with type 2 diabetes start their first injectable therapy, clinicians can choose between glucagon-like peptide-1 (GLP-1) receptor agonists and basal insulins. In DURATION-3, exenatide ...once weekly was compared with insulin glargine (henceforth, glargine) as first injectable therapy. Here, we report the results of the final 3-year follow-up.
DURATION-3 was an open-label randomised trial done between May 13, 2008, and Jan 30, 2012. Patients with type 2 diabetes aged 18 years or older were enrolled at 72 sites worldwide. They were eligible when they had suboptimum glycaemic control (HbA1c 7.1-11.0% 54-97 mmol/mol) despite maximum tolerated doses of metformin alone or with a sulfonylurea for at least 3 months, a stable bodyweight for at least 3 months, and a BMI of 25-45 kg/m(2) (23-45 kg/m(2) in South Korea and Taiwan). Patients were randomly assigned (1:1) by computer-generated random sequence with an interactive voice-response system (block size four, stratified by country and concomitant therapy) to once-weekly exenatide (2 mg subcutaneous injection) or once-daily glargine (titrated to target) to be given in addition to their existing oral glucose-lowering regimens. The primary efficacy measure at 3 years was change in HbA1c from baseline in patients given at least one dose of the assigned drug (ie, analyses by modified intention to treat). Patients, investigators, and data analysts were not masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT00641056.
456 patients underwent randomisation and received at least one dose of the assigned drug (233 given exenatide, 223 glargine). At 3 years, least-squares mean HbA1c change was -1.01% (SE 0.07) in the exenatide group versus -0.81% (0.07) in the glargine group (least-squares mean difference -0.20%, SE 0.10, 95% CI -0.39 to -0.02; p=0.03). Transient gastrointestinal adverse events characteristic of GLP-1 receptor agonists were more frequent with exenatide than glargine (nausea: 36 15% of 233 patients vs five 2% of 223; vomiting: 15 6% vs six 3%; diarrhoea: 32 14% vs 15 7%), although frequency of these events did decrease after week 26 in the exenatide group. The proportion of patients who reported serious adverse events in the exenatide group (36 patients 15%) was the same as that in the glargine group (33 15%). The exposure-adjusted rate of overall hypoglycaemia was three times higher in patients given glargine (0.9 events per patient per year) than in those given exenatide (0.3 events per patient per year).
Efficacy of once-weekly exenatide is sustained for 3 years. GLP-1 receptor agonists could be a viable long-term injectable treatment option in patients with type 2 diabetes who have not yet started taking insulin.
Amylin Pharmaceuticals and Eli Lilly.
Purpose The hypothesis for this prospective evaluation is that resorbable plates are equal to the performance of titanium 2-mm plates, regarding healing of the fracture with bone union and ...restoration of function. To prove this hypothesis, specific end points will be compared with literature norms for titanium 2-mm miniplate rigid fixation. The primary end point variable for this analysis is the union of the fracture and return to normal function. Secondary end point variables included the incidence of complications such as infection, malunion with malocclusion, soft tissue dehiscence, the need for revision surgery, specific technical challenges, operative time, and the learning curve for the surgeon. Patients and Methods This prospective study consisted of a sequential enrollment of 50 fractures that met the inclusion criteria of having a fracture of the mandibular body, symphysis, angle, or ramus, and required an open reduction and internal fixation for stabilization and repair. The resorbable plates and screws used consisted of an amorphous injection molded copolymer of L-lactide/D-lactide/trimethylene carbonate (Inion CPS system, Tampere, Finland). Data were collated and compared with literature norms for titanium plates and also compared with nonrigid fixation data from a prospective study performed on a similar population in the same institution. Results Clinical and radiographic evaluation indicated union of all fractures at the eighth follow-up visit. Three sites (6%) noted to have clinical signs of infection were treated immediately upon presentation, with fracture union by 8 weeks. There was no need for revision surgery in this series of patients; 12 screw heads fractured during screw placement and were immediately replaced without significant fracture sequelae. Conclusion Based on this limited series of patients, the hypothesis formulated for this study was validated.
To estimate the changes in birth weight- and gestational age-specific sudden infant death syndrome (SIDS) mortality rates since the publication of the sleep-positioning recommendations by the ...American Academy of Pediatrics Task Force on Infant Positioning and SIDS.
This is a historical cohort study using US vital statistic linked birth and infant death certificate files for the years 1991 and 1995. SIDS deaths were identified as any death attributed to International Classification of Diseases, Ninth Revision code 7980, occurring between the 28th and 365th days of life.
There were 4871 deaths attributed to SIDS in 1991 for a postneonatal mortality rate of 1.2/1000 postneonatal survivors compared with 3114 deaths in 1995 for a rate of.8/1000. This represents a 33% drop in the postneonatal SIDS mortality from 1991 to 1995. Between 1991 and 1995, SIDS rates declined 38%, 38%, 35%, and 32% for birth weight groupings of 500 to 999 g, 1000 to 1499 g, 1500 to 2499 g, and >/=2500 g, respectively. There were no SIDS deaths attributed to infants weighing <500 g. The SIDS rates declined 27%, 21%, 40%, and 23% for gestational age groups of <29 weeks, 29 to 32 weeks, 33 to 36 weeks, and >/=37 weeks. The rate of decline did not differ significantly across birth weight- or gestational age-specific categories. There was a significant increase in the black:non-black postneonatal SIDS mortality ratio from 2.00 to 2.28, reflecting a smaller decline in birth weight- and gestational age-specific mortality for blacks than observed for the non-black population.
Postneonatal SIDS mortality decreased significantly across all broad birth weight and gestational age categories. If the decline in the prevalence of prone positioning that has been reported since 1992 has occurred across all birth weight and gestational age, these data support the hypothesis that supine or side sleep positioning is effective in preterm/low birth weight infants as well as term infants.
