Prediction of successful labor induction in persons with a low Bishop score using machine learning: Secondary analysis of two randomized controlled trials.

BACKGROUND: The objective of this paper was to identify predictors of a vaginal birth in individuals with singleton pregnancies and a Bishop Score <4, following Induction of Labor (IoL) using dinoprostone vaginal insert (DVI). Secondarily, we sought to understand the association between oxytocin use for labor augmentation and IoL outcomes. METHODS: We developed and internally validated a multivariate prediction model using machine learning (ML) applied to data from two Phase-III randomized controlled double-blind trials (NCT01127581, NCT00308711). The model was internally validated using 10-fold cross-validation. RESULTS: This study included 1107 participants. Despite unfavorable cervical status and inclusion of high-risk pregnancies, 72% of participants had vaginal births. The model's area under receiver operating characteristic curve was 0.73. The following factors increased the chance of vaginal birth: being parous; being between 37 and 41 weeks of gestation; having a lower Body Mass Index; having a lower maternal age; having fewer maternal comorbidities; and having a higher Bishop score. Parity alone correctly predicted the outcome in ~50% of cases, at a ~10% false-negative rate. Participants whose labors progressed without requiring oxytocin had a higher probability of vaginal birth than those requiring oxytocin for either induction or augmentation (81% vs 70% vs 77%, respectively). DISCUSSION: Even in high-risk pregnancies and with low Bishop scores, the use of DVI results in a high chance of vaginal birth. Parity is a critical predictor of success. The judicious use of oxytocin for labor induction or augmentation can increase the chance of vaginal birth. Our study validates the use of ML and predictive modeling for treatment response prediction when considering IoL.

17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial.

BACKGROUND: Women with a history of spontaneous preterm birth (SPTB) are at a significantly increased risk for recurrent preterm birth (PTB). To date, only one large U.S. clinical trial comparing 17-OHPC (17-α-hydroxyprogesterone caproate or "17P") to placebo has been published, and this trial was stopped early due to a large treatment benefit. OBJECTIVE: This study aimed to assess whether 17-OHPC decreases recurrent PTB and neonatal morbidity in women with a prior SPTB in a singleton gestation. STUDY DESIGN: This was a double-blind, placebo-controlled international trial involving women with a previous singleton SPTB (clinicaltrials.gov: NCT01004029). Women were enrolled at 93 clinical centers (41 in the United States and 52 outside the United States) between 160/7 to 206/7 weeks in a 2:1 ratio, to receive either weekly intramuscular (IM) injections of 250 mg of 17-OHPC or an inert oil placebo; treatment was continued until delivery or 36 weeks. Co-primary outcomes were PTB < 35 weeks and a neonatal morbidity composite index. The composite included any of the following: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, or proven sepsis. A planned sample size of 1,707 patients was estimated to provide 98% power to detect a 30% reduction in PTB < 35 weeks (30% to 21%) and 90% power to detect a 35% reduction in neonatal composite index (17%-11%) using a two-sided type-I error of 5%. Finally, this sample size would also provide 82.8% power to rule out a doubling in the risk of fetal/early infant death assuming a 4% fetal/early infant death rate. Analysis was performed according to the intention-to-treat principle. RESULTS: Baseline characteristics between the 1,130 women who received 17-OHPC and 578 women who received placebo were similar. Overall, 87% of enrolled women were Caucasian, 12% had >1 prior SPTB, 7% smoked cigarettes, and 89% were married/lived with partner. Prior to receiving study drug, 73% women had a transvaginal cervical length measurement performed and <2% had cervical shortening <25 mm. There were no significant differences in the frequency of PTB < 35 weeks (17-OHPC 11.0% vs. placebo 11.5%; relative risk = 0.95 [95% confidence interval (CI): 0.71-1.26]) or neonatal morbidity index (17-OHPC 5.6% vs. placebo 5.0%; relative risk = 1.12 [95% CI: 0.68-1.61]). There were also no differences in frequency of fetal/early infant death (17-OHPC 1.7% vs. placebo 1.9%; relative risk = 0.87 [95% CI: 0.4-1.81]. Maternal outcomes were also similar. In the subgroup of women enrolled in the United States (n = 391; 23% of all patients), although the rate of PTB < 35 weeks was higher than the overall study population, there were no statistically significant differences between groups (15.6% vs. 17.6%; relative risk = 0.88 [95% CI: 0.55, 1.40]. CONCLUSION: In this study population, 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death.

PROLONG Clinical Study Protocol: Hydroxyprogesterone Caproate to Reduce Recurrent Preterm Birth.

The objective of this commentary is to describe the background, rationale, and methods of the PROLONG (Progestin's Role in Optimizing Neonatal Gestation) trial, which is a multicenter, multinational, placebo-controlled, randomized clinical trial (RCT) designed to assess the safety and efficacy of Makena (hydroxyprogesterone caproate injection, 250 mg/mL) in reducing the risk of preterm birth (PTB) and neonatal morbidity/mortality in women pregnant with a singleton gestation who had a previous singleton spontaneous PTB. The total sample size of the RCT will include 1,707 women. The trial has two coprimary outcomes: PTB less than 35 weeks and a composite neonatal morbidity and mortality index. This study sample size will provide 90% power to assess for a 35% reduction in neonatal morbidity and mortality. Secondary outcomes will include 2-year follow-up of infants. The trial is ongoing and targeted to complete recruitment in 2018.

Optimising daytime deliveries when inducing labour using prostaglandin vaginal inserts.

OBJECTIVE: To determine induction start time(s) that would maximise daytime deliveries when using prostaglandin vaginal inserts. METHODS: Women enrolled into the Phase III trial, EXPEDITE (clinical trial registration: NCT01127581), had labour induced with either a misoprostol or dinoprostone vaginal insert (MVI or DVI). A secondary analysis was conducted to determine the optimal start times for induction by identifying the 12-h period with the highest proportion of deliveries by parity and treatment. RESULTS: Optimal start times for achieving daytime deliveries when using MVI appear to be 19:00 in nulliparae and 23:00 in multiparae. Applying these start times, the median time of onset of active labour would be approximately 08:30 for both parities and the median time of delivery would be the following day at approximately 16:30 for nulliparae and 12:00 (midday) for multiparae. Optimal start times when using DVI appear to be 07:00 for nulliparae and 23:00 for multiparae. Using these start times, the median time of onset of active labour would be the following day at approximately 04:00 and 11:50, and the median time of delivery would be approximately 13:40 and 16:10, respectively. CONCLUSIONS: When optimising daytime deliveries, different times to initiate induction of labour may be appropriate depending on parity and the type of retrievable prostaglandin vaginal insert used.

17-hydroxyprogesterone caproate for preterm rupture of the membranes: a multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Preterm rupture of membranes (PROM) is associated with an increased risk of preterm birth and neonatal morbidity. Prophylactic 17-hydroxyprogesterone caproate (17OHP-C) reduces the risk of preterm birth in some women who are at risk for preterm birth. We sought to test whether 17OHP-C would prolong pregnancy or improve perinatal outcome when given to mothers with preterm rupture of the membranes. STUDY DESIGN: This is a multicenter, double-blind, placebo-controlled, randomized clinical trial. The study included singleton pregnancies with gestational ages from 23(0/7) to 30(6/7) weeks at enrollment, documented PROM, and no contraindication to expectant management. Consenting women were assigned randomly to receive weekly intramuscular injections of 17OHP-C (250 mg) or placebo. The primary outcome was continuation of pregnancy until a favorable gestational age, which was defined as either 34(0/7) weeks of gestation or documentation of fetal lung maturity at 32(0/7) to 33(6/7) weeks of gestation. The 2 prespecified secondary outcomes were interval from randomization to delivery and composite adverse perinatal outcome. The planned sample size was 222 total women. RESULTS: From October 2011 to April 2014, 152 women were enrolled; 74 women were allocated randomly to 17OHP-C, and 78 were allocated randomly to placebo. The trial was stopped when results of a planned interim analysis suggested that continuation was futile. The primary outcome was achieved in 3% of the 17OHP-C group and 8% of the placebo group (P = .18). There was no significant between-group difference in the prespecified secondary outcomes, randomization-to-delivery interval (17.1 ± 16.1 vs 17.0 ± 15.8 days, respectively; P = .76) or composite adverse perinatal outcome (63% vs 61%, respectively; P = .93). No significant differences were found in other outcomes, which included rates of chorioamnionitis, postpartum endometritis, cesarean delivery, individual components of the composite outcome, or prolonged neonatal length of stay. CONCLUSION: Compared with placebo, weekly 17OHP-C injections did not prolong pregnancy or reduce perinatal morbidity in patients with PROM in this trial.

Treatment of spontaneous preterm labour with retosiban: a phase 2 proof-of-concept study.

AIM: The aim was to investigate the efficacy and safety of intravenous retosiban in women with spontaneous preterm labour. METHODS: This was a randomized, double-blind, placebo-controlled, phase 2 trial. Retosiban was administered intravenously for 48 h to women in spontaneous preterm labour between 30(0/7) and 35(6/7) weeks' gestation with an uncomplicated singleton pregnancy in an in-patient obstetric unit. Outcome measures were uterine quiescence (primary endpoint), days to delivery, preterm delivery and safety. RESULTS: Uterine quiescence was achieved in 62% of women who received retosiban (n = 30) compared with 41% who received placebo (n = 34). The relative risk (RR) was 1.53 (95% credible interval [CrI] 0.98, 2.48; NS). Retosiban resulted in a significant increase in time to delivery compared with placebo (mean difference 8.2 days, 95% CrI 2.7, 13.74). This difference was consistent across all gestational ages. The proportion of preterm births in the retosiban and placebo groups was 18.7% (95% CrI 7.4%, 33.7%) and 47.2% (95% CrI 31.4%, 63.4%), respectively. The RR of preterm birth in women treated with retosiban was 0.38 (95% CrI 0.15, 0.81). There were no deliveries within 7 days in the retosiban group, but there were six (17.6%) births in the placebo group. The maternal, fetal and neonatal adverse events were comparable in the retosiban and placebo groups. CONCLUSIONS: Intravenous administration of retosiban in women with spontaneous preterm labour was associated with a greater than 1 week increase in time to delivery compared with placebo, a significant reduction in preterm deliveries, a non-significant increase in uterine quiescence and a favourable safety profile.

Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes.

OBJECTIVE: Microbial invasion of the amniotic cavity (MIAC) is common in early preterm labor and is associated with maternal and neonatal infectious morbidity. MIAC is usually occult and is reliably detected only with amniocentesis. We sought to develop a noninvasive test to predict MIAC based on protein biomarkers in cervicovaginal fluid (CVF) in a cohort of women with preterm labor (phase 1) and to validate the test in an independent cohort (phase 2). STUDY DESIGN: This was a prospective study of women with preterm labor who had amniocentesis to screen for MIAC. MIAC was defined by positive culture and/or 16S ribosomal DNA results. Nine candidate CVF proteins were analyzed by enzyme-linked immunosorbent assay. Logistic regression was used to identify combinations of up to 3 proteins that could accurately classify the phase 1 cohort (N = 108) into those with or without MIAC. The best models, selected by area under the curve (AUC) of the receiver operating characteristic curve in phase 1, included various combinations of interleukin (IL)-6, chemokine (C-X-C motif) ligand 1 (CXCL1), alpha fetoprotein, and insulin-like growth factor binding protein-1. Model performance was then tested in the phase 2 cohort (N = 306). RESULTS: MIAC was present in 15% of cases in phase 1 and 9% in phase 2. A 3-marker CVF model using IL-6 plus CXCL1 plus insulin-like growth factor binding protein-1 had AUC 0.87 in phase 1 and 0.78 in phase 2. Two-marker models using IL-6 plus CXCL1 or alpha fetoprotein plus CXCL1 performed similarly in phase 2 (AUC 0.78 and 0.75, respectively), but were not superior to CVF IL-6 alone (AUC 0.80). A cutoff value of CVF IL-6 ≥463 pg/mL (which had 81% sensitivity in phase 1) predicted MIAC in phase 2 with sensitivity 79%, specificity 78%, positive predictive value 38%, and negative predictive value 97%. CONCLUSION: High levels of IL-6 in CVF are strongly associated with MIAC. If developed into a bedside test or rapid laboratory assay, cervicovaginal IL-6 might be useful in selecting patients in whom the probability of MIAC is high enough to warrant amniocentesis or transfer to a higher level of care. Such a test might also guide selection of potential subjects for treatment trials.

Validation of a multigenic model to predict seizure control in newly treated epilepsy.

A multigenic classifier based on five single nucleotide polymorphisms (SNPs) was previously reported to predict treatment response in an Australian newly-diagnosed epilepsy cohort using a k-nearest neighbour (kNN) algorithm. We assessed the validity of this classifier in predicting response to initial antiepileptic drug (AED) treatment in two UK cohorts of newly-diagnosed epilepsy and investigated the utility of these five SNPs in predicting seizure control in general. The original Australian cohort constituted the training set for the classifier and was used to predict response to the first well-tolerated AED monotherapy in independently recruited UK cohorts (Glasgow, n=281; SANAD, n=491). A "leave-one-out" cross-validation was also employed, with training sets derived internally from the UK datasets. The multigenic classifier using the Australian cohort as the training set was unable to predict treatment response in either UK cohort. In the "leave-one-out" analysis, the five SNPs collectively predicted treatment response in both Glasgow and SANAD patients prescribed either carbamazepine or valproate (Glasgow OR=3.1, 95% CI=1.4-6.6, p=0.018; SANAD OR=2.8, 95% CI=1.3-6.1, p=0.048), but not those receiving lamotrigine (Glasgow OR=1.3, 95% CI=0.6-2.8, p=1.0; SANAD OR=2.2, 95% CI=0.9-5.4, p=0.36) or other AEDs (Glasgow OR=0.6, 95% CI=0.2-2.0, p=1.0; SANAD OR=1.9, 95% CI=0.9-4.2, p=0.36). The Australian-based multigenic kNN model is not predictive of initial treatment response in UK cohorts of newly-diagnosed epilepsy. However, the five SNPs identified in the original Australian study appear to collectively have a predictive influence in UK patients prescribed either carbamazepine or valproate.

Characteristics of adverse medication events in a children's hospital.

AIM: To compare adverse medication events (AMEs) reported in children, via the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) coding with events reported via other data sources. METHOD: AME reports were retrieved using codes Y40-Y59 and X40-X44 over 6 months. Patients' charts were manually reviewed to identify events associated with error and/or harm with medicines during a hospital admission. Medication name, group, error, harm and alert documentation were recorded. Clinical incidents and pharmacist interventions were reviewed for the same period. RESULTS: Two hundred sixty-three events from January to June 2011 were recorded by ICD-10 coding in 180 patients. After duplicated, missing or unrelated events were excluded and 146 AMEs remained. In the same period, 117 AMEs were reported as incidents and 190 as pharmacist interventions. In total, 276 children with 447 events were reported via all sources. Little duplication between data sources was evident. In total, 158 events involved harm, with 135 of these from ICD-10 coding, 16 from incident reports and 2 pharmacist interventions (including 6 events from multiple sources). Error was involved in 3% of ICD10 reports, 97% of incidents and 100% of interventions. Only 14% of harm-related events from ICD-10 were documented on the medical record clinical alert. Chemotherapy accounted for 31% of harm-related events, antimicrobials 18%, corticosteroids 14% and narcotics 12%. CONCLUSION: Of the harm-related events, 85% were documented via ICD-10 coding with few documented in other databases. Review of ICD-10-coded AMEs can provide valuable information to improve patient safety and quality.

A national study of the processes and outcomes of paediatric formulary applications in Australia.

OBJECTIVE: To evaluate the processes by which pharmaceuticals are added to the formularies of Australian paediatric hospitals. DESIGN: Descriptive study of the processes and outcomes of all submissions to Australian paediatric hospital drug and therapeutics committees from 1 July 2010 to 31 December 2011. SETTING: All eight tertiary paediatric hospitals in Australia. PARTICIPANTS: Interviews with committee secretaries or delegates and document analysis. MAIN OUTCOME MEASURES: Total number of formulary applications, stratified by therapeutic class, approval rates for each hospital and quality of supporting information. RESULTS: One hundred and twenty applications were considered during the study period, with most applications approved (range, 67%-100%). Neurological agents were the most common therapeutic class considered. A conflict of interest was declared for 10 applications (8%). Forty-five (38%) were independently reviewed by a statewide medicines advisory committee or hospital pharmacist. Several committees approved identical applications during the period of review and with different outcomes. For applications submitted for new drugs or new indications (95 applications), supporting data included randomised controlled trials (37/95), case series (36/95), product information (34/95) and narrative reviews (29/95). Few applications (14/95) included a systematic review or meta-analysis. No application included an evaluation of the risk of bias of supporting studies. CONCLUSIONS: There is limited high-quality evidence informing paediatric hospital-based drug approvals. Approval processes vary considerably among institutions with substantial duplication of effort and variable outcomes. Resources and training appear insufficient given the technical complexity of submissions. A national, standardised approach to hospital-based drug evaluation could reduce overlap and improve decision making.

Removal versus retention of cerclage in preterm premature rupture of membranes: a randomized controlled trial.

OBJECTIVE: The decision of whether to retain or remove a previously placed cervical cerclage in women who subsequently rupture fetal membranes in a premature gestation is controversial and all studies to date are retrospective. We performed a multicenter randomized controlled trial of removal vs retention of cerclage in these patients to determine whether leaving the cerclage in place prolonged gestation and/or increased the risk of maternal or fetal infection. STUDY DESIGN: A prospective randomized multicenter trial of 27 hospitals was performed. Patients included were those with cerclage placement at ≤23 weeks 6 days in singleton or twin pregnancies, with subsequent spontaneous rupture of membranes between 22 weeks 0 days and 32 weeks 6 days. Patients were randomized to retention or removal of cerclage. Patients were then expectantly managed and delivered only for evidence of labor, chorioamnionitis, fetal distress, or other medical or obstetrical indications. Management after 34 weeks was at the clinician's discretion. RESULTS: The initial sample size calculation determined that a total of 142 patients should be included but after a second interim analysis, futility calculations determined that the conditional power for showing statistical significance after randomizing 142 patients for the primary outcome of prolonging pregnancy was 22.8%. Thus the study was terminated after a total of 56 subjects were randomized with complete data available for analysis, 32 to removal and 24 to retention of cerclage. There was no statistical significance in primary outcome of prolonging pregnancy by 1 week comparing the 2 groups (removal 18/32, 56.3%; retention 11/24, 45.8%) P = .59; or chorioamnionitis (removal 8/32, 25.0%; retention 10/24, 41.7%) P = .25, respectively. There was no statistical difference in composite neonatal outcomes (removal 16/33, 50%; retention 17/30, 56%), fetal/neonatal death (removal 4/33, 12%; retention 5/30, 16%); or gestational age at delivery (removal mean 200 days; retention mean 198 days). CONCLUSION: Statistically significant differences were not seen in prolongation of latency, infection, or composite neonatal outcomes. However, there was a numerical trend in the direction of less infectious morbidity, with immediate removal of cerclage. These findings may not have met statistical significance if the original sample size of 142 was obtained, however they provide valuable data suggesting that there may be no advantage to retaining a cerclage after preterm premature rupture of membranes and a possibility of increased infection with cerclage retention.

Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes.

OBJECTIVE: The purpose of this study was to compare intraamniotic inflammation vs microbial invasion of the amniotic cavity (MIAC) as predictors of adverse outcome in preterm labor with intact membranes. STUDY DESIGN: Interleukin-6 (IL-6) was measured in prospectively collected amniotic fluid from 305 women with preterm labor. MIAC was defined by amniotic fluid culture and/or detection of microbial 16S ribosomal DNA. Cases were categorized into 5 groups: infection (MIAC; IL-6, ≥11.3 ng/mL); severe inflammation (no MIAC; IL-6, ≥11.3 ng/mL); mild inflammation (no MIAC; IL-6, 2.6-11.2 ng/mL); colonization (MIAC; IL-6, <2.6 ng/mL); negative (no MIAC; IL-6, <2.6 ng/mL). RESULTS: The infection (n = 27) and severe inflammation (n = 36) groups had similar latency (median, <1 day and 2 days, respectively) and similar rates of composite perinatal morbidity and mortality (81% and 72%, respectively). The colonization (n = 4) and negative (n = 195) groups had similar outcomes (median latency, 23.5 and 25 days; composite morbidity and mortality rates, 21% and 25%, respectively). The mild inflammation (n = 47) groups had outcomes that were intermediate to the severe inflammation and negative groups (median latency, 7 days; composite morbidity and mortality rates, 53%). In logistic regression adjusting for gestational age at enrollment, IL-6 ≥11.3 and 2.6-11.2 ng/mL, but not MIAC, were associated significantly with composite morbidity and mortality rates (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.2-11.2, OR, 3.1; 95% CI, 1.5-6.4, and OR, 1.8; 95% CI, 0.6-5.5, respectively). CONCLUSION: We confirmed previous reports that intraamniotic inflammation is associated with adverse perinatal outcomes whether or not intraamniotic microbes are detected. Colonization without inflammation appears relatively benign. Intraamniotic inflammation is not simply present or absent but also has degrees of severity that correlate with adverse outcomes. We propose the designation amniotic inflammatory response syndrome to denote the adverse outcomes that are associated with intraamniotic inflammation.

Misoprostol vaginal insert and time to vaginal delivery: a randomized controlled trial.

OBJECTIVE: To compare the efficacy and safety of a 200-microgram misoprostol vaginal insert with a 10-mg dinoprostone vaginal insert for reducing the time to vaginal delivery. METHODS: In a phase III, double-blind, multicenter study, women being induced with a modified Bishop score of 4 or less were randomly assigned to receive either a 200-microgram misoprostol vaginal insert or a 10-mg dinoprostone vaginal insert. Coprimary end points were time to vaginal delivery and rate of cesarean delivery. Secondary end points included time to any delivery mode, time to onset of active labor, and oxytocin use. RESULTS: A total of 1,358 women were randomized to receive the 200-microgram misoprostol vaginal insert (n=678) or dinoprostone vaginal insert (n=680). Women receiving the misoprostol vaginal insert had a significantly shorter median time to vaginal delivery compared with patients receiving the dinoprostone vaginal insert (21.5 hours compared with 32.8 hours, P<.001). Cesarean delivery occurred in 26.0% and 27.1% of women receiving the misoprostol vaginal insert and dinoprostone vaginal insert, respectively. A significant reduction in time to any delivery (18.3 hours compared with 27.3 hours), time to onset of active labor (12.1 hours compared with 18.6 hours), and proportion of women requiring predelivery oxytocin (48.1% compared with 74.1%) was observed with the misoprostol vaginal insert compared with dinoprostone vaginal insert (P<.001 for each). Uterine tachysystole requiring intervention occurred in 13.3% and 4.0% of participants receiving the misoprostol vaginal insert and dinoprostone vaginal insert, respectively (P<.001). CONCLUSION: Use of a 200-microgram misoprostol vaginal inset significantly reduced times to vaginal delivery and active labor with reduced need for oxytocin compared with the dinoprostone vaginal insert. Cesarean delivery rates were similar with both treatments. Tachysystole was more common in women receiving the 200-microgram misoprostol vaginal insert. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01127581. LEVEL OF EVIDENCE: I.

Enhancing severe injury surveillance: the association between severe injury events and fatalities in US coal mines.

This report evaluates the potential of using high degree (or severe) injuries as a proxy for fatal events. Injuries occurring at bituminous coal mines within the United States during the years 1996-2006 were classified by the degree of severity according to the Abbreviated Injury Scale (AIS). Using multivariate discrete and logistic models (via generalized estimating equations) and adjusting for number of employees and underground v. surface status, high degree (AIS≥3) injuries in the prior year were associated with an increased risk (OR 2.02, 95% CI 1.17 to 3.46) of fatalities within the same mine. While there is a need for improvements and standardization of injury surveillance and reporting, the findings support the study hypothesis that mining conditions resulting in high degree injuries can also result in fatalities, thus expanding the use and versatility of high degree injury surveillance data. With an improved understanding of the conditions and activities behind these two injury event types, these results enhance the ability for industry to more readily identify and develop technological advancements for safety and mitigating disasters.

Novel gene expression responses in the ovine abomasal mucosa to infection with the gastric nematode Teladorsagia circumcincta.

Infection of sheep with the gastric nematode Teladorsagia circumcincta results in distinct Th2-type changes in the mucosa, including mucous neck cell and mast cell hyperplasia, eosinophilia, recruitment of IgA/IgE producing cells and neutrophils, altered T-cell subsets and mucosal hypertrophy. To address the protective mechanisms generated in animals on previous exposure to this parasite, gene expression profiling was carried out using samples of abomasal mucosa collected pre- and post- challenge from animals of differing immune status, using an experimental model of T. circumcincta infection. Recently developed ovine cDNA arrays were used to compare the abomasal responses of sheep immunised by trickle infection with worm-naïve sheep, following a single oral challenge of 50 000 T. circumcincta L3. Key changes were validated using qRT-PCR techniques. Immune animals demonstrated highly significant increases in levels of transcripts normally associated with cytotoxicity such as granulysin and granzymes A, B and H, as well as mucous-cell derived transcripts, predominantly calcium-activated chloride channel 1 (CLCA1). Challenge infection also induced up-regulation of transcripts potentially involved in initiating or modulating the immune response, such as heat shock proteins, complement factors and the chemokine CCL2. In contrast, there was marked infection-associated down-regulation of gene expression of members of the gastric lysozyme family. The changes in gene expression levels described here may reflect roles in direct anti-parasitic effects, immuno-modulation or tissue repair.

Misoprostol vaginal insert for successful labor induction: a randomized controlled trial.

OBJECTIVE: To compare three doses of misoprostol vaginal insert for successful labor induction measured by the proportion of vaginal deliveries within 24 hours. METHODS: A total of 374 women with modified Bishop scores of 4 or lower before induction of labor were randomly assigned to receive misoprostol vaginal insert (MVI) 100 (n=118), MVI 150 (n=125), or MVI 200 (n=131) micrograms. The insert was removed for onset of active labor or adverse event. The primary outcome was proportion of vaginal deliveries within 24 hours. The comparison group was MVI 100. Safety was assessed by comparing rates of cesarean deliveries and adverse events. RESULTS: Twenty-four percent of women receiving MVI 200 failed to achieve vaginal delivery within 24 hours compared with 36.3% of those receiving MVI 100 (P=.057, relative risk [RR] 0.66, 95% confidence interval [CI] 0.42-1.04). Compared with MVI 100, MVI 200 reduced median time to vaginal delivery (1,181 compared with 1,744 minutes, P=.02) and need for oxytocin (48.9% compared with 70.9%, P<.001, RR 0.70, 95% CI 0.56-0.85). The cesarean rates for women assigned to MVI 200 and 100 were 22.9% (30/131) and 31.4% (37/118) (P=.15, RR 0.73, 95% CI 0.48-1.10). Misoprostol vaginal insert 200 was associated with an increased rate of tachysystole (41.2%) compared with MVI 100 (19.5%) (P<.001, RR 2.11, 95% CI 1.39-3.22). CONCLUSION: Compared with MVI 100, MVI 200 was associated with a significant reduction in time to vaginal delivery, but did not improve proportion with vaginal delivery by 24 hours. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00828711.

Motivational interviewing versus prescriptive advice for smokers who are not ready to quit.

OBJECTIVE: Smokers who are not ready to quit are a very difficult group to treat. Physicians, nurses, and nurse practitioners are in a unique position to encourage patients to quit smoking. However, the best approach to do so is not clear. METHODS: A two-group randomized controlled trial with 218 pack-a-day precontemplative and contemplative smokers recruited from the community. The laboratory-based study was designed to simulate outpatient visits to general practitioners. Participants were randomized to a 15-min intervention to compare the effectiveness of brief motivational or prescriptive counseling by a health professional. Thirteen outcome variables included intentions to quit and verbal reports at 1 and 6 months with biological verification. A composite outcome measure was constructed to provide greater power to detect study differences. RESULTS: Approximately 33% of the sample reported at least one 24-h quit period during the 6 months they were followed after the trial. Results suggest that while neither treatment was superior, there were subgroup differences. Participants in the motivational condition were also more likely to respond to follow-up calls. CONCLUSIONS AND PRACTICE IMPLICATIONS: Motivational interviewing and prescriptive advice were equally effective for precontemplative and contemplative smokers. Practitioners should use the method that appeals to them.

SYMBIOSIS: development, implementation, and assessment of a model curriculum across biology and mathematics at the introductory level.

"It takes a lot of courage to release the familiar and seemingly secure, to embrace the new. But there is no real security in what is no longer meaningful. There is more security in the adventurous and exciting, for in movement there is life, and in change there is power." Alan Cohen (Used by permission. All rights reserved. For more information on Alan Cohen's books and programs, see (www.alancohen.com.) With the support of the East Tennessee State University (ETSU) administration and a grant from Howard Hughes Medical Institute, the departments of Biological Sciences, Mathematics and Statistics, and Curriculum and Instruction have developed a biology-math integrated curriculum. An interdisciplinary faculty team, charged with teaching the 18 curriculum modules, designed this three-semester curriculum, known as SYMBIOSIS. This curriculum was piloted to two student cohorts during the developmental stage. The positive feedback and assessment results of this project have given us the foundation to implement the SYMBIOSIS curriculum as a replacement for the standard biology majors curriculum at the introductory level. This article addresses the history and development of the curriculum, previous assessment results and current assessment protocol, and the future of ETSU's approach to implementing the SYMBIOSIS curriculum.

Acute changes in sputum collected from exposed human subjects in mining conditions.

Neprilysin (NEP) is a key cell surface peptidase in the maintenance of airway homeostasis and the development of pulmonary disorders. However, little information is available about the effect of particulate matter (PM) on airway NEP. In this controlled human exposure study, changes in induced sputum were measured in 11 subjects at baseline, overshot (OS) mucking, and diesel exhaust (DE) exposure days. Neither OS condition nor DE exposure was found to induce significant changes in total protein, but DE induced significant increases in cell numbers of macrophages and epithelium. Moreover, significant increases in soluble NEP were observed following OS mining dust particulates (0.43 +/- 0.06 nmol/microg protein/min; p = .023) and DE exposure (0.40 +/- 0.03 nmol/microg protein/min; p = .035) when compared with the baseline control (0.30 +/- 0.04 nmol/microg protein/min), with 42% and 31% average net increase, respectively. Pearson's correlation analyses indicated that sputum NEP activity was significantly associated with personal exposure product (elemental carbon concentration [mg/m(3)] x time [min]; C x T). The data suggest that changes in NEP activity may be an early, accurate endpoint for airway epithelial injury and provide a new insight into the mechanism of airway effects following particulate exposure.

Expression of three intelectins in sheep and response to a Th2 environment.

Sheep intelectin1 and sheep intelectin3 (sITLN1 and sITLN3) were cloned and sequenced. The amino acid sequences of sITLN1 and sITLN3 shared 86% and 91% homology with the previously cloned sheep intelectin2 (sITLN2), respectively. Expression of sITLN1 and sITLN3 transcript was demonstrated in abomasum, lung, colon and gastric lymph node, terminal rectum, skin, jejunum, mesenteric lymph node, ileal peyer's patches, brain, kidney, liver, spleen, skin, ear pinna, heart and ovary in normal sheep tissues. sITLN2 transcript expression was restricted to the abomasal mucosa in normal sheep tissues. Using a non selective chicken anti-intelectin antibody, tissue intelectin protein was demonstrated in mucus neck cells in the abomasum, mucus cells in the colon, free mucus in ileum, goblet cells in the lung, small intestinal epithelium and brush border, epidermal layer of the skin and skin sebaceous glands. The expression of the three sITLN transcripts was examined in two nematode infections in sheep known to induce a Th2 response; a Teladorsagia circumcincta challenge infection model and a Dictyocaulus filaria natural infection. The three sITLN were absent in unchallenged naïve lambs and present in the abomasal mucosa of both naïve and immune lambs following T. circumcincta challenge infection. Upregulation of sITLN2 and sITLN3 was shown in sheep lung following D. filaria natural infection. Intelectins may play an important role in the mucosal response to nematode infections in ruminants.