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Objective: To evaluate whether there is a differential benefit of planned Cesarean delivery (CD) over planned vaginal delivery (VD) in women with a twin pregnancy and the first twin in cephalic presentation, depending on prespecified baseline maternal and pregnancy characteristics, and/or gestational age (GA) at delivery. Methods: This was a secondary analysis of the Twin Birth Study, which included 2804 women with a twin pregnancy and the first twin (Twin A) in cephalic presentation between 32 + 0 and 38 + 6 weeks' gestation at 106 centers in 25 countries. Women were assigned randomly to either planned CD or planned VD. The main outcome measure was composite adverse perinatal outcome, defined as the occurrence of perinatal mortality or serious neonatal morbidity in at least one twin. The baseline maternal and pregnancy characteristics (markers) considered were maternal age, parity, history of CD, use of antenatal corticosteroids, estimated fetal weight (EFW) of Twin A, EFW of Twin B, > 25% difference in EFW between the twins, presentation of Twin B, chorionicity on ultrasound, method of conception, complications of pregnancy, ruptured membranes at randomization and GA at randomization. Separate logistic regression models were developed for each marker in order to model composite adverse perinatal outcome as a function of the specific marker, planned delivery mode and the interaction between these two terms. In addition, multivariable logistic regression analysis with backward variable elimination was performed separately in each arm of the trial. The association between planned mode of delivery and composite adverse perinatal outcome, according to GA at delivery, was assessed using logistic regression analysis. Results: Of the 2804 women initially randomized, 1391 were included in each study arm. None of the studied baseline markers was associated with a differential benefit of planned CD over planned VD in the rate of composite adverse perinatal outcome. GA at delivery was associated differentially with composite adverse perinatal outcome in the treatment arms (P for interaction < 0.001). Among pregnancies delivered at 32 + 0 to 36 + 6 weeks, there was a trend towards a lower rate of composite adverse perinatal outcome in those in the planned‐VD group compared with those in planned‐CD group (29 (2.2%) vs 48 (3.6%) cases; odds ratio (OR) 0.62 (95% CI, 0.37–1.03)). In pregnancies delivered at or after 37 + 0 weeks, planned VD was associated with a significantly higher rate of composite adverse perinatal outcome, as compared with planned CD (23 (1.5%) vs 10 (0.7%) cases; OR, 2.25 (95% CI, 1.06–4.77)). Conclusion: The perinatal outcome of twin pregnancies with the first twin in cephalic presentation may differ depending on GA at delivery and planned mode of delivery. At 32–37 weeks, planned VD seems to be favorable, while, from around 37 weeks onwards, planned CD might be safer. The absolute risks of adverse perinatal outcomes at term are low and must be weighed against the increased maternal risks associated with planned CD. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objective: To compare outcomes at 3 months post partum for women randomised to give birth by planned caesarean section (CS) or by planned vaginal birth (VB) in the Twin Birth Study (TBS).Design: We invited women in the TBS to complete a 3-month follow-up questionnaire.Setting: Two thousand and eight hundred and four women from 25 countries.Population: Two thousand and five hundred and seventy women (92% response rate).Methods: Women randomised between 13 December 2003 and 4 April 2011 in the TBS completed a questionnaire and outcomes were compared using an intention-to-treat approach.Main Outcome and Measures: Breastfeeding, quality of life, depression, fatigue and urinary incontinence.Results: We found no clinically important differences between groups in any outcome. In the planned CS versus planned VB groups, breastfeeding at any time after birth was reported by 84.4% versus 86.4% (P = 0.13); the mean physical and mental Short Form (36) Health Survey (SF-36) quality of life scores were 51.8 versus 51.6 (P = 0.65) and 46.7 versus 46.0 (P = 0.09), respectively; the mean Multidimensional Assessment of Fatigue score was 20.3 versus 20.8 (P = 0.14); the frequency of probable depression on the Edinburgh Postnatal Depression Scale was 14.0% versus 14.8% (P = 0.57); the rate of problematic urinary incontinence was 5.5% versus 6.4% (P = 0.31); and the mean Incontinence Impact Questionnaire-7 score was 20.5 versus 20.4 (P = 0.99). Partner relationships, including painful intercourse, were similar between the groups.Conclusion: For women with twin pregnancies randomised to planned CS compared with planned VB, outcomes at 3 months post partum did not differ. The mode of birth was not associated with problematic urinary incontinence or urinary incontinence that affected the quality of life. Contrary to previous studies, breastfeeding at 3 months was not increased with planned VB.Tweetable Abstract: Planned mode of birth for twins doesn't affect maternal depression, wellbeing, incontinence or breastfeeding. [ABSTRACT FROM AUTHOR]

Boxazomycins A-C are potent broad-spectrum antibiotics isolated from Actinomycetes strain G495-1 in 1987. We now report that boxazomycin A inhibits bacterial growth by selectively inhibiting protein synthesis, its effect is bacteriostatic, and it is equally active against drug resistant bacterial strains. No cross-resistance to protein synthesis inhibitors was observed suggesting that its inhibition is distinct from clinical protein synthesis inhibitors. We also report in vivo efficacy in a Staphylococcus aureus murine infection model supported by corresponding pharmacokinetic studies., (© 2024. Merck & Co., Inc., Rahway, NJ, USA and its affiliates, under exclusive licence to the Japan Antibiotics Research Association.)

Background: Intrapartum magnesium sulfate administration is recommended for fetal neuroprotection in women with imminent very preterm birth. However, previous studies have not included or separately analyzed the outcomes of pregnancies with fetal growth restriction that were treated with intrapartum magnesium sulfate., Objective: We sought to evaluate the neonatal and neurodevelopmental outcomes of growth-restricted fetuses born <29 weeks' gestation and exposed to maternal intrapartum magnesium sulfate., Study Design: We conducted a retrospective cohort study of infants born <29 weeks' gestation from 2010 through 2011, admitted to participating Canadian Neonatal Network units, and followed by the Canadian Neonatal Follow-up Network centers. Growth restriction was defined either as estimated fetal or actual neonatal birthweight <10th percentile according to fetal or neonatal growth standards for gestational age and sex, respectively. Infants exposed to intrapartum magnesium sulfate were compared with unexposed infants. The primary outcome was composite of death or significant neurodevelopmental impairment at 18-36 months' corrected age. Secondary outcomes were death or any neurodevelopmental impairment at 18-36 months' corrected age. Neonatal morbidities were also compared., Results: Of the 336 growth-restricted fetuses, 112 (33%) received magnesium sulfate and of the 177 growth-restricted infants, 61 (34%) received magnesium sulfate. Administration of magnesium sulfate was at the discretion of the treating physician. Intrapartum magnesium sulfate was associated with reduced odds of composite of death or significant neurodevelopmental impairment for infants classified according to both fetal standards (adjusted odds ratio, 0.42; 95% confidence interval, 0.22-0.80) and neonatal standards (adjusted odds ratio, 0.44; 95% confidence interval, 0.20-0.98)., Conclusion: Intrapartum administration of magnesium sulfate to women with growth-restricted fetuses born <29 weeks' gestation was associated with reduced odds of composite of death or significant neurodevelopmental impairment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Vertical growth of plants is a dynamic process that is influenced by genetic and environmental factors and has a pronounced effect on overall plant architecture and biomass composition. We have performed six controlled growth trials of an interspecific Setaria italica x Setaria viridis recombinant inbred line population to assess how the genetic architecture of plant height is influenced by developmental queues, water availability and planting density. The non-destructive nature of plant height measurements has enabled us to monitor height throughout the plant life cycle in both field and controlled environments. We find that plant height is reduced under water limitation and high density planting and affected by growth environment (field vs. growth chamber). The results support a model where plant height is a heritable, polygenic trait and that the major genetic loci that influence plant height function independent of growth environment. The identity and contribution of loci that influence height changes dynamically throughout development and the reduction of growth observed in water limited environments is a consequence of delayed progression through the genetic program which establishes plant height in Setaria. In this population, alleles inherited from the weedy S. viridis parent act to increase plant height early, whereas a larger number of small effect alleles inherited from the domesticated S. italica parent collectively act to increase plant height later in development.

Background: This secondary analysis for the Twin Birth Study, an international, multicenter trial, aimed to compare the cesarean section rates and safety between methods of induction of labor in twin pregnancies., Methods: Women with twin pregnancies where the first twin was in a cephalic presentation and who presented for labor induction, were non-randomly assigned to receive prostaglandin or amniotomy and/or oxytocin. Main outcome measures were the rates of unplanned cesarean section and neonatal and maternal mortality or serious morbidity., Results: 153 (41.5%) were induced by prostaglandin (prostaglandin group) and 215 (58.5%) were induced by amniotomy and/or oxytocin alone (no prostaglandin group). Induction using prostaglandin was more common in countries with a low perinatal mortality rate <10/1000 (45.7 versus 32.5%, p = 0.02). Cesarean section rates were similar in the two groups: 62/153 (40.5%) in the prostaglandin group and 87/215 (40.5%) in the no prostaglandin group (odds ratio 1, 95% CI 0.65-1.5). Nulliparity, late maternal age, non-cephalic presentation of twin B and high country's perinatal mortality rate were found to be independently associated with the induction to end with an unplanned cesarean section. There were no significant differences between groups with respect to maternal or neonatal adverse outcomes., Conclusions: The need for cervical ripening by prostaglandin had no effect on the incidence of cesarean delivery or an abnormal outcome. There is a significant risk of unplanned cesarean section independent of chosen induction method., Trial Registration: This trial was registered at the International Standard Randomized Controlled Trial Register (identifier ISRCTN74420086 ; December 9, 2003) and retrospectively registered at the www.clinicaltrials.gov (identifier NCT 00187369 ; September 12, 2005).

Objective: The Twin Birth Study, an international, multi-center randomized controlled trial was conducted to compare the risks of planned cesarean with planned vaginal delivery for twin pregnancies. The aim of this component of the trial was to understand participants' perspectives of study participation and preferences for the mode of delivery., Methods: A mixed-methods questionnaire was distributed to study participants 3 months after giving birth. The questionnaire contained Likert scales and open-ended questions about the experience of being enrolled in a clinical trial and of childbirth, including the mode of delivery. Quantitative data were analyzed using SAS to generate descriptive statistics. Qualitative data were analyzed to identify categories and themes., Results: Ninety-one percent of trial participants completed the questionnaire. Across all groups, the majority of women would participate in a study like this one again if given the opportunity. Main benefits of participating were as follows: benefits to one and one's babies, altruism, and receiving quality care. Randomization for the mode of delivery was challenging for women because of the desire to be involved in decision-making. Findings related to childbirth experience and the mode of delivery demonstrated a preference for vaginal birth across all groups. Those who had a vaginal birth were more satisfied with their birth experience., Conclusions: This study provides evidence to inform practitioners about what women who have twin pregnancies like or dislike about birth and their desire for involvement in decision-making. Vaginal birth was preferred across all study groups and was associated with greater satisfaction with childbirth experience., (© 2016 Wiley Periodicals, Inc.)

Objectives: To assess the incidence of cerebral palsy among children born to mothers who had their pregnancy complicated by a motor vehicle crash., Design: Retrospective longitudinal cohort analysis of children born from 1 April 2002 to 31 March 2012 in Ontario, Canada., Participants: Cases defined as pregnancies complicated by a motor vehicle crash and controls as remaining pregnancies with no crash., Main Outcome: Subsequent diagnosis of cerebral palsy by age 3 years., Results: A total of 1 325 660 newborns were analysed, of whom 7933 were involved in a motor vehicle crash during pregnancy. A total of 2328 were subsequently diagnosed with cerebral palsy, equal to an absolute risk of 1.8 per 1000 newborns. For the entire cohort, motor vehicle crashes correlated with a 29% increased risk of subsequent cerebral palsy that was not statistically significant (95% CI -16 to +110, p=0.274). The increased risk was only significant for those with preterm birth who showed an 89% increased risk of subsequent cerebral palsy associated with a motor vehicle crash (95% CI +7 to +266, p=0.037). No significant increase was apparent for those with a term delivery (95% CI -62 to +79, p=0.510). A propensity score-matched analysis of preterm births (n=4384) yielded a 138% increased relative risk of cerebral palsy associated with a motor vehicle crash (95% CI +27 to +349, p=0.007), equal to an absolute increase of about 10.9 additional cases per 1000 newborns (18.2 vs 7.3, p=0.010)., Conclusions: Motor vehicle crashes during pregnancy may be associated with an increased risk of cerebral palsy among the subgroup of cases with preterm birth. The increase highlights a specific role for traffic safety advice in prenatal care., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: The incidence of type 2 diabetes in pregnancy is rising and rates of serious adverse maternal and fetal outcomes remain high. Metformin is a biguanide that is used as first-line treatment for non-pregnant patients with type 2 diabetes. We hypothesize that metformin use in pregnancy, as an adjunct to insulin, will decrease adverse outcomes by reducing maternal hyperglycemia, maternal insulin doses, maternal weight gain and gestational hypertension/pre-eclampsia. In addition, since metformin crosses the placenta, metformin treatment of the fetus may have a direct beneficial effect on neonatal outcomes. Our aim is to compare the effectiveness of the addition of metformin to insulin, to standard care (insulin plus placebo) in women with type 2 diabetes in pregnancy., Methods: The MiTy trial is a multi-centre randomized trial currently enrolling pregnant women with type 2 diabetes, who are on insulin, between the ages of 18-45, with a gestational age of 6 weeks 0 days to 22 weeks 6 days. In this randomized, double-masked, parallel placebo-controlled trial, after giving informed consent, women are randomized to receive either metformin 1,000 mg twice daily or placebo twice daily. A web-based block randomization system is used to assign women to metformin or placebo in a 1:1 ratio, stratified for site and body mass index. The primary outcome is a composite neonatal outcome of pregnancy loss, preterm birth, birth injury, moderate/severe respiratory distress, neonatal hypoglycemia, or neonatal intensive care unit admission longer than 24 h. Secondary outcomes are large for gestational age, cord blood gas pH < 7.0, congenital anomalies, hyperbilirubinemia, sepsis, hyperinsulinemia, shoulder dystocia, fetal fat mass, as well as maternal outcomes: maternal weight gain, maternal insulin doses, maternal glycemic control, maternal hypoglycemia, gestational hypertension, preeclampsia, cesarean section, number of hospitalizations during pregnancy, and duration of hospital stays. The trial aims to enroll 500 participants., Discussion: The results of this trial will inform endocrinologists, obstetricians, family doctors, and other healthcare professionals caring for women with type 2 diabetes in pregnancy, as to the benefits of adding metformin to insulin in this high risk population., Trial Registration: ClinicalTrials.gov Identifier: no. NCT01353391 . Registered February 6, 2009.

Background: The Twin Birth Study randomized women with uncomplicated pregnancies, between 32(0/7)-38(6/7) weeks' gestation where the first twin was in cephalic presentation, to a policy of either a planned cesarean or planned vaginal delivery. The primary analysis showed that planned cesarean delivery did not increase or decrease the risk of fetal/neonatal death or serious neonatal morbidity as compared with planned vaginal delivery., Objective: This study presents the secondary outcome of death or neurodevelopmental delay at 2 years of age., Study Design: A total of 4603 children from the initial cohort of 5565 fetuses/infants (83%) contributed to the outcome of death or neurodevelopmental delay. Surviving children were screened using the Ages and Stages Questionnaire with abnormal scores validated by a clinical neurodevelopmental assessment. The effect of planned cesarean vs planned vaginal delivery on death or neurodevelopmental delay was quantified using a logistic model to control for stratification variables and using generalized estimating equations to account for the nonindependence of twin births., Results: Baseline maternal, pregnancy, and infant characteristics were similar. Mean age at assessment was 26 months. There was no significant difference in the outcome of death or neurodevelopmental delay: 5.99% in the planned cesarean vs 5.83% in the planned vaginal delivery group (odds ratio, 1.04; 95% confidence interval, 0.77-1.41; P = .79)., Conclusion: A policy of planned cesarean delivery provides no benefit to children at 2 years of age compared with a policy of planned vaginal delivery in uncomplicated twin pregnancies between 32(0/7)-38(6/7)weeks' gestation where the first twin is in cephalic presentation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Twin pregnancies are associated with increased perinatal mortality, mainly related to prematurity, but complications during birth may contribute to perinatal loss or morbidity. The option of planned caesarean section to avoid such complications must therefore be considered. On the other hand, randomised trials of other clinical interventions in the birth process to avoid problems related to labour and birth (planned caesarean section for breech, and continuous electronic fetal heart rate monitoring), have shown an unexpected discordance between short-term perinatal morbidity and long-term neurological outcome. The risks of caesarean section for the mother in the current and subsequent pregnancies must also be taken into account., Objectives: To determine the short- and long-term effects on mothers and their babies, of planned caesarean section for twin pregnancy., Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (18 November 2015) and reference lists of retrieved studies., Selection Criteria: Randomised trials comparing a policy of caesarean section with planned vaginal birth for women with twin pregnancy., Data Collection and Analysis: Two review authors independently assessed eligibility, quality and extracted data. Data were checked for accuracy. For important outcomes the quality of the evidence was assessed using the GRADE approach., Main Results: We included two trials comparing planned caesarean section versus planned vaginal birth for twin pregnancies.Most of the data included in the review were from a multicentre trial where 2804 women were randomised in 106 centres in 25 countries. All centres had facilities to perform emergency caesarean section and had anaesthetic, obstetrical, and nursing staff available in the hospital at the time of planned vaginal delivery. In the second trial carried out in Israel, 60 women were randomised. We judged the risk of bias to be low for all categories except performance (high) and outcome assessment bias (unclear).There was no clear evidence of differences between women randomised to planned caesarean section or planned vaginal birth for maternal death or serious morbidity (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.67 to 1.11; 2844 women; two studies; moderate quality evidence). There was no significant difference between groups for perinatal or neonatal death or serious neonatal morbidity (RR 1.15, 95% CI 0.80 to 1.67; data for 5565 babies, one study, moderate quality evidence). No studies reported childhood disability.For secondary outcomes there was no clear evidence of differences between groups for perinatal or neonatal mortality (RR 1.41, 95% CI 0.76 to 2.62; 5685 babies; two studies, moderate quality evidence), serious neonatal morbidity (RR 1.03, 95% CI 0.65 to 1.64; 5644 babies; two studies, moderate quality evidence) or any of the other neonatal outcomes reported.The number of women undergoing caesarean section was reported in both trials. Most women in the planned caesarean group had treatment as planned (90.9% underwent caesarean section), whereas in the planned vaginal birth group 42.9% had caesarean section for at least one twin. For maternal mortality; no events were reported in one trial and two deaths (one in each group) in the other. There were no significant differences between groups for serious maternal morbidity overall (RR 0.86, 95% CI 0.67 to 1.11; 2844 women; two studies) or for different types of short-term morbidity. There were no significant differences between groups for failure to breastfeed (RR 1.14, 95% CI 0.95 to 1.38; 2570 women, one study; moderate quality evidence) or the number of women with scores greater than 12 on the Edinbugh postnatal depression scale (RR 0.95, 95% CI 0.78 to 1.14; 2570 women, one study; moderate quality evidence)., Authors' Conclusions: Data mainly from one large, multicentre study found no clear evidence of benefit from planned caesarean section for term twin pregnancies with leading cephalic presentation. Data on long-term infant outcomes are awaited. Women should be informed of possible risks and benefits of labour and vaginal birth pertinent to their specific clinical presentation and the current and long-term effects of caesarean section for both mother and babies. There is insufficient evidence to support the routine use of planned caesarean section for term twin pregnancy with leading cephalic presentation, except in the context of further randomised trials.

Objective: To compare outcomes at 3 months post partum for women randomised to give birth by planned caesarean section (CS) or by planned vaginal birth (VB) in the Twin Birth Study (TBS)., Design: We invited women in the TBS to complete a 3-month follow-up questionnaire., Setting: Two thousand and eight hundred and four women from 25 countries., Population: Two thousand and five hundred and seventy women (92% response rate)., Methods: Women randomised between 13 December 2003 and 4 April 2011 in the TBS completed a questionnaire and outcomes were compared using an intention-to-treat approach., Main Outcome and Measures: Breastfeeding, quality of life, depression, fatigue and urinary incontinence., Results: We found no clinically important differences between groups in any outcome. In the planned CS versus planned VB groups, breastfeeding at any time after birth was reported by 84.4% versus 86.4% (P = 0.13); the mean physical and mental Short Form (36) Health Survey (SF-36) quality of life scores were 51.8 versus 51.6 (P = 0.65) and 46.7 versus 46.0 (P = 0.09), respectively; the mean Multidimensional Assessment of Fatigue score was 20.3 versus 20.8 (P = 0.14); the frequency of probable depression on the Edinburgh Postnatal Depression Scale was 14.0% versus 14.8% (P = 0.57); the rate of problematic urinary incontinence was 5.5% versus 6.4% (P = 0.31); and the mean Incontinence Impact Questionnaire-7 score was 20.5 versus 20.4 (P = 0.99). Partner relationships, including painful intercourse, were similar between the groups., Conclusion: For women with twin pregnancies randomised to planned CS compared with planned VB, outcomes at 3 months post partum did not differ. The mode of birth was not associated with problematic urinary incontinence or urinary incontinence that affected the quality of life. Contrary to previous studies, breastfeeding at 3 months was not increased with planned VB., Tweetable Abstract: Planned mode of birth for twins doesn't affect maternal depression, wellbeing, incontinence or breastfeeding., (© 2015 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Introduction: Pregnancy causes diverse physiologic and lifestyle changes that may contribute to increased driving and driving error. We compared the risk of a serious motor vehicle crash during the second trimester to the baseline risk before pregnancy., Methods: We conducted a population-based self-matched longitudinal cohort analysis of women who gave birth in Ontario between April 1, 2006, and March 31, 2011. We excluded women less than age 18 years, those living outside Ontario, those who lacked a valid health card identifier under universal insurance, and those under the care of a midwife. The primary outcome was a motor vehicle crash resulting in a visit to an emergency department., Results: A total of 507,262 women gave birth during the study period. These women accounted for 6922 motor vehicle crashes as drivers during the 3-year baseline interval (177 per mo) and 757 motor vehicle crashes as drivers during the second trimester (252 per mo), equivalent to a 42% relative increase (95% confidence interval 32%-53%; p<0.001). The increased risk extended to diverse populations, varied obstetrical cases and different crash characteristics. The increased risk was largest in the early second trimester and compensated for by the third trimester. No similar increase was observed in crashes as passengers or pedestrians, cases of intentional injury or inadvertent falls, or self-reported risky behaviours., Interpretation: Pregnancy is associated with a substantial risk of a serious motor vehicle crash during the second trimester. This risk merits attention for prenatal care., (© 2014 Canadian Medical Association or its licensors.)

The incidence of twin pregnancy has increased worldwide over the past 10 years, largely as a consequence of the assisted reproductive technologies. Issues such as intrapartum monitoring and operative interventions, especially relating to the second twin, provide a unique challenge in labour and delivery. Epidemiological and cohort data suggest that twins have a three-fold higher mortality rate than singletons, and that the second twin might have a better outcome if delivered by lower segment caesarean section. The recently completed Twin Birth Study has found that planned vaginal lower segment caesarean section is not advantageous to the fetus. In the light of this large randomised-controlled trial, vaginal delivery if twin A presents by the vertex is recommended as long as guidelines for the conduct of such delivery are followed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Twin birth is associated with a higher risk of adverse perinatal outcomes than singleton birth. It is unclear whether planned cesarean section results in a lower risk of adverse outcomes than planned vaginal delivery in twin pregnancy., Methods: We randomly assigned women between 32 weeks 0 days and 38 weeks 6 days of gestation with twin pregnancy and with the first twin in the cephalic presentation to planned cesarean section or planned vaginal delivery with cesarean only if indicated. Elective delivery was planned between 37 weeks 5 days and 38 weeks 6 days of gestation. The primary outcome was a composite of fetal or neonatal death or serious neonatal morbidity, with the fetus or infant as the unit of analysis for the statistical comparison., Results: A total of 1398 women (2795 fetuses) were randomly assigned to planned cesarean delivery and 1406 women (2812 fetuses) to planned vaginal delivery. The rate of cesarean delivery was 90.7% in the planned-cesarean-delivery group and 43.8% in the planned-vaginal-delivery group. Women in the planned-cesarean-delivery group delivered earlier than did those in the planned-vaginal-delivery group (mean number of days from randomization to delivery, 12.4 vs. 13.3; P=0.04). There was no significant difference in the composite primary outcome between the planned-cesarean-delivery group and the planned-vaginal-delivery group (2.2% and 1.9%, respectively; odds ratio with planned cesarean delivery, 1.16; 95% confidence interval, 0.77 to 1.74; P=0.49)., Conclusions: In twin pregnancy between 32 weeks 0 days and 38 weeks 6 days of gestation, with the first twin in the cephalic presentation, planned cesarean delivery did not significantly decrease or increase the risk of fetal or neonatal death or serious neonatal morbidity, as compared with planned vaginal delivery. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00187369; Current Controlled Trials number, ISRCTN74420086.).

Background: Twin pregnancies are associated with increased perinatal mortality, mainly related to prematurity, but complications during birth may contribute to perinatal loss or morbidity. The option of planned caesarean section to avoid such complications must therefore be considered. On the other hand, randomised trials of other clinical interventions in the birth process to avoid problems related to labour and birth (planned caesarean section for breech, and continuous electronic fetal heart rate monitoring), have shown an unexpected discordance between short-term perinatal morbidity and long-term neurological outcome. The risks of caesarean section for the mother in the current and subsequent pregnancies must also be taken into account., Objectives: To determine the short- and long-term effects on mothers and their babies, of planned caesarean section for twin pregnancy., Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2011)., Selection Criteria: Randomised trials comparing a policy of caesarean section with planned vaginal birth for women with twin pregnancy., Data Collection and Analysis: Two researchers independently assessed eligibility, quality and extracted data. Data were checked for accuracy., Main Results: One small trial with unconfirmed allocation concealment compared caesarean section with planned vaginal birth in 60 women with vertex/non-vertex twin pregnancies. There were no differences in perinatal outcome. The trial was too small to exclude the possibility of clinically meaningful benefits of either approach. There is one additional trial currently ongoing., Authors' Conclusions: There is a lack of robust evidence to guide clinical advice regarding the method of birth for twin pregnancies. Women should be informed of possible benefits and risks of either approach, including short-term and long-term consequences for both mother and babies. Future research should aim to provide unbiased evidence, including long-term outcomes.

Thiazolyl peptides are a class of highly rigid trimacrocyclic compounds consisting of varying but large numbers of thiazole rings. The need for new antibacterial agents to treat infections caused by resistant bacteria prompted a reinvestigation of this class, leading to the previous isolation of thiazolyl peptides, namely, thiazomycin (5) and thiazomycin A (6), congeners of nocathiacins (1-4). Continued chemical screening led to the isolation of six new thiazolyl peptide congeners (8-13), of which three had truncated structures lacking an indole residue. From these, compound 8 showed activity similar to thiazomycin. Two compounds (9 and 10) showed intermediate activities, and the three truncated compounds (11-13) were essentially inactive. The discovery of the truncated compounds revealed the minimal structural requirements for activity and suggested probable biosynthetic pathways for more advanced compounds. The isolation, structure elucidation, antibacterial activity, and proposed biogenesis of thiazomycins are herein described.

Thiazolyl peptides are a class of thiazole-rich macrocyclic potent antibacterial agents. Recently, we described thiazomycin, a new member of thiazolyl peptides, discovered by a thiazolyl peptide specific chemical screening. This method also allowed for the discovery of a new thiazolyl peptide, thiazomycin A, which carries modification in the oxazolidine ring of the amino sugar moiety. Thiazomycin A is a specific inhibitor of protein synthesis (IC(50) 0.7 microg/mL) and a potent Gram-positive antibacterial agent with minimum inhibitory concentration (MIC) ranging 0.002-0.25 microg/mL. The isolation and structure elucidation and biological activities of thiazomycin A are described.

Bacterial resistance to antibiotics, particularly to multiple drug resistant antibiotics, is becoming cause for significant concern. The only really viable course of action is to discover new antibiotics with novel mode of actions. Thiazolyl peptides are a class of natural products that are architecturally complex potent antibiotics but generally suffer from poor solubility and pharmaceutical properties. To discover new thiazolyl peptides potentially with better desired properties, we designed a highly specific assay with a pair of thiazomycin sensitive and resistant strains of Staphylococcus aureus, which led to the discovery of philipimycin, a new thiazolyl peptide glycoside. It was isolated along with an acid-catalyzed degradation product by bioassay-guided fractionation. Structure of both compounds was elucidated by extensive application of 2D NMR, 1D TOCSY, and HRESIFT-MS/MS. Both compounds showed strong antibacterial activities against gram-positive bacteria including MRSA and exhibited MIC values ranging from 0.015 to 1 microg/mL. Philipimycin was significantly more potent than the degradation product. Both compounds showed selective inhibition of protein synthesis, indicating that they targeted the ribosome. Philipimycin was effective in vivo in a mouse model of S. aureus infection exhibiting an ED50 value of 8.4 mg/kg. The docking studies of philipimycin suggested that a part of the molecule interacts with the ribosome and another part with Pro23, Pro22, and Pro26 of L11 protein, which helped in explaining the differential of activities between the sensitive and resistant strains. The design and execution of the bioassay, the isolation, structure, in vitro and in vivo antibacterial activity, and docking studies of philipimycin and its degradation product are described.

Thiazolyl peptides are a class of rigid macrocyclic compounds richly populated with thiazole rings. They are highly potent antibiotics but none have been advanced to clinic due to poor aqueous solubility. Recent progress in this field prompted a reinvestigation leading to the isolation of a new thiazolyl peptide, thiazomycin, a congener of nocathiacins. Thiazomycin possesses an oxazolidine ring as part of the amino-sugar moiety in contrast to the dimethyl amino group present in nocathiacin I. The presence of the oxazolidine ring provides additional opportunities for chemical modifications that are not possible with other nocathiacins. Thiazomycin is extremely potent against Gram-positive bacteria both in vitro and in vivo. The titer of thiazomycin in the fermentation broth was very low compared to the nocathiacins I and III. The lower titer together with its sandwiched order of elution presented significant challenges in large scale purification of thiazomycin. This problem was resolved by the development of an innovative preferential protonation based one- and/or two-step chromatographic method, which was used for pilot plant scale purifications of thiazomycin. The isolation and structure elucidation of thiazomycin is herein described.

Thiazomycin is a novel thiazolyl peptide closely related to nocathiacin I. It was isolated from Amycolatopsis fastidiosa by chemical and biological screening. Thiazomycin showed highly potent bactericidal activity against Gram-positive pathogens (MIC range 0.002 approximately 0.064 microg/ml) and did not show cross-resistance to clinically relevant antibiotic classes such as beta-lactams, vancomycin, oxazolidinone and quinolones. It was highly efficacious against Staphylococcus aureus infection in mice exhibiting an ED(99) value of 0.15 mg/kg by subcutaneous administration. It inhibited bacterial growth by selective inhibition of protein synthesis and it was thought to interact with L11 protein and 23S rRNA of the 50S ribosome. Structurally, it possesses an oxazolidine ring in the amino-sugar residue that provides further opportunities for selective chemical modifications that are not feasible with other thiazolyl peptides. More importantly such a modification can potentially lead to semi-synthetic compounds that overcome problems that have hampered clinical development of this class of compounds. Despite its positive attributes, emergence of an unacceptable frequency of resistance poses significant challenges for further development of thiazomycin and this class of molecules for therapeutic use.

Methicillin-resistant Staphylococcus aureus (MRSA) has posed an immense problem for clinicians in the hospital setting for years, emerging as the most frequent nosocomial infection. To deal with this problem pathogen and others, infectious disease specialists have developed a variety of procedures for their control and prevention, involving options from preventative measures such as decolonization and isolation of MRSA-confirmed patients, to the more simple procedures of hand washing, expanding glove use, and reducing time in the hospital. With the realization that MRSA is now a community problem, there are expanded efforts toward more direct intervention, such as the use of anti-MRSA antibacterials and vaccines, in an attempt to reduce the overall burden of MRSA.

The unmet medical need of emerging resistance among Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and penicillin-resistant Streptococcus pneumoniae, has driven industry towards the identification and development of novel anti-Gram-positive agents. Among the newer agents are improved quinolones, a lipopeptide, an oxazolidinone and novel glycopeptides. Scientific distinctions between these drugs, which impact on the placement, usage and, ultimately, the pharmacoeconomics of several of these new agents, may lead to further consideration despite poor initial observations of minimal improvement. Key differences in the characteristics of these drugs (i.e., spectrum, activity, resistance emergence, efficacy, target, safety) provide a basis for an emerging pharmacoeconomic-based distinction between these newer anti-Gram-positive agents.

The discovery of novel classes of antifungal drugs depends to a certain extent on the identification of new, unexplored targets that are essential for growth of fungal pathogens. Likewise, the broad-spectrum capacity of future antifungals requires the target gene(s) to be conserved among key fungal pathogens. Using a genome comparison (or concordance) tool, we identified 240 conserved genes as candidates for potential antifungal targets in 10 fungal genomes. To facilitate the identification of essential genes in Candida albicans, we developed a repressible C. albicans MET3 (CaMET3) promoter system capable of evaluating gene essentiality on a genome-wide scale. The CaMET3 promoter was found to be highly amenable to controlled gene expression, a prerequisite for use in target-based whole-cell screening. When the expression of the known antifungal target C. albicans ERG1 was reduced via down-regulation of the CaMET3 promoter, the CaERG1 conditional mutant strain became hypersensitive, specifically to its inhibitor, terbinafine. Furthermore, parallel screening against a small compound library using the CaERG1 conditional mutant under normal and repressed conditions uncovered several hypersensitive compound hits. This work therefore demonstrates a streamlined process for proceeding from selection and validation of candidate antifungal targets to screening for specific inhibitors.

Drug discovery research in the area of infectious diseases, in particular that dealing with antibacterial/antibiotic susceptibility and resistance, is in a process of continuing evolution. Steeped in the history of the highly successful intervention with chemotherapeutic agents to treat human infections, the emergence of drug-resistant pathogens worldwide presents a serious unmet medical need, if not a pending catastrophe. Research in both academia and industry over the past 30 years using molecular biology, genetics and more recently--bacterial genomics--has assembled key enabling technologies to increase productivity and success rates in the discovery and development of novel antibacterial agents. However genomics is not limited only to antibacterial target selection but provides the opportunity to further understand key interactions in the use of antibacterial compounds as therapeutic agents (such as resistance emergence, susceptibility, efflux, interactions between compound and pathogen, etc.). Genomics also offers the potential for insights into: bacterial niche adaptation, host susceptibility, treatment regimens, antibiotic resistance, pharmacokinetics (e.g., host metabolism differences), safety and the microbial genesis of chronic diseases (e.g., gastric ulceration).

Natural products have been a rich source in providing leads for the development of drugs for the treatment of bacterial infections. However, beyond the discovery of the natural product, thienamycin and the synthetic lead, oxazolidinone in the 1970s, there has been a dearth of new compounds. This commentary provides an overview of current antibiotic leads and their mechanism of action, and highlights tools that can be applied to the discovery of new antibiotics.

Condensing enzymes are essential in type II fatty acid synthesis and are promising targets for antibacterial drug discovery. Recently, a new approach using a xylose-inducible plasmid to express antisense RNA in Staphylococcus aureus has been described; however, the actual mechanism was not delineated. In this paper, the mechanism of decreased target protein production by expression of antisense RNA was investigated using Northern blotting. This revealed that the antisense RNA acts posttranscriptionally by targeting mRNA, leading to 5' mRNA degradation. Using this technology, a two-plate assay was developed in order to identify FabF/FabH target-specific cell-permeable inhibitors by screening of natural product extracts. Over 250,000 natural product fermentation broths were screened and then confirmed in biochemical assays, yielding a hit rate of 0.1%. All known natural product FabH and FabF inhibitors, including cerulenin, thiolactomycin, thiotetromycin, and Tü3010, were discovered using this whole-cell mechanism-based screening approach. Phomallenic acids, which are new inhibitors of FabF, were also discovered. These new inhibitors exhibited target selectivity in the gel elongation assay and in the whole-cell-based two-plate assay. Phomallenic acid C showed good antibacterial activity, about 20-fold better than that of thiolactomycin and cerulenin, against S. aureus. It exhibited a spectrum of antibacterial activity against clinically important pathogens including methicillin-resistant Staphylococcus aureus, Bacillus subtilis, and Haemophilus influenzae.

The evolution of support for the discovery and development of antibacterial (or antibiotic) agents from the larger pharmaceutical companies to the entrepreneur-like small biotechnology companies has been an experiment in the making for the past 15 years. The word 'experiment' is precisely chosen as the outcome is not certain. Many of the antibiotic biotech organizations that were most likely to undertake the task of picking up where large pharmaceutical companies left off have failed to survive, despite their use of outstanding science and their novel approaches to the development of discovery platforms. So this leaves one with the question of 'can biotech deliver the new antibiotics?'.

The glycopeptide class of antibiotics, namely vancomycin and teicoplanin, are intravenously administered in the hospital setting for the treatment of the most severe of Gram-positive infections. Although a mainstay of the hospital formulary for over four decades, the rise of increasingly frequent high-level vancomycin resistance in enterococci and low-level resistance in staphylococci (as well as a few high-level vancomycin resistance cases) has highlighted the need for the identification of naturally occurring and semi-synthetically modified glycopeptide derivatives that have antibacterial activity against these resistant strains. Among the leading development candidates are dalbavancin, oritavancin, telavancin and ramoplanin, each of which provides a unique microbiological and pharmacological profile to fill an important unmet medical need.

In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvoxtrade mark was the first oxazolidinone to be approved for clinical use against infections caused by multi-drug resistant Gram-positive bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-positive bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the phenyl ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compounds.

Background: The c-Myc oncogenic transcription factor heterodimerizes with Max, binds specific DNA sites and regulates transcription. The role of Myc in transcriptional activation involves its binding to TRRAP and histone acetylases; however, Myc's ability to activate transcription in transient transfection assays is remarkably weak (2 to 5 fold) when compared to other transcription factors. Since a deletion Myc mutant D106-143 and a substitution mutant W135E that weakly binds TRRAP are still fully active in transient transfection reporter assays and the TATA binding protein (TBP) has been reported to directly bind Myc, we sought to determine the effect of TBP on Myc transactivation., Results: We report here a potent stimulation of Myc transactivation by TBP, allowing up to 35-fold transactivation of reporter constructs. Although promoters with an initiator (InR) element briskly responded to Myc transactivation, the presence of an InR significantly diminished the response to increasing amounts of TBP. We surmise from these findings that promoters containing both TATA and InR elements may control Myc responsive genes that require brisk increased expression within a narrow window of Myc levels, independent of TBP. In contrast, promoters driven by the TATA element only, may also respond to modulation of TBP activity or levels., Conclusion: Our observations not only demonstrate that TBP is limiting for Myc transactivation in transient transfection experiments, but they also suggest that the inclusion of TBP in Myc transactivation assays may further improve the characterization of c-Myc target genes.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a serious nosocomial pathogen, and more recent reports in the scientific literature underscore the potential issues with emerging community-MRSA. MRSA is reported to be involved in > 50% of hospital S. aureus infections, more in the intensive care unit (ICU) than the non-ICU, and increases in multi-drug resistant MRSA and increasingly virulent MRSA have been reported. Together with its broad-based beta-lactam resistance, MRSA often possesses a multi-drug resistance genotype, including cephalosporins, aminoglycosides, fluoroquinolones, and macrolide resistances. MRSA has now emerged as the predominant nosocomial Gram-positive pathogen, and it has a high rate of morbidity and mortality. Action must be taken to contain and eradicate MRSA through a combination of infection control, the development of novel anti-MRSA agents, development of vaccines and other non-traditional approaches of intervention.

Type II fatty acid synthesis (FASII) is essential to bacterial cell viability and is a promising target for the development of novel antibiotics. In the past decade, a few inhibitors have been identified for this pathway, but none of them lend themselves to drug development. To find better inhibitors that are potential drug candidates, we developed a high throughput assay that identifies inhibitors simultaneously against multiple targets within the FASII pathway of most bacterial pathogens. We demonstrated that the inverse t(1/2) value of the FASII enzyme-catalyzed reaction gives a measure of FASII activity. The Km values of octanoyl-CoA and lauroyl-CoA were determined to be 1.1 +/- 0.3 and 10 +/- 2.7 microM in Staphylococcus aureus and Bacillus subtilis, respectively. The effects of free metals and reducing agents on enzyme activity showed an inhibition hierarchy of Zn2+ > Ca2+ > Mn2+ > Mg2+; no inhibition was found with beta-mercaptoethanol or dithiothreitol. We used this assay to screen the natural product libraries and isolated an inhibitor, bischloroanthrabenzoxocinone (BABX) with a new structure. BABX showed IC50 values of 11.4 and 35.3 microg/ml in the S. aureus and Escherichia coli FASII assays, respectively, and good antibacterial activities against S. aureus and permeable E. coli strains with minimum inhibitory concentrations ranging from 0.2 to 0.4 microg/ml. Furthermore, the effectiveness, selectivity, and the in vitro and in vivo correlations of BABX as well as other fatty acid inhibitors were elucidated, which will aid in future drug discovery.

In the late 1960s, the medical need for new antibiotics began to be questioned, and the pharmaceutical industry shifted its emphasis of antibacterials from that of a therapeutic leader to a low-priority research area. Although infectious diseases, in particular those caused by bacterial infections, are still among the top causes of mortality in the world, industrial support continues to wane. The shift from this important area of antimicrobial research has been attributed to a combination of science, medical, marketing and business reasons. This decline in antibacterial drug discovery, coupled with increasing risk as a result of infections caused by drug-resistant bacterial pathogens, represents a clear public health threat.

Methicillin-resistant Staphylococcus aureus (MRSA) is a serious nosocomial pathogen, and a related community-sourced MRSA is emerging. MRSA has evolved to become the major S. aureus phenotype in the hospital, emerging from just 30 to over 60% of the S. aureus population over the past 15 years. Together with its beta-lactam resistance, MRSA possesses multi-drug resistance genotype, including quinolones, macrolides and sulfonamides. MRSA has now emerged as the predominant nosocomial Gram-positive pathogen, and it has a high rate of mortality. Action must be taken to contain and eradicate MRSA through a combination of infection control and the development of novel anti-MRSA agents and vaccines.

Artifacts can seriously degrade the quality of computed tomographic (CT) images, sometimes to the point of making them diagnostically unusable. To optimize image quality, it is necessary to understand why artifacts occur and how they can be prevented or suppressed. CT artifacts originate from a range of sources. Physics-based artifacts result from the physical processes involved in the acquisition of CT data. Patient-based artifacts are caused by such factors as patient movement or the presence of metallic materials in or on the patient. Scanner-based artifacts result from imperfections in scanner function. Helical and multisection technique artifacts are produced by the image reconstruction process. Design features incorporated into modern CT scanners minimize some types of artifacts, and some can be partially corrected by the scanner software. However, in many instances, careful patient positioning and optimum selection of scanning parameters are the most important factors in avoiding CT artifacts., ((c) RSNA, 2004.)

Nocathiacins are cyclic thiazolyl peptides with inhibitory activity against gram-positive bacteria. BMS-249524 (nocathiacin I), identified from screening a library of compounds against a multiply antibiotic-resistant Enterococcus faecium strain, was used as a lead chemotype to obtain additional structurally related compounds. The MIC assay results of BMS-249524 and two more water-soluble derivatives, BMS-411886 and BMS-461996, revealed potent in vitro activities against a variety of gram-positive pathogens including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin intermediate-resistant S. aureus, vancomycin-resistant enterococci, Mycobacterium tuberculosis and Mycobacterium avium. Analysis of killing kinetics revealed that these compounds are bactericidal for S. aureus with at least a 3-log(10) reduction of bacterial growth within 6 h of exposure to four times the MICs. Nocathiacin-resistant mutants were characterized by DNA sequence analyses. The mutations mapped to the rplK gene encoding the L11 ribosomal protein in the 50S subunit in a region previously shown to be involved in the binding of related thiazolyl peptide antibiotics. These compounds demonstrated potential for further development as a new class of antibacterial agents with activity against key antibiotic-resistant gram-positive bacterial pathogens.

A series of potential antimicrobial derivatives possessing bioisosteric replacements for the central oxazolidinone ring found in oxazolidinone antibacterials have been prepared. The design concept involved replacement of the requisite sp(3)-hybridized stereogenic center found at the 5-position of the oxazolidinone with a nitrogen atom. The synthesis and antibacterial activity of three such ring systems, the benzisoxazolinones, pyrroles, and isoxazolinones is described.

The ever-increasing incidence of twin pregnancies world wide, together with the increasing trend to caesarean delivery, has resulted in intense scrutiny of the most appropriate method of twin delivery. The term twin has an increased risk of twin mortality compared to term singletons and this might be a result of the increase risk of labour and delivery compared to that of singletons. There are three ways to address this from the literature. The first is to compare outcome for the second twin versus the first twin, and to compare these outcomes in those twins delivered vaginally compared to those delivered by lower section caesarean section (LSCS). The second is to compare outcomes for twins delivered vaginally and for those delivered by caesarean section (CS). These data show higher rates of adverse perinatal outcome for the twin at or near term if delivery is vaginal versus CS. The third method is to compare outcomes for twins delivered by planned vaginal birth (VB; actual VB plus emergency CS) versus planned CS. This chapter will review this data thus outline an ongoing randomized controlled trial--the Twin Birth Study.