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The exclusion of pregnant populations, women of reproductive age, and the fetus from clinical trials of therapeutics is a major global public health issue. It is also a problem of inequity in medicines development, as pregnancy is a protected characteristic. The current regulatory requirements for drugs in pregnancy are being analyzed by a number of agencies worldwide. There has been considerable investment in developing expertise in pregnancy clinical trials (for the pregnant person and the fetus) such as the Obstetric-Fetal Pharmacology Research Centers funded by the National Institute of Child Health and Human Development. Progress has also been made in how to define and grade clinical trial safety in pregnant women, the fetus, and neonate. Innovative methods to model human pregnancy physiology and pharmacology using computer simulations are also gaining interest. Novel ways to assess fetal well-being and placental function using magnetic resonance imaging, computerized cardiotocography, serum circulating fetoplacental proteins, and mRNA may permit better assessment of the safety and efficacy of interventions in the mother and fetus. The core outcomes in women’s and newborn health initiative is facilitating the consistent reporting of data from pregnancy trials. Electronic medical records integrated with pharmacy services should improve the strength of pharmacoepidemiologic and pharmacovigilance studies. Incentives such as investigational plans and orphan disease designation have been taken up for obstetric, fetal, and neonatal diseases. This review describes the progress that is being made to better understand the extent of the problem and to develop applicable solutions.

This paper makes a case for placing knowledge at the centre of the school mathematics curriculum, and for knowledge building and knowledge differentiation as critical for both equity and excellence, emphasising that knowledge is much more than a set of descriptions of content as might typically be found in a curriculum document or textbook. The paper commences by discussing the implications of the traditional epistemological view of knowledge as justified true belief for mathematics education and uses this to build a preliminary description of knowledge building. Ideas from critical realism are then used to show that it is not so much the content of knowledge that matters but the production of knowledge and to build an enhanced conception of knowledge building in school mathematics. A distinction is made between knowledge and knowing that provides a non-relativist yet fallible view of knowledge, recognising its emergent but directed nature through its production and legitimation within established fields. The importance of knowledge building as a democratic right is then discussed, highlighting the importance of specialised knowledge and arguing that knowledge differentiation provides a basis for a conception of school mathematics curriculum that is dynamic and empowering. The paper concludes by discussing a range of potential theoretical and empirical research projects arising from a focus on knowledge and knowledge building in school mathematics.

OBJECTIVE: Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive framework to define and grade maternal and fetal AEs in pregnancy trials severely limits understanding risks in pregnant women. We created AE terminology to improve safety monitoring for developing pregnancy drugs, devices and interventions. METHOD: Existing severity grading for pregnant AEs and definitions/indicators of 'severe' and 'life-threatening' conditions relevant to maternal and fetal clinical trials were identified through a literature search. An international multidisciplinary group identified and filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on Common Terminology Criteria for Adverse Event (CTCAE) generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives. RESULTS: Fetal AEs were defined as being diagnosable in utero with potential to harm the fetus, and were integrated into MedDRA. AE severity was graded independently for the pregnant woman and her fetus. Maternal (n = 12) and fetal (n = 19) AE definitions and severity grading criteria were developed and ratified by consensus. CONCLUSIONS: This Maternal and Fetal AE Terminology version 1.0 allows systematic consistent AE assessment in pregnancy trials to improve safety. ispartof: PRENATAL DIAGNOSIS vol:42 issue:1 pages:15-26 ispartof: location:England status: published

Retosiban, an oxytocin receptor antagonist, was developed for treating spontaneous preterm labor (sPTL) in women with intact membranes. This ARIOS follow-up study aimed to characterize clinical safety, morbidity, and mortality of infants exposed to retosiban or comparator over 2 years. ARIOS prospectively assessed outcomes in infants whose mothers received at least one dose of retosiban or comparator (placebo/atosiban) in two Phase 3 sPTL trials. Both trials were terminated prematurely owing to poor enrolment. Infants could be enrolled into ARIOS from 28 days after estimated due date until hospital discharge or up to 9 months (corrected age). An internally developed questionnaire detailing medical conditions, mortality and resource use (Child Health Inventory; CHI), Ages and Stages Questionnaire-3 (ASQ-3), Modified Checklist for Autism in Toddlers-Revised with Follow-Up, and Child Behavior Checklist for Ages 1.5 to 5 were completed remotely by parents or legal guardians at prespecified intervals. Serious adverse events (SAEs) were primarily captured via CHI. No comparative statistical analysis was conducted between treatment arms. A total of 49 (86%) infants who had received retosiban and 49 (78%) infants who had received a comparator were enrolled in ARIOS. No deaths occurred during the study. Nine infants experienced SAEs: 6/49 (12.2%) infants in the comparators group and 3/49 (6.1%) in the retosiban group. Of the nine SAEs, seven were due to infections, three, and four in the retosiban and comparators groups, respectively. Based on ASQ-3 score, the incidence of neurodevelopmental delay at 18 and 24 months were 0/18 (0%) and 2/25 (8%) with retosiban and 7/22 (31.8%) and 3/21 (14.3%) with comparator, respectively. The current study showed no unexpected adverse outcome or impairment with retosiban based on safety monitoring and neurodevelopment assessments. No further follow-up is intended owing to the discontinuation of clinical development of retosiban.· There is a need for an effective and safe treatment for sPTL.. · ARIOS was a follow-up study of two Phase 3 trials in sPTL.. · There were no safety concerns with retosiban treatment.. · Slow recruitment led to termination of the Phase 3 trials..

Background The traditional method of risk assessment for pre-eclampsia recommended by the National Institute for Health and Care Excellence is based on maternal factors and it recommends that high-risk women should be treated with aspirin. An alternative method of screening is based on the competing risk model, which uses Bayes’ theorem to combine maternal factors with mean arterial pressure, the uterine artery pulsatility index, serum placental growth factor and pregnancy-associated plasma protein-A at 11–13 weeks’ gestation. Objective The primary aim was to compare the performance of screening by risks obtained using the competing risk model with risk assessment using the National Institute for Health and Care Excellence guidelines. Design This was a prospective multicentre observational study. Setting The setting was seven NHS maternity hospitals in England. Participants Participants were women with singleton pregnancy attending for a routine hospital visit at 11+0–13+6 weeks’ gestation between April and December 2016. Main outcome measures The performance of screening for pre-eclampsia by the competing risk model was compared with the National Institute for Health and Care Excellence method. Relative reductions in risk with aspirin prophylaxis of 30% and 60% were assumed for all pre-eclampsia and preterm pre-eclampsia, respectively. The primary comparison was the detection rate of the National Institute for Health and Care Excellence method with the detection rate of a mini-combined test (including maternal factors, mean arterial pressure and pregnancy-associated plasma protein-A) in the prediction of all pre-eclampsia for the same screen-positive rate determined by the National Institute for Health and Care Excellence method. Results In 473 (2.8%) of the 16,747 pregnancies there was development of pre-eclampsia, including 142 (0.8%) women with preterm pre-eclampsia. The screen-positive rate by the National Institute for Health and Care Excellence method was 10.3%. For all pre-eclampsia, the false-positive and detection rates by the National Institute for Health and Care Excellence method were 9.7% and 31.6%, respectively. For preterm pre-eclampsia, the false-positive and detection rates were 10.0% and 42.8%, respectively. Compliance with the National Institute for Health and Care Excellence recommendation that high-risk women should be treated with aspirin from the first trimester was 23%. For the same screen-positive rate, the detection rate of the mini-combined test for all pre-eclampsia was 42.8%, which was superior to that of the National Institute for Health and Care Excellence method by 11.2% (95% confidence interval 6.9% to 15.6%). The increase in detection for the same screen-positive rate was accompanied by a reduction in false-positive rate of 0.3%. For the same screen-positive rate as National Institute for Health and Care Excellence, the detection rate for preterm pre-eclampsia by combining maternal factors, mean arterial pressure and placental growth factor was 67.3% compared with 44.1% with the National Institute for Health and Care Excellence method. With the addition of the uterine artery pulsatility index, the detection rate was 78.6%. This was higher than that of the National Institute for Health and Care Excellence method by 35.5% (95% confidence interval 25.2% to 45.8%). Calibration of risks for pre-eclampsia was generally good, with the calibration slope very close to 1.0. The feasibility of incorporating a new biomarker was demonstrated. However, the addition of inhibin A to the full combined test did not improve the detection rates for all pre-eclampsia and preterm pre-eclampsia (61% and 80%, respectively). The same screening model for preterm pre-eclampsia by a combination of maternal factors, mean arterial pressure, the uterine artery pulsatility index and placental growth factor achieved detection rates of 45.8% and 56.3%, respectively, for preterm small for gestational age and early small for gestational age neonates. Limitation The study did not include a health economic assessment. Conclusion The findings suggest that performance of screening for pre-eclampsia provided by a combination of maternal factors and biomarkers is superior to that achieved by current National Institute for Health and Care Excellence guidelines. Future work Future work is required to identify potential biomarkers for further improvement of the competing risk model and to carry out a health economic assessment. Trial registration Current Controlled Trials ISRCTN83611527. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 8. See the NIHR Journals Library website for further project information.

Threshold concepts are those which are characteristic of the discipline, and without which students are able to make only limited progress in developing disciplinary ways of thinking. They are characterised by being: transformative, in that once understood, they result in a significant shift in the perception of a subject; irreversible, in that the change of perspective is unlikely to be forgotten; integrative; in that they expose the previously hidden relatedness of ideas; bounded, in that they open up new conceptual spaces, and; potentially troublesome, in that they are hard to acquire. This chapter examines curriculum resources from the Primary Connections and reSolve: Maths by Inquiry projects and proposes some threshold concepts in primary mathematics and science. The identification of threshold concepts is important for the research community, for educational designers and for teachers as explicit attention to the concepts may help to address the misconceptions that often lie at the heart of the troublesomeness of concepts encountered in higher education.

BackgroundThere is an inherent tension in neonatal services between the efficiency and specialised care that comes with centralisation and the provision of local services with associated ease of access and community benefits. This study builds on previous work in South West England to address these issues at a national scale.Objectives(1) To develop an analytical framework to address key issues of neonatal service configuration in England, (2) to investigate visualisation tools to facilitate the communication of findings to stakeholder groups and (3) to assess parental preferences in relation to service configuration alternatives.Main outcome measuresThe ability to meet nurse staffing guidelines, volumes of units, costs, mortality, number and distance of transfers, travel distances and travel times for parents.DesignDescriptive statistics, location analysis, mathematical modelling, discrete event simulation and economic analysis were used. Qualitative methods were used to interview policy-makers and parents. A parent advisory group supported the study.SettingNHS neonatal services across England.DataNeonatal care data were sourced from the National Neonatal Research Database. Information on neonatal units was drawn from the National Neonatal Audit Programme. Geographic and demographic data were sourced from the Office for National Statistics. Travel time data were retrieved via a geographic information system. Birth data were sourced from Hospital Episode Statistics. Parental cost data were collected via a survey.ResultsLocation analysis shows that to achieve 100% of births in units with ≥ 6000 births per year, the number of birth centres would need to be reduced from 161 to approximately 72, with more parents travelling > 30 minutes. The maximum number of neonatal intensive care units (NICUs) needed to achieve 100% of very low-birthweight infants attending high-volume units is 36 with existing NICUs, or 48 if NICUs are located wherever there is currently a neonatal unit of any level. Simulation modelling further demonstrated the workforce implications of different configurations. Mortality modelling shows that the birth of very preterm infants in high-volume hospitals reduces mortality (a conservative estimate of a 1.2-percentage-point lower risk) relative to these births in other hospitals. It is currently not possible to estimate the impact of mortality for infants transferred into NICUs. Cost modelling shows that the mean length of stay following a birth in a high-volume hospital is 9 days longer and the mean cost is £5715 more than for a birth in another neonatal unit. In addition, the incremental cost per neonatal life saved is £460,887, which is comparable to other similar life-saving interventions. The analysis of parent costs identified unpaid leave entitlement, food, travel, accommodation, baby care and parking as key factors. The qualitative study suggested that central concerns were the health of the baby and mother, communication by medical teams and support for families.LimitationsThe following factors could not be modelled because of a paucity of data – morbidity outcomes, the impact of transfers and the maternity/neonatal service interface.ConclusionsAn evidence-based framework was developed to inform the configuration of neonatal services and model system performance from the perspectives of both service providers and parents.Future workTo extend the modelling to encompass the interface between maternity and neonatal services.FundingThe National Institute for Health Research Health Services and Delivery Research programme.

Background Educating doctors is expensive and poor performance by future graduates can literally cost lives. Whilst the practice of medicine is highly evidence based, medical education is much less so. Research on medical school selection, undergraduate progression, Fitness to Practise (FtP) and postgraduate careers has been hampered across the globe by the challenges of uniting the data required. This paper describes the creation, structure and access arrangements for the first UK-wide attempt to do so. Overview A collaborative approach has created a research database commencing with all entrants to UK medical schools in 2007 and 2008 (UKMED Phase 1). Here the content is outlined, governance arrangements considered, system access explained, and the potential implications of this new resource discussed. The data currently include achievements prior to medical school entry, admissions tests, graduation point information and also all subsequent data collected by the General Medical Council, including FtP, career progression, annual National Training Survey (NTS) responses, career choice and postgraduate exam performance data. UKMED has grown since the pilot phase with additional datasets; all subsequent years of students/trainees and stronger governance processes. The inclusion of future cohorts and additional information such as admissions scores or bespoke surveys or assessments is now being piloted. Thus, for instance, new scrutiny can be applied to selection techniques and the effectiveness of educational interventions. Data are available free of charge for approved studies from suitable research groups worldwide. Conclusion It is anticipated that UKMED will continue on a rolling basis. This has the potential to radically change the volume and types of research that can be envisaged and, therefore, to improve standards, facilitate workforce planning and support the regulation of medical education and training. This paper aspires to encourage proposals to utilise this exciting resource.

The design and implementation of Data-Driven Fuzzy Models (DDFMs) to learn balanced industrial/manufacturing data has demonstrated to be a popular machine learning methodology. However, DDFMs have also proven to perform poorly when it comes to learn from heavily imbalanced data, particularly in manufacturing systems. In order to tackle real-world imbalanced problems, we propose a DDFM for rail manufacturing classification. This framework includes Feature Selection, iterative information granulation, and a Fuzzy Decision Engine (FDE) that is based on an Interval Type-2 Radial Basis Function Neural Network (IT2-RBF-NN). The proposed modelling framework is then tested against a real manufacturing case study provided by TATA Steel, UK. Simulation results showed the proposed framework outperformed the generalisation properties of various well known methodologies including a DDFM that employs the RBF-NN of type-1.

This concluding chapter draws on the work of previous chapters to draw out three dimensions of connection. The first dimension is the connection between mathematical ideas that is characteristic of deep understanding and the distinctive epistemological basis of the discipline of mathematics. The second is the connection between mathematics and culture, in which the joy and delight of playing with and discovering mathematical ideas permeate learning. The third is the deep connection between mathematics and the world, in which mathematics both arises from a consideration of real-world problems and models those problems. Such connections take time and are often undervalued in an era of accountability and easily measured standards. The chapter challenges three dominant metaphors of education—those of education as factory, clinic, or race—and proposes a metaphor of slow maths, borrowing from the slow food movement in which connections to people, to culture, to history, to knowledge, to learning, to the world, and to self, are paramount.

Background Concerns have been raised that a lack of senior obstetricians (“consultants”) on the labour ward outside normal hours may lead to worse outcomes among babies born during periods of reduced cover. Methods and Findings We carried out a multicentre cohort study using data from 19 obstetric units in the United Kingdom between 1 April 2012 and 31 March 2013 to examine whether rates of obstetric intervention and outcome change “out-of-hours,” i.e., when consultants are not providing dedicated, on-site labour ward cover. At the 19 hospitals, obstetric rotas ranged from 51 to 106 h of on-site labour ward cover per week. There were 87,501 singleton live births during the year, and 55.8% occurred out-of-hours. Women who delivered out-of-hours had slightly lower rates of intrapartum caesarean section (CS) (12.7% versus 13.4%, adjusted odds ratio [OR] 0.94; 95% confidence interval [CI] 0.90 to 0.98) and instrumental delivery (15.6% versus 17.0%, adj. OR 0.92; 95% CI 0.89 to 0.96) than women who delivered at times of on-site labour ward cover. There was some evidence that the severe perineal tear rate was reduced in out-of-hours vaginal deliveries (3.3% versus 3.6%, adj. OR 0.92; 95% CI 0.85 to 1.00). There was no evidence of a statistically significant difference between out-of-hours and “in-hours” deliveries in the rate of babies with a low Apgar score at 5 min (1.33% versus 1.25%, adjusted OR 1.07; 95% CI 0.95 to 1.21) or low cord pH (0.94% versus 0.82%; adjusted OR 1.12; 95% CI 0.96 to 1.31). Key study limitations include the potential for bias by indication, the reliance upon an organisational measure of consultant presence, and a non-random sample of maternity units. Conclusions There was no difference in the rate of maternal and neonatal morbidity according to the presence of consultants on the labour ward, with the possible exception of a reduced rate of severe perineal tears in out-of-hours vaginal deliveries. Fewer women had operative deliveries out-of-hours. Taken together, the available evidence provides some reassurance that the current organisation of maternity care in the UK allows for good planning and risk management. However there is a need for more robust evidence on the quality of care afforded by different models of labour ward staffing., In a multicenter cohort study, Hannah Knight and colleagues assess differences in birth-related outcomes associated with the presence of senior obstetricians on the labor ward., Editors' Summary Background In an ideal world, expert medical care would be available for anyone who needs it 24 hours a day, 7 days a week. But in the real world, a lower level of medical cover is often available in the evening and at weekends, a situation that potentially puts lives at risk. In the United Kingdom, for example, the National Health Service (NHS) does not currently provide consultant-level care or full laboratory and imaging services in the evenings and at weekends (in the UK, a consultant is a senior, hospital-based doctor who provides care in a medical or surgical specialty). Consequently, patients admitted out of normal hours have to wait to see a consultant and to have tests and scans done. Citing studies that suggest that people admitted to hospital at the weekend are more likely to die than those admitted on weekdays, the UK government recently made a pledge to improve access to consultants and other NHS services during evenings and weekends. Why Was This Study Done? Maternity care is a specialty in which a 24-hour hospital service is clearly required. Women can go into labor at any time of the day, and intrapartum emergencies (emergencies that arise during labor) can develop rapidly and without warning in previously uncomplicated pregnancies. Concerns have been raised that a lack of senior obstetricians (consultants who look after women during pregnancy, childbirth, and the postpartum period immediately after childbirth) on labor wards outside normal working hours may lead to worse outcomes among babies born during periods of reduced cover. However, few studies have examined the extent to which variation in consultant presence on labor wards affects maternal and neonatal (newborn) outcomes. In this multicenter cohort study, the researchers use data from UK obstetric units to evaluate the relationship between the presence of obstetric consultants on labor wards and the rates of obstetric interventions (surgical delivery by cesarean section and “instrumental” delivery using forceps or a vacuum) and of several maternal and neonatal outcomes. What Did the Researchers Do and Find? For their study, the researchers used electronic patient data collected over a 12-month period by 19 obstetric units and administrative data on obstetric rotas at the participating hospitals, which were mainly teaching hospitals. On-site labor ward cover by consultants ranged from 51 to 106 hours per week at the participating hospitals, where there were 87,501 singleton live births over the study period, 55.8% of which occurred “out-of-hours.” Women who delivered out-of-hours had slightly lower rates of intrapartum cesarean section (operations initiated after labor had started; 12.7% versus 13.4%) and of instrumental delivery (15.6% versus 17.0%) than women who delivered when there was on-site labor ward cover (“in-hours”). Moreover, whereas 3.6% of women who had an in-hours vaginal delivery had a severe perineal tear (damage to the soft tissue between the vagina and the anus), only 3.3% of women who delivered out-of-hours had a tear. Finally, there was no difference between out-of-hours and in-hours deliveries in the rate of babies with a low Apgar score 5 minutes after birth (a measure of newborn health) or a low cord pH (a measure of oxygen deprivation during birth) or in the rate of mothers with severe postpartum bleeding. What Do These Findings Mean? These findings show no association between maternal and neonatal outcomes and the presence of consultants on the labor ward, with the exception of weak evidence for a reduced likelihood of severe perineal tears following out-of-hours delivery. However, women who deliver out-of-hours may be less likely to have an obstetric intervention than women who deliver in-hours, possibly because obstetric teams will usually try to undertake operative deliveries during in-hours shifts. The accuracy of these findings may be limited by the use of administrative records to determine when consultants were present on labor wards and by the potential for “bias by indication.” That is, obstetric teams may have tried to ensure that women with a greater risk of a poor outcome delivered in-hours rather than out-of-hours. Nevertheless, these findings suggest that the current organization of maternity care in the UK allows for good planning and risk management. Thus, although further robust evidence on the quality of care delivered at all times of the week by UK maternity units is needed, politically driven efforts to increase senior obstetrician attendance “out-of-hours” may not lead to improved clinical outcomes for women and babies. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1002000. This study is further discussed in a PLOS Medicine Perspective by Jenny Myers and Edward Johnstone Information from the UK Department of Health on research into the weekend effect on hospital mortality and the UK government's plans to provide NHS 7-day services by 2020 is available; a news article from the BBC discusses an ongoing controversy about how the UK government has used a recent research study to back its case for more 7-day NHS care The UK National Health Service website provides information on current out-of-hours NHS services, labor and childbirth (including a video about giving birth in hospital), cesarean section, assisted delivery (including a video), and perineal tears The UK Royal College of Obstetricians and Gynaecologists provides patient information leaflets on all aspects of pregnancy and childbirth MedlinePlus provides links to sources of other information on childbirth

This chapter examines the philosophical underpinnings of Australasian mathematics education research between 2012 and 2015. It takes a hermeneutic approach, seeking to uncover often hidden assumptions about ontology, epistemology , aesthetics, ethics and logic. The first part of the chapter explains the approach taken and outlines the set of papers considered. The chapter then examines the set of keywords used in Australasian mathematics education research papers published in major international journals, seeking to identify broad themes or omissions. It then takes a more detailed look at a purposive selection of 26 papers, chosen to reflect the themes in this Review. Finally it examines papers that explicitly discuss epistemology to identify researchers’ underlying assumptions about the nature of knowledge and its acquisition. The chapter points to some important tensions within the research and suggests that such tensions can be used as a creative force to enable mathematics education researchers to better identify and question the philosophical assumptions that underpin their research.

Uterine activation is associated with increased oxytocin receptor (OXTR) expression and myometrial sensitivity to oxytocin. The OXTR promoter contains binding sites for CCAAT/enhancer-binding protein (CEBP) and nuclear factor-kappa B p65 (RELA). RELA and CEBP beta (CEBPB) play a synergistic role in OXTR promoter activation. We created deletions in a DNA construct consisting of 850 bp upstream of the transcription start site linked to luc reporter to identify the CIS element of the OXTR promoter responsible for the synergistic activation by RELA and CEBPB. Deletion from -712 to -692 bp eliminated synergy, demonstrating that the critical region lies within these 20 bp. Binding studies showed that this sequence binds both RELA and CEBPB. The 20-bp critical region for synergistic activation of OXTR requires full-length RELA but only the basic leucine zipper domain of CEBPB.

When I qualified as a Librarian, all those librarians who didn’t work in National, Public or Academic libraries were “Special”. Nowadays the trend is to call them Workplace librarians, but even so I still think that we really were “Special”. During the third of a century that I worked as a librarian within the Ministry of Defence’s research organisation I often had the opportunity to work as the information gathering component of research project teams (which was a lot more fun than run-of-the-mill library work). Indeed, I consider my development of this role into that of today’s Knowledge Agent as my main contribution to the profession. However, in addition to this I had several opportunities to carry out original research projects on top of this normal work – workplace research.

Since the controversies regarding the use of non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclo-oxygenase (COX)-2 antagonists for the treatment of preterm labour (PTL), more emphasis has been placed on investigating the terminal synthases involved in the production of prostaglandins (PGs) to allow more targeted therapy in PTL. Prostaglandin E(2) (PGE(2)) is synthesized by one of three enzymes, cytosolic prostaglandin E synthase (cPGES), microsomal PGES-1 (mPGES-1) and microsomal PGES-2 (mPGES-2). We have determined (i) the immuno-localization of all three PGES enzymes in lower segment pregnant human myometrium, (ii) the expression of PGES and COX-2 mRNA expression at term and preterm gestation with and without labour and (iii) the effect of interleukin (IL)-1beta on COX-2 and PGES mRNA and protein expression in human myometrial smooth muscle (HMSM) cell cultures. We show mPGES-1 protein located predominantly in myometrial and vascular smooth muscle cells (SMCs), whilst mPGES-2 protein is largely in stromal cells surrounding the SMC and cPGES is diffusely located throughout the myometrium. Expression of mPGES-2 mRNA increased with term labour and PTL and expression of COX-2 and mPGES-1 mRNA with term labour, whereas cPGES expression did not change. IL-1beta stimulated release of PGE(2) by HMSM cells and increased COX-2 and mPGES-1 mRNA and protein expression. Thus, COX-2 expression and mPGES-1 expression are co-ordinately up-regulated in lower segment myometrium with term labour and with IL-1beta treatment in HMSM cells.

PurposeThe paper aims to describe the development of a practical approach to the provision of knowledge facilitation in a major research organisation.Design/methodology/approachThe paper examines the UK's Defence Science and Technology Laboratory and its Knowledge Services Department's approach to knowledge facilitation.FindingsThe ready availability of information/subject experts in the organisation encourages effective information gathering and use, together with the informal creation of knowledge networks running in parallel with the formal ones within the organisation.Practical implicationsDefines pragmatic and effective services, philosophy and tools introduced to improve the effective use and reuse of information and corporate knowledge. In addition there is a steady move from the provision of standard services to an information consultancy environment.Originality/valueRedefines the role of library and information services to meet twenty‐first century needs.

PurposeFollowing the partial privatisation of Dstl's parent organisation, a major change in the structure and philosophy of the LIS has been carried through and, although many of its services appear unchanged to its clients, a great deal of resources have been invested to change the content, delivery and technology behind them. This paper aims to describe the use of an impact survey to identify the effect of these changes from the clients' viewpoint.Design/methodology/approachThe author's IMPACT survey, which produces baseline figures for the impact of library and information services (LIS) offerings to a research organisation, has been reported on earlier. It surveys the authors of the research papers generated by the organisation to identify the impact that identified services had on their ability to produce the final intellectual product.FindingsThe results demonstrate to the organisation and its management that the investment strategy has produced a step‐change in service delivery.Originality/valueThe IMPACT survey, though limited to those organisations where a tangible intellectual product is the main output, provides a demonstrable valuation of offered services.

PurposeAims to provide a quantifiable metric for a library management activity.Design/methodology/approachA light‐hearted view of a serious and commonly undertaken library management activity. For the last nine years the author has been trying to identify effective and easily quantifiable metrics for customer satisfaction for special libraries.FindingsThis has proved far more difficult than the author had hoped, as customers always seemed perfectly satisfied, and even when they were not, they usually blamed themselves. Following the creation of the Defence Science and Technology Laboratory (Dstl) after the partial privatisation of the UK's Defence Evaluation and Research Agency, the drive for more accurate satisfaction measurement became more urgent, and became a personal performance target on the author's annual review.Originality/valueA light hearted view of a topic of concern for all library professionals.

Prematurity is a major cause of perinatal death and childhood disability. The risks are increased at early gestational ages so that a delay in delivery by preventing preterm labour or inhibiting uterine contractions can improve outcome for the newborn. Here, we review the mechanism of action and clinical evidence for the renewed enthusiasm for prevention of preterm delivery in high-risk women by administration of progesterone. At present, there is also controversy regarding the optimal management of threatened preterm labour, so we outline the rationale for treatment and clinical evidence for administration of an oxytocin antagonist in acute situations.

Oxytocin receptor (OTR) expression is increased before the onset of labor in all models of parturition. However, the mechanisms responsible for the increase in OTR expression are uncertain. Animal data suggest that uterine stretch increases OTR mRNA expression. In primary cultures of human uterine smooth muscle cells obtained from nonpregnant (NP) women and pregnant women before (NL) and after (L) the onset of labor, we investigated the effect of stretch on the expression of OTR mRNA and DNA binding of activator protein-1 (AP-1), CCAAT/enhancer binding protein (C/EBP)β, and nuclear factor-κB transcription factors. OTR expression was least in NL, intermediate in NP, and greatest in L cells. Stretch of NL cells resulted in up-regulation of OTR mRNA expression associated with increased OTR gene promoter activity. Stretch of NP and L cells did not affect OTR mRNA expression. The increased promoter activity was associated with increased DNA binding of C/EBP and AP-1 but not nuclear factor-κB transcription factors. Overexpression of C/EBP, but not AP-1, increased OTR promoter activity. We conclude that stretch of NL cells results in increased OTR mRNA expression probably through increased C/EBPβ DNA binding. These data suggest that stretch contributes to the massive increase in OTR expression before the onset of human labor.

Proteomics is a new field of research. It has developed rapidly in the last five years and is turning more and more into a mature science with relevance to the clinic. The recent elucidation of the human genome sequence has provided a wealth of useful information but does not provide information on diseases caused by changes at the protein level. Proteomics includes the characterisation and functional analysis of all proteins that are expressed by the genome at a certain moment, under certain conditions. Since expression levels of many proteins strongly depend on complex, but well-balanced regulatory systems, the proteome, unlike the genome, is highly dynamic. This variation depends on the biological function of a cell, but also on signals from its environment. In (bio)medical research it has become increasingly apparent that cellular processes, in particular in disease, are determined by multiple proteins. Hence it is important not to focus on one single gene product (one protein), but to study the complete set of gene products (the proteome). In this way the multi-factorial relations underlying certain diseases may be unravelled potentially identifying therapeutical targets. For many diseases characterisation of the functional proteome is crucial for elucidating alterations in protein expression and modifications. When proteins undergo non-genetically determined alterations such as alternative splicing, or post-translational modifications, e.g. phosphorylation or glycosylation, it may effect their function. Although abnormalities in splicing or post-translational modifications can cause a disease process, they can also be a consequence. An example is that patients with diabetes have a high blood glucose which glycosylates hundreds or even thousands of proteins, including HbA1c which is used to monitor diabetic control.

(2002). Secondary postpartum haemorrhage. Journal of Obstetrics and Gynaecology: Vol. 22, No. 2, pp. 119-122.

Editor – There are some significant misconceptions in the letter on UKMED by Best et al .1 UKMED is a partnership between data providers from across the health and education sectors to evaluate medical career progression. This will help to raise education standards by enabling us to assess the

Preterm delivery is the primary cause of neonatal mortality and morbidity worldwide. Labour at term occurs as a culmination of maturational events in both the fetus and maternal uterus. This process exhibits diurnal variation, with the onset of labour being more common at night. We have confirmed that this diurnal variation is present in gestations between 28 and 36 weeks, but is absent below 28 weeks. We hypothesise that this is because before 28 weeks of gestation, the onset of labour may result from a pathological rather than a physiological process. This may have important implications regarding any pharmacological approach to the prevention and/or treatment of very early preterm labour.

This paper has been updated from the article ‘The use of an impact survey as a measure of special library performance’, which appeared in the ‘Proceedings of the 3rd Northumbria International Conference on Performance Measurement in Libraries and Information Services 1999’. It describes an electronic survey of authors at a major research agency, and presents an analysis of their assessments of the impact a special library‘s services has on their ability to carry out and report on scientific research.

Uterine activation is associated with increased oxytocin receptor (OXTR) expression and myometrial sensitivity to oxytocin. The OXTR promoter contains binding sites for CCAAT/enhancer-binding protein (CEBP) and nuclear factor-kappa B p65 (RELA). RELA and CEBP beta (CEBPB) play a synergistic role in OXTR promoter activation. We created deletions in a DNA construct consisting of 850 bp upstream of the transcription start site linked to luc reporter to identify the CIS element of the OXTR promoter responsible for the synergistic activation by RELA and CEBPB. Deletion from -712 to -692 bp eliminated synergy, demonstrating that the critical region lies within these 20 bp. Binding studies showed that this sequence binds both RELA and CEBPB. The 20-bp critical region for synergistic activation of OXTR requires full-length RELA but only the basic leucine zipper domain of CEBPB.

This paper describes the creation, and philosophy of, a Department whose structure and functions were all aimed at supporting knowledge creation by both individuals and project teams for the UK’s Ministry of Defence. Underlying these services was a deep understanding gathered over 30 years of how research scientists learn, and how we need to aid that learning process. This process is demonstrated graphically by a development of Max Boisot’s “Social Learning Cycle”.

It is not known whether human labour is associated with increased fetal oxytocin production or transfer of oxytocin across the placenta. Previous reports are contradictory, due in part, to the influence of maternal analgesia on fetal production. We determined plasma oxytocin concentration in the umbilical artery and vein of women after vaginal delivery and after caesarean section with general anaesthesia before or after the onset of labour. The results demonstrate that fetal production of oxytocin is not influenced by general anaesthesia, thus enabling comparison of labour and nonlabour samples at caesarean section. Labour was not associated with an increase in fetal oxytocin production. Oxytocin was also measured in the umbilical artery and vein during maternal oxytocin infusion to assess placental transfer. The results do not support transfer of oxytocin across the placenta in women.