Continual reassessment method for dose escalation clinical trials in oncology: a comparison of prior skeleton approaches using AZD3514 data.

BACKGROUND: The continual reassessment method (CRM) requires an underlying model of the dose-toxicity relationship ("prior skeleton") and there is limited guidance of what this should be when little is known about this association. In this manuscript the impact of applying the CRM with different prior skeleton approaches and the 3 + 3 method are compared in terms of ability to determine the true maximum tolerated dose (MTD) and number of patients allocated to sub-optimal and toxic doses. METHODS: Post-hoc dose-escalation analyses on real-life clinical trial data on an early oncology compound (AZD3514), using the 3 + 3 method and CRM using six different prior skeleton approaches. RESULTS: All methods correctly identified the true MTD. The 3 + 3 method allocated six patients to both sub-optimal and toxic doses. All CRM approaches allocated four patients to sub-optimal doses. No patients were allocated to toxic doses from sigmoidal, two from conservative and five from other approaches. CONCLUSIONS: Prior skeletons for the CRM for phase 1 clinical trials are proposed in this manuscript and applied to a real clinical trial dataset. Highly accurate initial skeleton estimates may not be essential to determine the true MTD, and, as expected, all CRM methods out-performed the 3 + 3 method. There were differences in performance between skeletons. The choice of skeleton should depend on whether minimizing the number of patients allocated to suboptimal or toxic doses is more important. TRIAL REGISTRATION: NCT01162395 , Trial date of first registration: July 13, 2010.

Using a meta-ethnographic approach to explore the nature of facilitation and teaching approaches employed in interprofessional education.

BACKGROUND: Interprofessional facilitators and teachers are regarded as central to the effective delivery of interprofessional education (IPE). As the IPE literature continues to expand, most studies have focused on reporting learner outcomes, with little attention paid to IPE facilitation. However, a number of studies have recently emerged reporting on this phenomenon. AIM: To present a synthesis of qualitative evidence on the facilitation of IPE, using a meta-ethnographic approach. METHODS: Electronic databases and journals were searched for the past 10 years. Of the 2164 abstracts initially found, 94 full papers were reviewed and subsequently 12 papers were included. Teams of two reviewers independently completed each step in the review process. The quality of these papers was assessed using a modified critical appraisal checklist. RESULTS: Seven key concepts embedded in the included studies were synthesized into three main factors which provided an insight into the nature of IPE facilitation. Specifically, the synthesis found that IPE facilitation is influenced by "contextual characteristics"; "facilitator experiences"; and the "use of different facilitation strategies". CONCLUSIONS: IPE facilitation is a complex activity affected by contextual, experiential and pedagogical factors. Further research is needed to explore the effects of these factors on the delivery of IPE.

Hands-on or hands-poised: what does the evidence say?

A majority of women will experience some degree of perineal trauma during vaginal birth. The morbidity of women related to perineal trauma can reveal in perineal pain, urinary or faecal incontinence and dyspareunia. Midwives can adopt many techniques to protect the perineum from injury. However, there are still no clear guidelines regarding the hands-on and hands-poised approaches of perineal management during the second stage of labour. The current evidence remains contradictory, so which technique should midwives adopt?

'Hands on', 'hands off' or 'hands poised'? Exploring intrapartum midwifery decision making through ethnographic research.

ISSUE: Injury to the perineal tissues during childbirth is a frequent occurrence with most women likely to experience perineal injury during a first birth which, in some cases, can lead to significant long-term morbidity. The techniques used to minimise perineal injury are frequently termed 'hands on' and 'hands poised' or 'hands off'. These terms are often undefined and used inconsistently in the literature, making it difficult to identify the best available evidence to inform midwifery practice. AIM: This study aimed to answer the research questions: What do midwives do to minimise perineal injury during birth and what influences their decision-making? METHODS: An ethnographic study was undertaken during 2016 in a maternity unit in the southeast of England. Data were collected through participant-observation, ethnographic and semi-structured interviews and analysed using thematic analysis, informed by the pedagogic theory of threshold concepts. FINDINGS: 31 midwives participated in the study. Evidence-based decision-making to minimise perineal injury during birth was identified as a complex concept. Within the context of threshold concept theory, three main themes were identified that contributed to the complexity: troublesome language, troublesome knowledge, and troublesome environments. CONCLUSIONS: Midwifery decision-making in the context of minimising perineal injury during birth is more varied and conceptually complex than has been previously described. Identification of the various aspects of troublesomeness in this context suggests that this element of practice is a midwifery threshold concept. Addressing this within midwifery curricula and practice education to enable evidence-based decision-making is important.

Smoking in pregnancy, where are we now?

The harmful effects of smoking during pregnancy have been well documented within the literature (Eastham and Gosakan 2010; British Medical Association (BMA) 2004). However, although the number of women smoking during pregnancy has fallen over the last few years, this still remains a major health concern for both women and their families. This paper aims to explore recent media campaigns and social policies focusing on smoking in pregnancy and the general population. Midwives need to be aware of current policies with regard to smoking cessation to enable high quality evidence based information and support to be provided at an optimum time in women's lives.

Comparing Go/No-Go Decision-Making Properties Between Single Arm Phase II Trial Designs in Oncology.

INTRODUCTION: Simon's design has been widely used in oncology to conduct single arm phase II trials and to make Go/No-Go development decision. Other authors have proposed designs with decision-making frameworks that include a third, "Consider" outcome. For results in the Consider zone, a final Go/No-Go development decision must still be made; however it is typically a subjective decision based on the totality of data and the development landscape. Under this framework, the probability of continuing development when the candidate therapy is truly ineffective or the probability of stopping development when the candidate therapy is truly effective is undefined. METHODS: We use a motivating example to compare end of trial decision-making between Simon's two-stage approach and a Multilevel outcome approach. We present the minimum and maximum development decision error probabilities by varying whether candidates that end in the Consider zone would ultimately continue with development or not. RESULTS: The Multilevel approach typically requires fewer patients, but the risk of making an incorrect drug development decision is inflated above the statistically defined Type I and Type II error rates. Compared to a Type I error rate of 20%, the Multilevel trial's maximum probability of moving forward with an ineffective therapy is 22%, 27%, and 36% for Consider zone sizes of 10%, 20%, and 30%, respectively. CONCLUSION: The Multilevel approach provides flexibility in interpreting moderate efficacy results. However, the flexibility is accomplished with a lower sample size and corresponding uncertainty in the trial outcome that increases the risk of incorrect drug development decisions.

Perinatal/neonatal palliative care: Effecting improved knowledge and multi-professional practice of midwifery and children's nursing students through an inter-professional education initiative.

This paper presents a study that examines the potential value of a new and innovative inter-professional education (IPE) experience for final year midwifery and children's nursing students focused on improving awareness of end-of-life care for infants in conjunction with the support of their families. The study uses an action research approach to examine midwifery and children's nursing student experiences of an IPE initiative in developing knowledge regarding perinatal/neonatal palliative care. The setting is a Higher Education Institute in the South of England that included final year midwifery students (n = 39) and children's nursing students (n = 34) taking part in the study. Qualitative and quantitative data indicated that the IPE intervention had proven worth in developing knowledge and confidence in the students as both student groupings felt they lacked knowledge and confidence about perinatal/neonatal palliative care before attending the study day. Students felt that learning with, from and about the other profession represented was important in generating their knowledge. Educators should explore innovative ways to enable the further development of the fledgling speciality of perinatal/neonatal palliative care through education on an interprofessional platform.

Experiences of student midwives learning and working abroad in Europe: The value of an Erasmus undergraduate midwifery education programme.

BACKGROUND: universities in the United Kingdom are being challenged to modify policies and curricula that reflect the changing global reality through internationalisation. An aspect of internationalisation is study abroad which the European Commission Erasmus exchange programme is just one means of addressing this. OBJECTIVE: to explore the experiences of student midwives who are engaged in the Erasmus exchange programme and the effect it has on their learning and working in an international context. DESIGN: approval for the small phenomenological cohort study was obtained from two participating universities: the University of Malta and University of Nottingham. Data were collected from 13 student midwives from a total of five cohorts in the form of diaries to explore their experiences of learning and working in another country. Thematic analysis supported by Computer-Assisted Qualitative Data Analysis Software was used to identify five recurrent themes emerging from the data: the findings of which have served further in developing this programme. FINDINGS: students valued the opportunity of undertaking study and midwifery practice in another culture and healthcare system, extending their knowledge and development of clinical competence and confidence. For some, this was the first time outside of their home country and adaptation to a new environment took time. Support from their contemporaries, lecturers and midwife mentors however, was overwhelmingly positive, enabling the students to feel 'part of the local university / midwifery team' By the end of the programme, the students recognised that they had become more independent and felt empowered to facilitate developments in practice when they returned home. IMPLICATIONS FOR EDUCATION / PRACTICE: this innovative development embracing internationalisation within the curricula has the potential to increase students' employability and further study within Europe and beyond. It can be used as a vehicle to share best practice within an international context, ultimately making a difference to the quality of care childbearing women, their babies and families experience worldwide.

Neurokinin B Receptor Antagonism in Women With Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Trial.

CONTEXT: Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women, is characterized by high secretion levels of LH and T. Currently, there is no treatment licensed specifically for PCOS. OBJECTIVE: The objective of this study was to investigate whether a targeted therapy would decrease LH pulse frequency in women with PCOS, subsequently reducing serum LH and T concentrations and thereby presenting a novel therapeutic approach to the management of PCOS. DESIGN: This study is a double-blind, double-dummy, placebo-controlled, phase 2 trial. SETTINGS: University hospitals and private clinical research centers were included. PARTICIPANTS: Women with PCOS aged 18-45 years participated. INTERVENTION: Intervention included AZD4901 (a specific neurokinin-3 [NK3] receptor antagonist) at a dose of 20, 40, or 80 mg/day or matching placebo for 28 days. MAIN OUTCOME MEASURE: Change from baseline in the area under the LH serum concentration-time curve over 8 hours (area under the curve) on day 7 relative to placebo was measured. RESULTS: Of a total 67 randomized patients, 65 were evaluable. On day 7, the following baseline-adjusted changes relative to placebo were observed in patients receiving AZD4901 80 mg/day: 1) a reduction of 52.0% (95% confidence interval [CI], 29.6-67.3%) in LH area under the curve; 2) a reduction of 28.7% (95% CI, 13.9-40.9%) in total T concentration; and 3) a reduction of 3.55 LH pulses/8 hours (95% CI, 2.0-5.1) (all nominal P < .05). CONCLUSIONS: The NK3 receptor antagonist AZD4901 specifically reduced LH pulse frequency and subsequently serum LH and T concentrations, thus presenting NK3 receptor antagonism as a potential approach to treating the central neuroendocrine pathophysiology of PCOS.

Hands-poised technique: The future technique for perineal management of second stage of labour? A modified systematic literature review.

BACKGROUND: vaginal birth is often accompanied with perineal trauma that affects postpartum morbidity. There are many techniques for protecting the perineum from injury during childbirth. The Hands-On or Hands Poised (HOOP) study (McCandlish et al., 1998) was the first trial that compared different techniques of perineal protection during the second stage of labour with very little research subsequently being undertaken. OBJECTIVES: to systematically review all available literature that compares the hands-on and hands-poised techniques of perineal management during the second stage of labour. METHODS: using the principles of a modified systematic literature review, quantitative, comparative and primary research studies were selected. These were assessed for quality using the Critical Appraisal Skills Programme (CASP) framework including a data extraction form. The results were reported narratively. MAIN RESULTS: five studies were included and outlined the importance of both techniques. The hands-poised technique appeared to cause less perineal trauma and reduced rates of episiotomy. The hands-on technique resulted in increased perineal pain after birth and higher rates of postpartum haemorrhage. CONCLUSION: as the five studies selected for this review have widely differing variables, comparisons that have been drawn must be viewed with caution. Evidence would suggest that the hands-poised technique is a safe and recommended technique for perineal management and discussions of such a technique should be included in all midwifery education and training programmes. The challenge for midwives is how to support women in making informed choices about perineal management during childbirth. Until there is conclusive evidence, the choice of the hands-on or hands-poised technique will ultimately be determined by the clinical judgment of the individual midwife at the time of birth. Further research is recommended. Thorough conclusions could significantly impact on reducing postpartum morbidity and improving women's sexual health and well-being in the long term, throughout the world.

Developing midwifery practice through work-based learning: an exploratory study.

AIM: To explore what effect the introduction of a Work-Based Learning Module undertaken by midwives in a range of maternity settings has had on their personal professional development, as well as the impact on developing local maternity and neonatal care provision. METHODOLOGY: A case study approach was used consisting of mixed methods. Quantitative data were collected through questionnaires from midwives and their Clinical Supervisors at the end of the module, with a survey questionnaire to each midwifery manager, six months following the implementation of the midwives' project in practice. Qualitative data were collected by focus groups at six different work place locations, with health professionals who had experienced the midwives' projects within the workplace. Quantitative data were manually analysed whereas content analysis was used to identify recurrent themes from the qualitative data, with the support of Computer Assisted Qualitative Data Analysis Software. The University of Nottingham granted ethical approval for the study. PARTICIPANTS AND SETTING: Twelve midwives who undertook the work-based module, their respective Clinical Supervisors (n = 12), their employers/managers (n = 12) and health professionals (n = 28) within six individual National Health Service Trusts in the East Midlands of the United Kingdom took part in the study. FINDINGS: The work-based learning module not only led to the personal and professional development of the midwife, but also to improving multi-professional collaboration and the consequential development of maternity services within the local Trusts. The value of leading change by completing an innovative and tangible work-based project through a flexible mode of study strengthened the midwives' clinical credibility among colleagues and employers and supports the philosophy of inter-professional learning and working. IMPLICATIONS FOR PRACTICE: This novel Work Based approach to learning has the potential to further develop the provision of post-registration education for midwives and other health professionals, as it helps to bridge the theory-practice gap. Learning in the workplace is efficient and cost effective to employee and employer and serves in increasing the link between higher education and the workplace. Furthermore, as the principles of work-based learning could be transferred to other contexts outside of the United Kingdom, such an approach has the potential to directly influence the development of global midwifery education and maternity services and ultimately benefit mothers, their babies and families throughout the world.

The effect of the developing role of the maternity support worker on the professional accountability of the midwife.

The recent rise in the number of maternity support workers (MSWs) in the United Kingdom (UK) has been welcomed by midwifery managers and supported by social policy surrounding improvements in maternity care. The training and role of the MSW varies considerably. Whilst most training is undertaken through clinical practice, more recent advances in the preparation of MSWs have resulted in them not only being trained to National Vocational Qualification (NVQ) Level 3, but also to foundation certificate or degree level. Consequently some MSWs are performing tasks that would traditionally be undertaken by a midwife, potentially leading to the erosion of the midwife's role in the future. From current evidence, midwives are not fully aware of how the developing role of MSWs may affect their own professional accountability. This paper therefore aims to challenge midwives into reconsidering how MSWs may be effectively incorporated into the midwifery team such that the quality of care is not compromised and the midwife's professional accountability is never put at risk.

Comparison of accuracy and certainty of results of six home pregnancy tests available over-the-counter.

BACKGROUND: The aim of the study was to determine the accuracy of home pregnancy tests (HPTs) in detecting human chorionic gonadotrophin (hCG) in human female urine and consumer certainty in reading the results. The Clearblue Digital Pregnancy Test (CBDPT) was compared with five alternative over-the-counter (OTC) brands of HPT. METHODS: HPTs (CBDPT [SPD, Geneva, Switzerland], Answer [Church & Dwight, Princeton, NJ], Predictor [Omega Teknika, Dublin, Ireland], Clearblue (non-digital) [SPD], EPT [McNeill, Fort Washington, PA], First Response [Church & Dwight]) were tested by study co-ordinators on samples of pooled urine containing hCG at 0 IU/l (negative control) or 25 IU/l (positive standard, typical of level found in early pregnancy), in a coded, randomised scheme. Results and level of certainty about the results were interpreted by 120 female volunteers. RESULTS: The CBDPT detected hCG in the 25 IU/l positive urine with 100% accuracy when read by volunteers. Accuracy of four alternative HPTs ranged from 65.8 to 87.5%, but was only 8.3% with the fifth test, Predictor. CBDPT was statistically significantly better than any of the alternative brands. All volunteers (100%) rated the results with the CBDPT as 'very certain' or 'certain' (score 1 or 2), whereas a score of 1 or 2 was recorded by only 40.3-58.3% for the other brands, except Predictor which was scored with certainty by 87.5%, although volunteers interpreted the result for the positive standard as not pregnant. A certainty score of 1 or 2 was recorded by a significantly (p<0.001) greater proportion of volunteers with CBDPT than any of the other HPTs. CONCLUSIONS: The CBDPT was significantly better in terms of accuracy and certainty than non-digital OTC HPTs tested at a low hCG concentration. These results demonstrate that a digital reading offers significant benefits to the consumer over traditional non-digital tests.