Estimating and comparing the reliability of a suite of workplace-based assessments: an obstetrics and gynaecology setting.

This paper reports on a study that compares estimates of the reliability of a suite of workplace based assessment forms as employed to formatively assess the progress of trainee obstetricians and gynaecologists. The use of such forms of assessment is growing nationally and internationally in many specialties, but there is little research evidence on comparisons by procedure/competency and form-type across an entire specialty. Generalisability theory combined with a multilevel modelling approach is used to estimate variance components, G-coefficients and standard errors of measurement across 13 procedures and three form-types (mini-CEX, OSATS and CbD). The main finding is that there are wide variations in the estimates of reliability across the forms, and that therefore the guidance on assessment within the specialty does not always allow for enough forms per trainee to ensure that the levels of reliability of the process is adequate. There is, however, little evidence that reliability varies systematically by form-type. Methodologically, the problems of accurately estimating reliability in these contexts through the calculation of variance components and, crucially, their associated standard errors are considered. The importance of the use of appropriate methods in such calculations is emphasised, and the unavoidable limitations of research in naturalistic settings are discussed.

Progestogens with or without oestrogen for irregular uterine bleeding associated with anovulation.

BACKGROUND: Irregular menstrual bleeding may arise due to exogenous sex steroids, lesions of the genital tract or be associated with anovulation. Irregular bleeding due to oligo/anovulation (previously called dysfunctional uterine bleeding or DUB) is more common at the extremes of reproductive life, and in women with ovulatory disorders such as polycystic ovary syndrome (PCOS). In anovulatory cycles there may be prolonged oestrogen stimulation of the endometrium without progesterone withdrawal and so cycles are irregular and bleeding may be heavy. This is the rationale for using cyclical progestogens during the second half of the menstrual cycle, in order to provoke a regular withdrawal bleed. Continuous progestogen is intended to induce endometrial atrophy and hence to prevent oestrogen-stimulated endometrial proliferation. Progestogens, and oestrogens and progestogens in combination, are widely used in the management of irregular menstrual bleeding, but the regime, dose and type of progestogen used vary widely, with little consensus about the optimum treatment approach. OBJECTIVES: To determine the effectiveness and acceptability of progestogens alone or in combination with oestrogens in the regulation of irregular menstrual bleeding associated with oligo/anovulation. SEARCH METHODS: We searched the following databases in February 2012: Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and reference lists of articles. SELECTION CRITERIA: All randomised controlled trials of progestogens (via any route) alone or in combination with oestrogens in the treatment of irregular menstrual bleeding associated with oligo/anovulation. DATA COLLECTION AND ANALYSIS: Study quality assessment and data extraction were carried out independently by two review authors. All authors were experts in the content of this review. MAIN RESULTS: No randomised trials were identified that compared progestogens with oestrogens and progestogens or with placebo in the management of irregular bleeding associated with oligo/anovulation. AUTHORS' CONCLUSIONS: There is a paucity of randomised studies relating to the use of progestogens and of oestrogens and progestogens in combination in the treatment of irregular menstrual bleeding associated with anovulation. There is no consensus about which regimens are most effective. Further research is needed to establish the role of these hormonal treatments in the management of this common gynaecological problem.

Silencing of the JNK pathway maintains progesterone receptor activity in decidualizing human endometrial stromal cells exposed to oxidative stress signals.

Survival of the conceptus is dependent on continuous progesterone signaling in the maternal decidua but how this is achieved under conditions of oxidative stress that characterize early pregnancy is unknown. Using primary cultures, we show that modest levels of reactive oxygen species (ROS) increase sumoylation in human endometrial stromal cells (HESCs), leading to enhanced modification and transcriptional inhibition of the progesterone receptor (PR). The ability of ROS to induce a sustained hypersumoylation response, or interfere with PR activity, was lost upon differentiation of HESCs into decidual cells. Hypersumoylation in response to modest levels of ROS requires activation of the JNK pathway. Although ROS-dependent JNK signaling is disabled on decidualization, the cells continue to mount a transcriptional response, albeit distinct from that observed in undifferentiated HESCs. We further show that attenuated JNK signaling in decidual cells is a direct consequence of altered expression of key pathway modulators, including induction of MAP kinase phosphatase 1 (MKP1). Overexpression of MKP1 dampens JNK signaling, prevents hypersumoylation, and maintains PR activity in undifferentiated HESCs exposed to ROS. Thus, JNK silencing uncouples ROS signaling from the SUMO conjugation pathway and maintains progesterone responses and cellular homeostasis in decidual cells under oxidative stress conditions imposed by pregnancy.

Key challenges in simulated patient programs: an international comparative case study.

BACKGROUND: The literature on simulated or standardized patient (SP) methodology is expanding. However, at the level of the program, there are several gaps in the literature. We seek to fill this gap through documenting experiences from four programs in Australia, Canada, Switzerland and the United Kingdom. We focused on challenges in SP methodology, faculty, organisational structure and quality assurance. METHODS: We used a multiple case study method with cross-case synthesis. Over eighteen months during a series of informal and formal interactions (focused meetings and conference presentations) we documented key characteristics of programs and drew on secondary document sources. RESULTS: Although programs shared challenges in SP methodology they also experienced differences. Key challenges common to programs included systematic quality assurance and the opportunity for research. There were differences in the terminology used to describe SPs, in their recruitment and training. Other differences reflected local conditions and demands in organisational structure, funding relationships with the host institution and national trends, especially in assessments. CONCLUSION: This international case study reveals similarities and differences in SP methodology. Programs were highly contextualised and have emerged in response to local, institutional, profession/discipline and national conditions. Broader trends in healthcare education have also influenced development. Each of the programs experienced challenges in the same themes but the nature of the challenges often varied widely.

Proteomic analysis of endometrium from fertile and infertile patients suggests a role for apolipoprotein A-I in embryo implantation failure and endometriosis.

Pregnancy is dependent upon the endometrium acquiring a receptive phenotype that facilitates apposition, adhesion and invasion of a developmentally competent embryo. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry of mid-secretory endometrial biopsies revealed a 28 kDa protein peak that discriminated highly between samples obtained from women with recurrent implantation failure and fertile controls. Subsequent tandem mass spectroscopy unambiguously identified this peak as apolipoprotein A-I (apoA-I), a potent anti-inflammatory molecule. Total endometrial apoA-I levels were, however, comparable between the study and control group. Moreover, endometrial apoA-I mRNA expression was not cycle-dependent although there was partial loss of apoA-I immunoreactivity in luminal and glandular epithelium in mid-secretory compared with proliferative endometrial samples. Because of its putative anti-implantation properties, we examined whether endometrial apoA-I expression is regulated by embryonic signals. Human chorionic gonadotrophin (hCG) strongly inhibited apoA-I expression in differentiating explant cultures but not when established from eutopic endometrium from patients with endometriosis. Pelvic endometriosis was associated with elevated apoA-I mRNA levels, increased secretion by differentiating eutopic endometrial explant cultures and lack of hCG-dependent down-regulation. To corroborate these observations, we examined endometrial apoA-I expression and its regulation by hCG in a non-human primate model of endometriosis. As in humans, hCG strongly inhibited endometrial apoA-I mRNA expression in disease-free baboons, but this response was entirely lost upon induction of pelvic endometriosis. Together, these observations indicate that perturbations in endometrial apoA-I expression, modification or regulation by paracrine embryonic signals play a major role in implantation failure and infertility.

Taking the Pressure Off the Patient - Understanding Digital Rectal Examinations on a Real Subject.

Better understanding of palpation techniques during unsighted physical examinations has mostly been limited to qualitative and quantitative studies of performance of experts whilst conducting examinations on plastic benchtop models. However, little is known about their performance when conducting such examinations on real subjects. OBJECTIVE: The aim of this paper is to better understand palpation techniques of experts whilst conducting a Digital Rectal Examination on a real subject. METHODS: We recruited four consultants from relevant specialties and asked them to conduct two DREs on a Rectal Teaching Assistant whilst wearing small position and pressure sensors on their examining finger. We segmented the relevant anatomy from an MRI taken of the pelvic region, registered 3D models and analysed retrospectively performance in relation to executed tasks, supination/pronation, palpation convex hull and pressure applied. RESULTS: Primary care consultants examined the anatomy more holistically compared to secondary care experts, the maximum pressure applied across experiments is 3.3N, overall the pressure applied on the prostate is higher than that applied to rectal walls, and the urologist participant not only applied the highest pressure but also did so with the highest most prominent frequency (15.4 and 25.3 Hz). CONCLUSIONS: The results of our research allow for better understanding of experts' technical performance from relevant specialities when conducting a DRE, and suggest the range of pressure applied whilst palpating anatomy. SIGNIFICANCE: This research will be valuable in improving the design of haptics-based learning tools, as well as in encouraging reflection on palpation styles across different specialities to develop metrics of performance.

Transcriptional cross talk between the forkhead transcription factor forkhead box O1A and the progesterone receptor coordinates cell cycle regulation and differentiation in human endometrial stromal cells.

Differentiation of human endometrial stromal cells (HESCs) into decidual cells is associated with induction of the forkhead transcription factor forkhead box O1A (FOXO1). We performed a genomic screen to identify decidua-specific genes under FOXO1 control. Primary HESCs were transfected with small interfering RNA targeting FOXO1 or with nontargeting control small interfering RNA before treatment with a cAMP analogue and the progestin, medroxyprogesterone acetate for 72 h. Total RNA was processed for whole genome analysis using high-density oligonucleotide arrays. We identified 3405 significantly regulated genes upon decidualization of HESCs, 507 (15.3%) of which were aberrantly expressed upon FOXO1 knockdown. Among the most up-regulated FOXO1-dependent transcriptional targets were WNT signaling-related genes (WNT4, WNT16 ), the insulin receptor (INSR), differentiation markers (PRL, IGFBP1, and LEFTY2), and the cyclin-dependent kinase inhibitor p57(Kip2) (CDKN1C). Analysis of FOXO1-dependent down-regulated genes uncovered several factors involved in cell cycle regulation, including CCNB1, CCNB2, MCM5, CDC2 and NEK2. Cell viability assay and cell cycle analysis demonstrated that FOXO1 silencing promotes proliferation of differentiating HESCs. Using a glutathione-S-transferase pull-down assay, we confirmed that FOXO1 interacts with progesterone receptor, irrespectively of the presence of ligand. In agreement, knockdown of PR disrupted the regulation of FOXO1 target genes involved in differentiation (IGFBP1, PRL, and WNT4) and cell cycle regulation (CDKN1, CCNB2 and CDC2) in HESCs treated with either cAMP plus medroxyprogesterone acetate or with cAMP alone. Together, the data demonstrate that FOXO1 engages in transcriptional cross talk with progesterone receptor to coordinate cell cycle regulation and differentiation of HESCs.

Exploring the underperformance of male and minority ethnic medical students in first year clinical examinations.

Evidence shows that medical students from Minority Ethnic (ME) backgrounds and male medical students underperform in undergraduate examinations. Our study confirmed these findings in first year clinical (year 3) medical students, and further explored this disparity in performance. We conducted a series of meta-analyses to measure the effects of sex and ethnic group on the written examination and Objective Structured Clinical Examination (OSCE) scores of three groups of year 3 medical students at two London UK medical schools (n = 1,051; 46.0% male; 48.7% White). Male and ME students scored lower on written and OSCE assessments. Both assessments were statistically significantly correlated (mean r = 0.45) and therefore the effects of sex and ethnic group were measured on each exam after being adjusted for the effect of the other. Although sex and ethnic differences remained on the OSCE when adjusted for written performance, these differences disappeared on the written when it was adjusted for OSCE performance. These findings may reflect a relative deficit in practical clinical knowledge in male and ME year 3 students. Results were unlikely to be due to examiner bias, as the machine-marked unadjusted written exam results showed significant sex and ethnic differences.

Real-time Visualisation and Analysis of Clinicians' Performance during Palpation in Physical Examinations.

OBJECTIVE: Motivated by the fact that palpation skills are challenging to learn and teach, particularly during Digital Rectal Examinations (DRE), and the lack of understanding of what constitutes adequate performance, we present a visualisation and analysis system that uses small position and pressure sensors located on the examining finger, allowing the quantitative analysis of duration, steps and pressure applied. METHODS: The system is first described, followed by an experimental study of twenty experts from four clinical specialties performing ten DREs each on a benchtop model using the proposed system. Analysis of the constitutive steps was conducted to improve understanding of the examination. A Markov model representing executed tasks and analysis of pressure applied is also introduced. RESULTS: The proposed system successfully allowed the visualisation and analysis during the experimental study. General Practitioners and Nurses were found to execute more tasks compared to Urologists and Colorectal Surgeons. Urologists executed the least number of tasks and were the most consistent group compared to others. CONCLUSION: The ability to "see through" allowed us to better characterise the performance of experts when conducting a DRE on a benchtop model, comparing the performance of relevant specialties, and studying executed tasks and the pressure applied. The Markov model presented summarises task execution of experts and could be used to compare performance of novices against that of experts. SIGNIFICANCE: This approach allows for the analysis of performance based on continuous sensor data recording that can be easily extended to real subjects and other types of physical examinations.

Role and regulation of the serum- and glucocorticoid-regulated kinase 1 in fertile and infertile human endometrium.

Using cDNA microarray analysis, we identified SGK1 (serum- and glucocorticoid-regulated kinase 1) as a gene aberrantly expressed in midsecretory endometrium of women with unexplained infertility. SGK1 is a serine/threonine kinase involved primarily in epithelial ion transport and cell survival responses. Real-time quantitative PCR analysis of a larger, independent sample set timed to coincide with the period of uterine receptivity confirmed increased expression of SGK1 transcripts in infertile women compared with fertile controls. We further demonstrate that SGK1 expression is regulated by progesterone in human endometrium in vivo as well as in explant cultures. During the midsecretory phase of the cycle, SGK1 mRNA and protein were predominantly but not exclusively expressed in the luminal epithelium, and expression in this cellular compartment was higher in infertile women. In the stromal compartment, SGK1 expression was largely confined to decidualizing cells adjacent to the luminal epithelium. In primary culture, SGK1 was induced and phosphorylated upon decidualization of endometrial stromal cells in response to 8-bromo-cAMP and progestin treatment. Moreover, overexpression of SGK1 in decidualizing cells enhanced phosphorylation and cytoplasmic translocation of the forkhead transcription factor FOXO1 and inhibited the expression of PRL, a major decidual marker gene. Conversely, knockdown of endogenous SGK1 by small interfering RNA increased nuclear FOXO1 levels and enhanced PRL expression. The observation that SGK1 targets FOXO1 in differentiating human endometrium, together with its distinct temporal and spatial expression pattern and increased expression in infertile patients, suggest a major role for this kinase in early pregnancy events.

Diagnosis of abnormal uterine bleeding.

Abnormal uterine bleeding is an extremely common indication for referral to a gynaecologist. This chapter examines the modes of presentation and the causes of such symptoms, which range from physiological variations to more sinister underlying pathology. A thorough understanding of these causes is required to direct investigation in an appropriate manner. The full range of possible investigations is discussed with emphasis on how to choose the most appropriate tests for a particular patient. This is fundamental to ensure that tests are pertinent and streamlined, and to prevent unnecessary anxiety and delay. Once the underlying causes have been clarified, a suitable management plan can be made.

Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization.

The integrity of the feto-maternal interface is critical for survival of the conceptus. This interface, consisting of the maternal decidua and the invading placental trophoblast, is exposed to profound changes in oxygen tension during pregnancy. We demonstrate that human endometrial stromal cells become extraordinarily resistant to oxidative stress-induced apoptosis upon decidualization in response to cAMP and progesterone signaling. This differentiation process is associated with the induction of the forkhead transcription factor FOXO1, which in turn increases the expression of the mitochondrial antioxidant manganese superoxide dismutase. However, silencing of FOXO1 did not increase the susceptibility of decidualized cells to oxidative cell death. Comparative analysis demonstrated that hydrogen peroxide, a source of free radicals, strongly induces FOXO3a mRNA and protein expression in undifferentiated human endometrial stromal cells but not in decidualized cells. Expression of a constitutively active FOXO3a mutant elicited apoptosis in decidualized cells. Furthermore, silencing of endogenous FOXO3a in undifferentiated cells abrogated apoptosis induced by hydrogen peroxide. These results suggest that the induction of FOXO1 may enhance the ability of decidualized cells to prevent oxidative damage while the simultaneous repression of FOXO3a expression disables the signaling pathway responsible for oxidative cell death. The differential regulation of FOXO expression provides the decidua with a robust system capable of coping with prolonged episodes of oxidative stress during pregnancy.

Progestins regulate the expression and activity of the forkhead transcription factor FOXO1 in differentiating human endometrium.

Menstruation, or cyclic shedding of nonpregnant endometrial tissue with associated bleeding, occurs only in humans and a few other species. This breakdown of the endometrium in response to falling ovarian progesterone levels is a complex process, characterized by local leukocyte infiltration, expression and activation of matrix metalloproteinases, and apoptosis. Spontaneous decidualization (differentiation) of the stromal compartment precedes the cyclic shedding of the endometrium in various menstruating species but the mechanisms that link these processes are not understood. In this study, we identified FOXO1 as a key transcription factor responsible for mediating apoptosis of decidualized human endometrial stromal cells (HESCs) in response to progesterone withdrawal. We demonstrate that medroxyprogesterone acetate (MPA, a synthetic progestin) enhances the expression of FOXO1 in differentiating HESCs while simultaneously inducing cytoplasmic retention and inactivation of FOXO1. Withdrawal of MPA from decidualized HESCs results in rapid nuclear accumulation of FOXO1, increased BIM expression, a proapoptotic FOXO1 target gene, and cell death. Conversely, silencing of FOXO1 expression completely abolishes cell death induced by MPA withdrawal. In summary, the observation that differentiating HESCs become dependent on progesterone signaling for survival through induction and reversible inactivation of FOXO1 suggests a novel mechanism that links decidualization of the endometrium to menstruation.

Standardizing bimanual vaginal examination using cognitive task analysis.

OBJECTIVE: To create a standardized universal list of procedural steps for bimanual vaginal examination (BVE) for teaching, assessment, and simulator development. METHODS: This observational study, conducted from June-July 2012 and July-December 2014, collected video data of 10 expert clinicians performing BVE in a nonclinical environment. Video data were analyzed to produce a cognitive task analysis (CTA) of the examination steps performed. The CTA was further refined through structured interviews to make it suitable for teaching or assessment. It was validated through its use as a procedural examination checklist to rate expert clinician performance. RESULTS: BVE was deconstructed into 88 detailed steps outlining the complete examination process. These initial 88 steps were reduced to 35 by focusing on the unseen internal examination, then further refined through interviews with five experts into 30 essential procedural steps, five of which are additional steps if pathology is suspected. Using the CTA as a procedural checklist, the mean number of steps performed and/or verbalized was 21.6 ± 3.12 (72% ± 10.4%; range, 15.9-27.9, 53%-93%). CONCLUSION: This approach identified 30 essential steps for performing BVE, producing a new technique and standardized tool for teaching, assessment, and simulator development.

Outcome measures for heavy menstrual bleeding.

Heavy menstrual bleeding is one of the most commonly encountered gynecological problems. While accurate objective quantification of menstrual blood loss is of value in the research setting, it is the subjective assessment of blood loss that is of greater importance when assessing the severity of heavy menstrual bleeding and any subsequent response to treatment. In this review the various approaches to objective, subjective and semi-subjective assessment of menstrual blood loss will be discussed.

Aromatase P450 messenger RNA expression in eutopic endometrium is not a specific marker for pelvic endometriosis.

OBJECTIVE: To determine whether expression of aromatase P450 mRNA in eutopic endometrium is predictive of the presence of pelvic endometriosis. DESIGN: A prospective, multicenter, observational study. SETTING: Four tertiary centers for reproductive medicine. PATIENT(S): Sixty subjects of reproductive age undergoing laparoscopy for subfertility exploration, pain assessment, or sterilization. INTERVENTION(S): Endometrial biopsy at time of laparoscopy. MAIN OUTCOME MEASURE(S): The expression of aromatase P450 mRNA in endometrial specimens was determined by single-tube reverse transcription-polymerase chain reaction (RT-PCR). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was amplified in parallel to exclude amplification failure. RESULT(S): The RT-PCR amplification was successful in 56 of the 60 biopsies (93%). Pelvic endometriosis was diagnosed in 34 patients (61%) and was strongly associated with aromatase P450 mRNA expression in eutopic endometrium. As a diagnostic marker for endometriosis, aromatase P450 mRNA expression yielded a sensitivity of 82%, a specificity of 59%, a positive predictive value of 76%, and a negative predictive value of 67%. If additional uterine pathology was taken in account, the sensitivity increased to 84%, the specificity to 72%, the positive predictive value to 87%, but the negative predictive value remained unchanged (67%). CONCLUSION(S): Although endometrial aromatase P450 gene expression is highly predictive of the presence of pelvic disease, the relative high incidence of false-negative results and lack of specificity is likely to impair clinical application.

Real-time visualisation and analysis of internal examinations--seeing the unseen.

Internal examinations such as Digital Rectal Examination (DRE) and bimanual Vaginal Examination (BVE) are routinely performed for early diagnosis of cancer and other diseases. Although they are recognised as core skills to be taught on a medical curriculum, they are difficult to learn and teach due to their unsighted nature. We present a framework that combines a visualisation and analysis tool with position and pressure sensors to enable the study of internal examinations and provision of real-time feedback. This approach is novel as it allows for real-time continuous trajectory and pressure data to be obtained for the complete examination, which may be used for teaching and assessment. Experiments were conducted performing DRE and BVE on benchtop models, and BVE on Gynaecological Teaching Assistants (GTA). The results obtained suggest that the proposed methodology may provide an insight into what constitutes an adequate DRE or BVE, provide real-time feedback tools for learning and assessment, and inform haptics-based simulator design.