Key separable events in the remodelling of the pharyngeal arches.

The pharyngeal arches are a series of bulges on the lateral surface of the embryonic head. They are a defining feature of the most conserved, the phylotypic, stage of vertebrate development. In many vertebrate clades, the segmental arrangement of the pharyngeal arches is translated into the iterative anatomy of the gill arches. However, in amniotes the pharyngeal arches undergo a rearrangement during development and the segmental organisation of the pharynx is lost. This remodelling involves the expansion of the second arch which comes to overlie the more posterior arches. A transient sinus forms between the expanded second arch and the posterior arches, that is then lost, and the posterior arches are internalised. The morphogenesis of the second arch has been viewed as being central to this remodelling. Yet little is known about this process. Therefore, in this study, we have characterised the development of the second arch. We show that as the second arch expands, its posterior margin forms a leading edge and that the mesenchymal cells subjacent to this are in an elevated proliferative state. We further show that the posterior marginal epithelium is the site of expression of three key developmental signalling molecules: BMP7, FGF8 and SHH, and that their expression continues throughout the period of expansion. Using a novel approach, we have been able to simultaneously inhibit these three pathways, and we find that when this is done the second arch fails to establish its caudal projection and that there is a loss of proliferation in the posterior mesenchymal cells of the second arch. We have further used this manipulation to ask if the internalisation of the posterior arches is dependent upon the expansion of the second arch. We find that it is not-the posterior arches are still internalised when the expansion of the second arch is curtailed. We further show that while the collapse of the sinus is dependent upon thyroid hormone signalling, that this is not the case for the internalisation of the posterior pouches. Thus, the internalisation of the posterior arches is not dependent on the expansion of the second arch or on the collapse of the sinus. Finally, we show that the termination of expansion of the second arch correlates with a burst of morphogenetic cell death suggesting a mechanism for ending this. Thus, while it has long been thought that it is the morphogenesis of the second arch that drives the remodelling of the pharyngeal arches, we show that this is not the case. Rather the remodelling of the pharyngeal arches is a composite process that can split into contemporaneous but separate events: the expansion of the second arch, the internalisation of the posterior arches and the collapse of the sinus.

Diminution of pharyngeal segmentation and the evolution of the amniotes.

BACKGROUND: The pharyngeal arches are a series of bulges found on the lateral surface of the head of vertebrate embryos, and it is within these segments that components of the later anatomy are laid down. In most vertebrates, the post-otic pharyngeal arches will form the branchial apparatus, while in amniotes these segments are believed to generate the larynx. It has been unclear how the development of these segments has been altered with the emergence of the amniotes. RESULTS: In this study, we examined the development of pharyngeal arches in amniotes and show that the post-otic pharyngeal arches in this clade are greatly diminished. We find that the post-otic segments do not undergo myogenesis or skeletogenesis, but are remodelled before these processes occur. We also find that nested DLX expression, which is a feature of all the pharyngeal arches in anamniotes, is associated with the anterior segments but less so with the posterior arches in amniotes. We further show that the posterior arches of the mouse embryo fail to properly delineate, which demonstrates the lack of function of these posterior segments in later development. CONCLUSION: In amniotes, there has been a loss of the ancestral "branchial" developmental programme that is a general feature of gnathostomes; myogenesis and skeletogenesis This is likely to have facilitated the emergence of the larynx as a new structure not constrained by the segmental organisation of the posterior pharyngeal region.

Performance of candidates disclosing dyslexia with other candidates in a UK medical licensing examination: cross-sectional study.

PURPOSE OF THE STUDY: The aim of this study was to compare performance of candidates who declared an expert-confirmed diagnosis of dyslexia with all other candidates in the Applied Knowledge Test (AKT) of the Membership of the Royal College of General Practitioners licensing examination. STUDY DESIGN: We used routinely collected data from candidates who took the AKT on one or more occasions between 2010 and 2015. Multivariate logistic regression was used to analyse performance of candidates who declared dyslexia with all other candidates, adjusting for candidate characteristics known to be associated with examination success including age, sex, ethnicity, country of primary medical qualification, stage of training, number of attempts and time spent completing the test. RESULTS: The analysis included data from 14 examinations involving 14 801 candidates of which 2.6% (379/14 801) declared dyslexia. The pass rate for candidates who declared dyslexia was 83.6% compared with 95.0% for other candidates. After adjusting for covariates linked to examination success including age, sex, ethnicity, country of primary medical qualification, stage of training, number of attempts and time spent completing the test dyslexia was not significantly associated with pass rates in the AKT. Candidates declaring dyslexia after initially failing the AKT were more likely to have a primary medical qualification outside the UK. CONCLUSIONS: Performance was similar in AKT candidates disclosing dyslexia with other candidates once covariates associated with examination success were adjusted for. Candidates declaring dyslexia after initially failing the AKT were more likely to have a primary medical qualification outside the UK.

Case-control study to investigate variables associated with incidents and adverse events in the emergency department.

OBJECTIVE: To detect and analyse incidents (Is) and adverse events (AEs) in the ED. We hypothesised that I/AE are associated with patient load. METHODS: We undertook a case-control study in a tertiary level hospital ED (from 1 April 2012 to 31 March 2013). Three percent of patients were randomly selected and screened for I/AEs. I/AEs were adjudicated by consensus of four FACEMs. Controls were matched to cases 2:1. Logistic regression was used to analyse the data. RESULTS: We sampled 2167 patients. After exclusions, 217 I/AEs were detected and analysed. The I and AE rates were 6.0 and 4.1%, respectively. The serious AE rate was 0.8% and 30 day mortality was 0.1%. Diagnostic error occurred in 3.7% of all patients and adverse drug reactions in 2.5%. Seventy-seven percent of the I/AEs were judged preventable. ED occupancy of <35 patients was the reference group. Compared with this group, if 36-40 or 41-45 patients were in the ED, I/AEs were more likely to occur (odds ratio [OR] 2.37 [95% confidence interval (CI) 1.40-4.01, P < 0.0] and 1.8 [95% CI 1.03-3.15, P = 0.04], respectively) but not when there were >46 patients (OR 1.7, 95% CI 1.0-3.1). Higher hospital occupancy (90-99%) was a protective factor for sustaining an I/AE (OR 0.57, 95% CI 0.35-0.92, P = 0.02). CONCLUSION: I/AEs are common in the ED and a large proportion is preventable. Strategies for prevention are required. The relationship with patient load needs further clarification, since our data suggests increased I/AE rates with higher occupancy but not highest occupancy.

Leader Cells Define Directionality of Trunk, but Not Cranial, Neural Crest Cell Migration.

Collective cell migration is fundamental for life and a hallmark of cancer. Neural crest (NC) cells migrate collectively, but the mechanisms governing this process remain controversial. Previous analyses in Xenopus indicate that cranial NC (CNC) cells are a homogeneous population relying on cell-cell interactions for directional migration, while chick embryo analyses suggest a heterogeneous population with leader cells instructing directionality. Our data in chick and zebrafish embryos show that CNC cells do not require leader cells for migration and all cells present similar migratory capacities. In contrast, laser ablation of trunk NC (TNC) cells shows that leader cells direct movement and cell-cell contacts are required for migration. Moreover, leader and follower identities are acquired before the initiation of migration and remain fixed thereafter. Thus, two distinct mechanisms establish the directionality of CNC cells and TNC cells. This implies the existence of multiple molecular mechanisms for collective cell migration.

Network analysis of social changes in a captive chimpanzee community following the successful integration of two adult groups.

Chimpanzees are highly territorial and have the potential to be extremely aggressive toward unfamiliar individuals. In the wild, transfer between groups is almost exclusively completed by nulliparous females, yet in captivity there is often a need to introduce and integrate a range of individuals, including adult males. We describe the process of successfully integrating two groups of chimpanzees, each containing 11 individuals, in the Budongo Trail facility at the Royal Zoological Society of Scotland's Edinburgh Zoo. We use social network analysis to document changes in group dynamics within this population over the 16 months following integration. Aggression rates were low overall and members of the two original groups engaged in significantly fewer aggressive interactions over time. Association and grooming data indicate that relationships between members of the original groups became stronger and more affiliative with time. Despite these positive indicators the association data revealed the continued existence of two distinct subgroups, a year after integration. Our data show that when given complex space and freedom to exhibit natural fission-fusion groupings, in which the chimpanzees choose whom they wish to associate and interact with, the building of strong affiliative relationships with unfamiliar individuals is a very gradual process.

Developmental and evolutionary origins of the pharyngeal apparatus.

The vertebrate pharyngeal apparatus, serving the dual functions of feeding and respiration, has its embryonic origin in a series of bulges found on the lateral surface of the head, the pharyngeal arches. Developmental studies have been able to discern how these structures are constructed and this has opened the way for an analysis of how the pharyngeal apparatus was assembled and modified during evolution. For many years, the role of the neural crest in organizing pharyngeal development was emphasized and, as this was believed to be a uniquely vertebrate cell type, it was suggested that the development of the pharyngeal apparatus of vertebrates was distinct from that of other chordates. However, it has now been established that a key event in vertebrate pharyngeal development is the outpocketing of the endoderm to form the pharyngeal pouches. Significantly, outpocketing of the pharyngeal endoderm is a basal deuterostome character and the regulatory network that mediates this process is conserved. Thus, the framework around which the vertebrate pharyngeal apparatus is built is ancient. The pharyngeal arches of vertebrates are, however, more complex and this can be ascribed to these structures being populated by neural crest cells, which form the skeletal support of the pharynx, and mesoderm, which will give rise to the musculature and the arch arteries. Within the vertebrates, as development progresses beyond the phylotypic stage, the pharyngeal apparatus has also been extensively remodelled and this has seemingly involved radical alterations to the developmental programme. Recent studies, however, have shown that these alterations were not as dramatic as previously believed. Thus, while the evolution of amniotes was believed to have involved the loss of gills and their covering, the operculum, it is now apparent that neither of these structures was completely lost. Rather, the gills were transformed into the parathyroid glands and the operculum still exists as an embryonic entity and is still required for the internalization of the posterior pharyngeal arches. Thus, the key steps in our phylogenetic history are laid out during the development of our pharyngeal apparatus.

Comparing performance among male and female candidates in sex-specific clinical knowledge in the MRCGP.

BACKGROUND: Patients often seek doctors of the same sex, particularly for sex-specific complaints and also because of a perception that doctors have greater knowledge of complaints relating to their own sex. Few studies have investigated differences in knowledge by sex of candidate on sex-specific questions in medical examinations. AIM: The aim was to compare the performance of males and females in sex-specific questions in a 200-item computer-based applied knowledge test for licensing UK GPs. DESIGN AND SETTING: A cross-sectional design using routinely collected performance and demographic data from the first three versions of the Applied Knowledge Test, MRCGP, UK. METHOD: Questions were classified as female specific, male specific, or sex neutral. The performance of males and females was analysed using multiple analysis of covariance after adjusting for sex-neutral score and demographic confounders. RESULTS: Data were included from 3627 candidates. After adjusting for sex-neutral score, age, time since qualification, year of speciality training, ethnicity, and country of primary medical qualification, there were differences in performance in sex-specific questions. Males performed worse than females on female-specific questions (-4.2%, 95% confidence interval [CI] = -5.7 to -2.6) but did not perform significantly better than females on male-specific questions (0.3%, 95% CI = -2.6 to 3.2%. CONCLUSION: There was evidence of better performance by females in female-specific questions but this was small relative to the size of the test. Differential performance of males and females in sex-specific questions in a licensing examination may have implications for vocational and post-qualification general practice training.

The presence of an embryonic opercular flap in amniotes.

The operculum is a large flap consisting of several flat bones found on the side of the head of bony fish. During development, the opercular bones form within the second pharyngeal arch, which expands posteriorly and comes to cover the gill-bearing arches. With the evolution of the tetrapods and the assumption of a terrestrial lifestyle, it was believed that the operculum was lost. Here, we demonstrate that an embryonic operculum persists in amniotes and that its early development is homologous with that of teleosts. As in zebrafish, the second pharyngeal arch of the chick embryo grows disproportionately and comes to cover the posterior arches. We show that the developing second pharyngeal arch in both chick and zebrafish embryos express orthologous genes and require shh signalling for caudal expansion. In amniotes, however, the caudal edge of the expanded second arch fuses to the surface of the neck. We have detailed how this process occurs and also demonstrated a requirement for thyroid signalling here. Our results thus demonstrate the persistence of an embryonic opercular flap in amniotes, that its fusion mirrors aspects of amphibian metamorphosis and gives insights into the origin of branchial cleft anomalies in humans.

Abusive experiences and psychiatric morbidity in women primary care attenders.

BACKGROUND: Abusive experiences in childhood and adulthood increase risks of psychiatric morbidity in women and independently increase risks of further abuse over the lifetime. It is unclear which experiences are most damaging. AIMS: To measure lifetime prevalence of abusive experiences and psychiatric morbidity, and to analyse associations in women primary care attenders. METHOD: A cross-sectional, self-report survey of 1207 women attending 13 surgeries in the London borough of Hackney, UK. Independent associations between demographic measures, abusive experiences and psychiatric outcome were established using logistic regression. RESULTS: Childhood sexual abuse had few associations with adult mental health measures, in contrast to physical abuse. Sexual assault in adulthood was associated with substance misuse; rape with anxiety, depression and post-traumatic stress disorder but not substance misuse. Domestic violence showed strongest associations with most mental health measures, increased for experiences in the past year. CONCLUSIONS: Abuse in childhood and adulthood have differential effects on mental health; effects are increased by recency and severity. Women should be routinely questioned about ongoing and recent experiences as well as childhood.

Sexual violence against adult women primary care attenders in east London.

BACKGROUND: Sexual violence against women is common. The prevalence appears to be higher in north America than Europe. However, not all surveys have differentiated the experience of forced sex by a current or former partner. Few women are thought to report these experiences to their general practitioner (GP). AIM: To measure the prevalence of rape, sexual assault, and forced sexual intercourse by a partner among women attending general practices, to test the association between these experiences of sexual violence and demographic factors, and to assess the acceptability to women of screening for sexual violence by GPs. DESIGN OF STUDY: Cross-sectional survey. METHOD: A self-administered questionnaire survey of 1207 women aged over 15 years was carried out in 13 general practices in Hackney, east London. RESULTS: Eight per cent (95% confidence interval [CI] = 6.2 to 9.6) of women have experienced rape, 9% (95% CI = 7.0 to 10.6) another type of sexual assault, and 16% (95% CI = 13.6 to 18.1) forced sex by a partner in adulthood: 24% (95% CI = 21.2 to 26.5) have experienced one or more of these types of sexual violence. Experiences of sexual violence demonstrated high levels of lifetime co-occurrence. Women forced to have sex by partners experienced the most severe forms of domestic violence. One in five women would object to routine questioning about being raped and/or sexually assaulted, and one in nine about being forced to have sex by a partner. CONCLUSION: Experiences of sexual violence are common in the lives of adult women in east London, and they represent a significant public health problem. Those women who have one experience appear to be at risk of being victims again. A substantial minority object to routine questions about sexual violence.

Should health professionals screen women for domestic violence? Systematic review.

OBJECTIVE: To assess the evidence for the acceptability and effectiveness of screening women for domestic violence in healthcare settings. DESIGN: Systematic review of published quantitative studies. SESRCH STRATEGY: Three electronic databases (Medline, Embase, and CINAHL) were searched for articles published in the English language up to February 2001. INCLUDED STUDIES: Surveys that elicited the attitudes of women and health professionals on the screening of women in health settings; comparative studies conducted in healthcare settings that measured rates of identification of domestic violence in the presence and absence of screening; studies measuring outcomes of interventions for women identified in health settings who experience abuse from a male partner or ex-partner compared with abused women not receiving an intervention. RESULTS: 20 papers met the inclusion criteria. In four surveys, 43-85% of women respondents found screening in healthcare settings acceptable. Two surveys of health professionals' views found that two thirds of physicians and almost half of emergency department nurses were not in favour of screening. In nine studies of screening compared with no screening, most detected a greater proportion of abused women identified by healthcare professionals. Six studies of interventions used weak study designs and gave inconsistent results. Other than increased referral to outside agencies, little evidence exists for changes in important outcomes such as decreased exposure to violence. No studies measured quality of life, mental health outcomes, or potential harm to women from screening programmes. CONCLUSION: Although domestic violence is a common problem with major health consequences for women, implementation of screening programmes in healthcare settings cannot be justified. Evidence of the benefit of specific interventions and lack of harm from screening is needed.

Identifying domestic violence: cross sectional study in primary care.

OBJECTIVES: To measure the prevalence of domestic violence among women attending general practice; test the association between experience of domestic violence and demographic factors; evaluate the extent of recording of domestic violence in records held by general practices; and assess acceptability to women of screening for domestic violence by general practitioners or practice nurses. DESIGN: Self administered questionnaire survey. Review of medical records. SETTING: General practices in Hackney, London. PARTICIPANTS: 1207 women (>15 years) attending selected practices. MAIN OUTCOME MEASURES: Prevalence of domestic violence against women. Association between demographic factors and domestic violence reported in questionnaire. Comparison of recording of domestic violence in medical records with that reported in questionnaire. Attitudes of women towards being questioned about domestic violence by general practitioners or practice nurses. RESULTS: 425/1035 women (41%, 95% confidence interval 38% to 44%) had ever experienced physical violence from a partner or former partner and 160/949 (17%, 14% to 19%) had experienced it within the past year. Pregnancy in the past year was associated with an increased risk of current violence (adjusted odds ratio 2.11, 1.39 to 3.19). Physical violence was recorded in the medical records of 15/90 (17%) women who reported it on the questionnaire. At least 202/1010 (20%) women objected to screening for domestic violence. CONCLUSIONS: With the high prevalence of domestic violence, health professionals should maintain a high level of awareness of the possibility of domestic violence, especially affecting pregnant women, but the case for screening is not yet convincing.