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Abstract Background Professionalism is expected of health professionals and advocated by professional regulators in the United Kingdom (UK). Concepts of professionalism have evolved in sociological discourse and its meaning for dentistry is unclear. It is, none-the-less, considered a core domain of dental education and professional practice by the United Kingdom regulator, the General Dental Council. This paper reports the sense-making process, or social process, of professionalism in practice within England. Aim To explore the research question ‘What does dental professionalism mean in practice? Methods Taking a constructivist grounded theory approach, involving purposive and theoretical sampling, 24 dental professionals were recruited to participate in this qualitative study. In-depth, semi-structured interviews were conducted by one interviewer (AT). Interviews were recorded, transcribed verbatim, and analysed leading to the development of a theory grounded in the data. Results A focus on the social-professional constructs used by participants to make sense of their experiences, resulted in a grounded theory where Reconciling Duty emerged as the core category. This represents a process of meeting professional duties to different parties that are often mutually exclusive. It is comprised of three supporting categories: Applying order to the system, where individuals attempt to identify what constitutes professional attitudes and behaviours, Rationalising what is fair, where individuals make judgements on how the conflict between duties should be resolved, and finally Responding to the System, where individuals attempt to actualise these desired resolutions in the context of the complex social system in which they practice. Three dentist archetypes (typologies) emerged, which involved a personal (Type 1), patient (Type 2), or a societal (Type 3) compromise. Conclusion Professionalism can be conceptualised as process of reconciling multiple, competing, legitimate duties to different parties, in seeking a fair solution. Once this has been identified, individuals need to work within the complex system of dentistry to make their identified outcome a reality. The findings suggest that using the theory of Reconciling Duty helps us to engage with the meaning that the participants drew from the term ‘professionalism’, and anchors it in the lived, everyday professional experiences and challenges faced. A novel typology is proposed, commensurate with calls for a systems approach to the topic.

BackgroundGlobally, there is growing attention towards health system strengthening, and the importance of quality in health systems. However, fragile and conflict-affected states present particular challenges. The aim of this study was to explore health system strengthening in fragile and conflict-affected states by synthesising the evidence from published literature.MethodsWe conducted a review of systematic reviews (Prospero Registration Number: CRD42022371955) by searching Ovid (Medline, Embase, and Global Health), Scopus, Web of Science, and the Cochrane Library databases. Only English-language publications were considered. The Joanna Briggs Institute (JBI) Critical Appraisal Tool was employed to assess methodological quality of the included studies. The findings were narratively synthesised and presented in line with the Lancet's 'high-quality health system framework'.ResultsTwenty-seven systematic reviews, out of 2,704 identified records, considered key dimensions of health systems in fragile and conflict-affected states, with the 'foundations' domain having most evidence. Significant challenges to health system strengthening, including the flight of human capital due to safety concerns and difficult working conditions, as well as limited training capacities and resources, were identified. Facilitators included community involvement, support systems and innovative financing mechanisms. The importance of coordinated and integrated responses tailored to the context and stage of the crisis situation was emphasised in order to strengthen fragile health systems. Overall, health system strengthening initiatives included policies encouraging the return and integration of displaced healthcare workers, building local healthcare workers capacity, strengthening education and training, integrating healthcare services, trust-building, supportive supervision, and e-Health utilisation.ConclusionThe emerging body of evidence on health system strengthening in fragile and conflict-affected states highlights its complexity. The findings underscore the significance of adopting a comprehensive approach and engaging various stakeholders in a coordinated manner considering the stage and context of the situation.

Introduction: The Global Strategy for Human Resources for Health 2030, requires member states to half their dependency on an international workforce by 2030. In order to design policies towards that goal, country-specific research on migration motivations of the health workforce is required. The United Kingdom (UK) is a net importer of health professionals and whilst there is a body of research on doctors’ and nurses’ migration, there is no research on the migration motivations of migrant dentists in the UK. This research explored the migration motivations of internationally qualified dentists (IQDs) in the UK and presents a typology to understand the global migration of dentists in the context of oral health workforce. Methods: The paper presents qualitative data from semi-structured interviews conducted between August 2014 and October 2017, of IQDs working in the United Kingdom. The topic guide for interviews was informed by the literature, with new themes added inductively. A phenomenological approach involving an epistemological stance of interpretivism, was used with framework analysis. Results: A total of 38 internationally qualified dentists (M = 18, F = 20), migrating from the five World Health Organization regions, and working in general practice, NHS hospitals and in community dental services across the four nations of the UK were interviewed. Seven types of internationally qualified dentists were identified working in the UK. They were livelihood migrants, career-orientated migrants, dependant migrants, backpacker migrants, commuter migrants, undocumented migrants, and education-tourist migrant. The categories were based on their migration motivations, which were complex, multifactorial, and included personal, professional, national, and international drivers. The typology, based on their migration motivations, offered a structured, comprehensive understanding of the migrant dental workforce. This typology involving dentists provides additional dimensions to commuter and undocumented migrants described in the context of other health professionals. The education-tourist migrant is a new category proposed as an extension to existing typology in health professional migration. Conclusions: The typology of internationally qualified dentists has congruency with other health professionals’ typology in categories previously described and demonstrates that each of these categories are complex, fluid and change in response to policy changes. The new category of education-tourist migrant along with oral health dimensions of commuter and undocumented migrants adds to the existing typology in health professional migration.

Few descriptions of using the femoral vein as an arterial replacement exist in the pediatric surgical literature. A 3-year-old child sustained a gunshot wound to the right subclavian artery, which resulted in ischemia to the upper extremity. The left femoral vein was harvested and used to reconstruct the subclavian artery. This report highlights a rare case of subclavian artery reconstruction using a femoral vein conduit in a young child after a penetrating injury.

BackgroundComparative optimism, the belief that negative events are more likely to happen to others rather than to oneself, is well established in health risk research. It is unknown, however, whether comparative optimism also permeates people's health expectations and potentially behaviour during the COVID-19 pandemic.ObjectivesData were collected through an international survey (N = 6485) exploring people's thoughts and psychosocial behaviours relating to COVID-19. This paper reports UK data on comparative optimism. In particular, we examine the belief that negative events surrounding risk and recovery from COVID-19 are perceived as more likely to happen to others rather than to oneself.MethodsUsing online snowball sampling through social media, anonymous UK survey data were collected from N = 645 adults during weeks 5-8 of the UK COVID-19 lockdown. The sample was normally distributed in terms of age and reflected the UK ethnic and disability profile.FindingsRespondents demonstrated comparative optimism where they believed that as compared to others of the same age and gender, they were unlikely to experience a range of controllable (eg accidentally infect/ be infected) and uncontrollable (eg need hospitalization/ intensive care treatment if infected) COVID-19-related risks in the short term (P

The sustained governmental assault on the National Health Service (NHS) in England during post-1970s financialised or rentier capitalism has received considerable attention by the research community. There is some evidence, however, that many of those members of the public who have not had occasion to use the NHS remain largely ill-informed about the extent of, and reasons for, its present troubles. In this paper I offer an auto/biographic account of my own recent experiences as a patient with type 2 diabetes and subsequent polymyalgia in both primary and secondary care. I then deploy analytic induction to consider, and explain, my personal travails against the background of the shifting nature of doctor-patient interaction occasioned by governmental politics in relation to the NHS. The result is an illustrated story of the decline of health care at a political juncture when the ever-expanding capital assets of a tiny minority of the population trumps the health care needs of the population as a whole. The present impoverishment of management and care must be understood with reference to wider aspects of macro-social change. The paper concludes with some ideas about how to (re)fund a severely ailing NHS.

Abstract Background There is a social expectation that dentists demonstrate professionalism. Although the General Dental Council puts it at the heart of their regulatory agenda, there is not yet consensus on the meaning and implications of the term. Objective To explore practising dentists’ understanding of the character traits commonly associated with professionalism and what these mean in practice. Method Constructivist grounded theory was employed throughout this study. Qualitative, in-depth interviews were conducted with dental professionals in England recruited through theoretical sampling to saturation point. Interviews used a topic guide informed by the literature, and analysis was conducted through constant comparison during data collection. Results The study found that traits commonly associated with professionalism in the literature were difficult for dentists to define clearly or operationalise in a clinical setting. There was disagreement over how some traits should be understood, and it was unclear to participants how, or indeed if, the listed traits were directly relevant to practice in their current form. Conclusion Rather than expecting unconditional adherence to an externally imposed definition, further exploration is required to understand how health professionals make sense of professionalism by reference to their lived experiences and worldviews. In Brief Institutional expectations of professionalism, defined through character traits and behaviours, do not appear to map neatly on to the experiences of dental professionals. Straightforward, apparently uncontroversial terms elicited a wide range of responses, including disagreement. This brought in to question whether achieving consensus is possible. Analysing how our respondents understood the terms by reference to the meanings they constructed from lived experience offers deeper insights.

The chemokine SDF-1 (CXCL12) and its receptor CXCR4 control several processes during embryonic development such as the regulation of stem cell proliferation, differentiation, and migration. However, the role of this pathway in the formation of the pituitary gland is not understood. We sought to characterise the expression patterns of CXCR4, SDF-1 and CXCR7 at different stages of pituitary gland development. Our expression profiling revealed that SDF-1 is expressed in progenitor-rich regions of the pituitary anterior lobe, that CXCR4 and CXCR7 have opposite expression domains and that CXCR4 expression is conserved between mice and human embryos. We then assessed the importance of this signalling pathway in the development and function of the murine pituitary gland through conditional deletion of CXCR4 in embryonic pituitary progenitors. Successful and specific ablation of CXCR4 expression in embryonic pituitary progenitors did not lead to observable embryonic nor postnatal defects but allowed the identification of stromal CXCR4+ cells not derived from HESX1+ progenitors. Further analysis of constitutive SDF-1, CXCR7 and CXCR4 mutants of the pathway indicates that CXCR4 expression in HESX1+ cells and their descendants is not essential for normal pituitary development in mice.

In this wide-ranging interview Graham Scambler provides an overview of his long academic career. He discusses how he became a medical sociologist, his early work on epilepsy and stigma, his part in the development of sociology textbooks for medical students, the diversity of his work and his many collaborations, his 'theoretical turn', his longstanding interest in critical realism and his attitude to 'bridge building' between philosophy and empirical work. [ABSTRACT FROM AUTHOR]

Summary: Cxcl12-null embryos have dysplastic, misaligned, and hyperplastic semilunar valves (SLVs). In this study, we show that CXCL12 signaling via its receptor CXCR4 fulfills distinct roles at different stages of SLV development, acting initially as a guidance cue to pattern cellular distribution within the valve primordia during the endocardial-to-mesenchymal transition (endoMT) phase and later regulating mesenchymal cell proliferation during SLV remodeling. Transient, anteriorly localized puncta of internalized CXCR4 are observed in cells undergoing endoMT. In vitro, CXCR4+ cell orientation in response to CXCL12 requires phosphatidylinositol 3-kinase (PI3K) signaling and is inhibited by suppression of endocytosis. This dynamic intracellular localization of CXCR4 during SLV development is related to CXCL12 availability, potentially enabling activation of divergent downstream signaling pathways at key developmental stages. Importantly, Cxcr7-/- mutants display evidence of excessive CXCL12 signaling, indicating a likely role for atypical chemokine receptor CXCR7 in regulating ligand bioavailability and thus CXCR4 signaling output during SLV morphogenesis.

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous ciliopathy disorder affecting cilia and sperm motility. A range of ultrastructural defects of the axoneme underlie the disease, which is characterised by chronic respiratory symptoms and

Mouse embryo imaging is conventionally carried out on ex vivo embryos excised from the amniotic sac, omitting vital structures and abnormalities external to the body. Here, we present an in amnio MR imaging methodology in which the mouse embryo is retained

Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 in 9 families with the clinical diagnosis of Jeune syndrome (asphyxiating thoracic dystrophy). WDR34 encodes a WD40 repeat-containing protein orthologous to Chlamydomonas FAP133, a dynein intermediate chain associated with the retrograde intraflagellar transport motor. Three-dimensional protein modeling suggests that the identified mutations all affect residues critical for WDR34 protein-protein interactions. We find that WDR34 concentrates around the centrioles and basal bodies in mammalian cells, also showing axonemal staining. WDR34 coimmunoprecipitates with the dynein-1 light chain DYNLL1 in vitro, and mining of proteomics data suggests that WDR34 could represent a previously unrecognized link between the cytoplasmic dynein-1 and IFT dynein-2 motors. Together, these data show that WDR34 is critical for ciliary functions essential to normal development and survival, most probably as a previously unrecognized component of the mammalian dynein-IFT machinery.

Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1β, caspase-1 activity and ASC speck release (Scambler et al. eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1β was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1β only declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1β and pro-IL-1β mRNA. This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes.

Heterogeneity of lymphatic vessels during embryogenesis is critical for organ-specific lymphatic function. Little is known about lymphatics in the developing kidney, despite their established roles in pathology of the mature organ. We performed three-dimensional imaging to characterize lymphatic vessel formation in the mammalian embryonic kidney at single-cell resolution. In mouse, we visually and quantitatively assessed the development of kidney lymphatic vessels, remodeling from a ring-like anastomosis under the nascent renal pelvis; a site of VEGF-C expression, to form a patent vascular plexus. We identified a heterogenous population of lymphatic endothelial cell clusters in mouse and human embryonic kidneys. Exogenous VEGF-C expanded the lymphatic population in explanted mouse embryonic kidneys. Finally, we characterized complex kidney lymphatic abnormalities in a genetic mouse model of polycystic kidney disease. Our study provides novel insights into the development of kidney lymphatic vasculature; a system which likely has fundamental roles in renal development, physiology and disease.

Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR-mediated chloride and bicarbonate transport, with dysregulation of epithelial sodium channels (ENaC). These changes alter fluid and electrolyte homeostasis and result in an exaggerated proinflammatory response driven, in part, by infection. We tested the hypothesis that NLRP3 inflammasome activation and ENaC upregulation drives exaggerated innate-immune responses in this multisystem disease. We identify an enhanced proinflammatory signature, as evidenced by increased levels of IL-18, IL-1β, caspase-1 activity and ASC-speck release in monocytes, epithelia and serum with CF-associated mutations; these differences were reversed by pretreatment with NLRP3 inflammasome inhibitors and notably, inhibition of amiloride-sensitive sodium (Na+) channels. Overexpression of β-ENaC, in the absence of CFTR dysfunction, increased NLRP3-mediated inflammation, indicating that dysregulated, ENaC-dependent signalling may drive exaggerated inflammatory responses in CF. These data support a role for sodium in modulating NLRP3 inflammasome activation.

TNFAIP3 encodes the NF-κB regulatory protein A20. High-penetrance heterozygous mutations in TNFAIP3 cause a haploinsufficiency of A20 (HA20), inadequate inhibition of NF-κB pathway, and an early onset autoinflammatory disorder. However, the clinical phenotype of patients with HA20 varies greatly and clinical diagnoses prior to establishing the genetic cause, included both autoimmune and autoinflammatory conditions. Here, we present the first patient with HA20, who was previously diagnosed with AOSD but was later found to have a novel heterozygous variant in TNFAIP3 and who was successfully treated with anti-IL6 receptor biologic tocilizumab (RoActemra). We discovered a novel heterozygous mutation in TNFAIP3 c.1906C>T, not previously found in ExAC database. Further analysis shows that this single-nucleotide variant at the terminal residue of TNFAIP3 exon 7 produces an alternatively spliced mRNA resulting in p.His636fsTer1. Additional genetic analysis of family members shows that this variant does segregate with the inflammatory clinical phenotypes. Subsequent functional test show that NF-κB activation, measured as intracellular phosphorylation of p65 in CD14 + monocytes, was more enhanced in the patient compared with healthy controls (HC) following stimulation with LPS. This was associated with higher production of inflammatory cytokines by the patients PBMC in response to LPS and ATP and enhanced activation of NLRP3 inflammasome complex. Furthermore, increased activation of NLRP3 inflammasome was evident systemically, since we detected higher levels of ASC specks in patients’ sera compared with HC. Finally, we used population genetics data from GnomAD to construct a map of both genetic conservation and most probable disease-causing variants in TNFAIP3 which might be found in future cases of HA20.

Tumor necrosis factor (TNF)-receptor-associated periodic fever syndrome (TRAPS) is a rare monogenic autoinflammatory disorder characterized by mutations in the TNFRSF1A gene, causing TNF-receptor 1 (TNFR1) misfolding, increased cellular stress, activation of the unfolded protein response (UPR), and hyperresponsiveness to lipopolysaccharide (LPS). Both microRNA (miR)-146a and miR-155 provide negative feedback for LPS-toll-like receptor 2/4 signaling and cytokine production, through regulation of nuclear factor kappa B (NF-κB). In this study, we hypothesized that proinflammatory cytokine signaling in TRAPS downregulates these two miRs, resulting in LPS-induced hyperresponsiveness in TRAPS dermal fibroblasts (DFs), irrespective of the underlying genetic mutation. Primary DF were isolated from skin biopsies of TRAPS patients and healthy controls (HC). TNFR1 cell surface expression was measured using immunofluorescence. DF were stimulated with LPS, interleukin (IL)-1β, thapsigargin, or TNF, with and without inositol-requiring enzyme 1 (IRE1) inhibitor (4u8C), following which miR-146a and miR-155 expression was measured by RT-qPCR. IL-1β, IL-6, and TNF secretion was measured by enzyme-linked immunosorbent assays, and baseline expression of 384 different miRs was assessed using microfluidics assays. TNFR1 was found to be expressed on the surface of HC DF but expression was deficient in all samples with TRAPS-associated mutations. HC DF showed significant dose-dependent increases in both miR-146a and miR-155 expression levels in response to LPS; however, TRAPS DF failed to upregulate either miR-146a or miR-155 under the same conditions. This lack of miR-146a and miR-155 upregulation was associated with increased proinflammatory cytokine production in TRAPS DF in response to LPS challenge, which was abrogated by 4u8C. Incubation of HC DF with IL-1β led to downregulation of miR-146a and miR-155 expression, which was dependent on IRE1 enzyme. We observed global dysregulation of hundreds of other miRs at baseline in the TRAPS DF. In summary, these data suggest a mechanism whereby IL-1β, produced in response to activation of the UPR in TRAPS DF, downregulates miR-146a and miR-155, by inducing IRE1-dependent cleavage of both these miRs, thereby impairing negative regulation of NF-κB and increasing proinflammatory cytokine production.

G6PC3 deficiency typically causes severe congenital neutropenia, associated with susceptibility to infections, cardiac and urogenital abnormalities. However, here we describe two boys of Pakistani origin who were found to have G6PC3 deficiency due to c.130 C>T mutation, but who have clinical phenotypes that are typical for a systemic autoinflammatory syndrome. The index case presented with combination of unexplained fevers, severe mucosal ulcers, abdominal symptoms, and inflammatory arthritis. He eventually fully responded to anti-TNF therapy. In this study, we show that compared with healthy controls, neutrophils and monocytes from patients have reduced glycolytic reserve. Considering that healthy myeloid cells have been shown to switch their metabolic pathways to glycolysis in response to inflammatory cues, we studied what impact this might have on production of the inflammatory cytokines. We have demonstrated that patients’ monocytes, in response to lipopolysaccharide, show significantly increased production of IL-1β and IL-18, which is NLRP3 inflammasome dependent. Furthermore, additional whole blood assays have also shown an enhanced production of IL-6 and TNF from the patients’ cells. These cases provide further proof that autoinflammatory complications are also seen within the spectrum of primary immune deficiencies, and resulting from a wider dysregulation of the immune responses.

This article describes a manualized social skills intervention for children with peer relationship problems developed by Milich and colleagues (Milich et al., 1995, 2004). The program includes deficits-based components and problem-solving/anger-management components. This intervention is meant to be delivered in a group format over 8 sessions. It was designed for children ages 7 to 13 years and 2 treatment efficacy studies have been conducted with this age group (Antshel & Remer, 2003; Lefler et al., 2008). The program has also been adapted for use with younger children in a Head Start setting, but treatment outcome research with this age group has not yet been completed. This article addresses 3 issues. First, an introduction to social skills interventions is presented. Second, the Milich et al. social skills program is described. Third, our recommendations for adapting the Milich et al. intervention for younger children is detailed as well as our clinical experience in using the intervention in Head Start.

Research on social skills interventions has been mixed. This study evaluates a group-administered, manualized social skills intervention program. Twenty-three boys and 9 girls between the ages of 7 and 13 participated. Participants were included in the groups based on peer relationship difficulties rather than diagnostic status, resulting in a diagnostically heterogeneous sample. As a group, children who were symptomatic at pretest made statistically significant and, in some cases, clinically significant improvements on socially relevant constructs. The results provide modest support for this intervention. Implications for future research, clinical work, and younger children are discussed. (Contains 4 tables and 3 figures.)

Objective: Risk criteria for the Checklist for Autism in Toddlers (CHAT) and modified risk criteria (i.e. the Denver Criteria) were compared in a group of children with fragile X syndrome (FXS) and autism. Method: Participants were 17 children aged 2-4 years with DNA confirmation of FXS. Four children had autism and 13 children did not. Results: Preliminary findings regarding the sensitivity and specificity of the CHAT for detecting risk for autism in children with FXS are as follows: using the original CHAT risk criteria, sensitivity and specificity were 50% and 100%, respectively; and using the Denver Criteria, sensitivity and specificity were 75% and 92%, respectively. Conclusions: The CHAT and the Denver Criteria resulted in preliminary findings suggesting high levels of sensitivity to autism in children with FXS.

Twenty six children with autism, 24 children with developmental disabilities, and 15 typically developing children participated in tasks in which an adult displayed emotions. Child focus of attention, change in facial tone (i.e., hedonic tone), and latency to changes in tone were measured and summary scores of emotional contagion were created. Group differences existed in the ratio of episodes that resulted in emotional contagion. Correlations existed between measures of emotional contagion, measures of joint attention, and indices of severity of autism. Children with autism demonstrated muted changes in affect, but these responses occurred much less frequently than in comparison groups. The findings suggest directions for early identification and early treatment of autism.

Only too often critical realist contributions to understanding and explaining social phenomena fall into one of two discrete categories: exercises in philosophy or social theory, or empirical research that strikes as more or less atheoretical. This paper continues a long-term project to build bridges between abstruse issues of philosophy and theory and attempts to grasp the 'how' and 'why' of actual social events. The topic selected is elite professional rugby union and the principal theme is its emergence as an extreme sport and the risk of serious injury. It is argued that the injurious nature of elite rugby has its causal genesis in the professionalization of the sport and that a critical realist-oriented sociology has an important contribution to make in framing and gasping how and why this is. [ABSTRACT FROM AUTHOR]

Haploinsufficiency of the T-box transcription factor TBX1 is responsible for many features of 22q11.2 deletion syndrome. Tbx1 is expressed dynamically in the pharyngeal apparatus during mouse development and Tbx1 homozygous mutants display numerous severe defects including abnormal cranial ganglion formation and neural crest cell defects. These abnormalities prompted us to investigate whether parasympathetic (vagal) innervation of the heart was affected in Tbx1 mutant embryos. In this report, we used an allelic series of Tbx1 mouse mutants, embryo tissue explants and cardiac electrophysiology to characterise, in detail, the function of Tbx1 in vagal innervation of the heart. We found that total nerve branch length was significantly reduced in Tbx1+/− and Tbx1neo2/− mutant hearts expressing 50% and 15% levels of Tbx1. We also found that neural crest cells migrated normally to the heart of Tbx1+/−, but not in Tbx1neo2 mutant embryos. In addition, we showed that cranial ganglia IXth and Xth were fused in Tbx1neo2/− but neuronal differentiation appeared intact. Finally, we used telemetry to monitor heart response to carbachol, a cholinergic receptor agonist, and found that heart rate recovered more quickly in Tbx1+/− animals versus controls. We speculate that this condition of decreased parasympathetic drive could result in a pro-arrhythmic substrate in some 22q11.2DS patients.

Abstract Objectives To conduct a pilot population-based study within a general practice catchment area to determine whether the incidence of breast cancer was increased in the Ashkenazi population. Design Population-based cohort study. Setting A single general practice catchment area in North London. Participants 1947 women over the age of 16 who responded to a questionnaire about ethnicity and breast cancer. Main outcome measures Incidence of breast cancer, ethnicity. Results This study showed a 1.5-fold (95% CI 0.93–2.39) increase in breast cancer risk in the Ashkenazim compared with the non-Ashkenazi white population. The increased incidence was for both premenopausal and postmenopausal breast cancer (expected incidence pre:post is 1:4 whereas in the Ashkenazim it was 1:1; 51 and 52% of cases respectively). This increase was not shown in the Sephardim. Asians had a reduction in incidence (OR = 0.44; 95% CI 0.10–1.89). Results were adjusted for other risk factors for breast cancer. Conclusion This study showed a 1.5-fold increase in breast cancer rates in Ashkenazim compared with the non-Jewish white population when adjusted for age (i.e. corrections were made to allow comparison of age groups) and this is not observed in the Sephardic population. The proportion of premenopausal breast cancer was just over double that of the general population. This is the first general practice population-based study in the UK to address this issue and has implications for general practitioners who care for patients from the Ashkenazi community.