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Objective: Erdheim‐Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome‐wide association study. Methods: After quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed. Results: A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10−11; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease. Conclusion: Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role. [ABSTRACT FROM AUTHOR]

Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells. [ABSTRACT FROM AUTHOR]

The applied knowledge test (AKT) is a computer-delivered multiple choice test offered three times a year. It forms part of the Membership of the Royal College of General Practitioners (MRCGP) examination, which licenses doctors for UK general practice. This paper investigates the effect of current quality assurance processes in the AKT on the reliability of questions which are not pretested. Test questions in the AKT are based on the RCGP curriculum blueprint, referenced to current evidence, peer-reviewed and critically appraised before they are added to the question bank. There is a standardised process for question selection and test construction. Standard setting for the AKT follows a modified Angoff process where a panel of experts make individual judgements on each question of the test estimating the likelihood of the 'just-passing candidate' answering correctly. In the three examinations delivered in 2011 (AKT 11 (January), 12 (May) and 13 (October)) Cronbach's alpha was 0.88, 0.92, 0.91, respectively. For pretested questions, the predicted alpha was 0.90, 0.93, 0.92 and for non-pretested questions 0.84, 0.91, 0.92, respectively adjusting for test length using the Spearman-Brown formula. Pretesting of questions is unnecessary provided there is a systematic process of question and test construction which quality assures the AKT. This ensures that pretesting does not delay the use of questions to examine current knowledge and guidelines. [ABSTRACT FROM AUTHOR]

The applied knowledge test (AKT) is a computer-delivered multiple choice test offered three times a year. It forms part of the Membership of the Royal College of General Practitioners (MRCGP) examination, which licenses doctors for UK general practice. This paper investigates the effect of current quality assurance processes in the AKT on the reliability of questions which are not pretested. Test questions in the AKT are based on the RCGP curriculum blueprint, referenced to current evidence, peer-reviewed and critically appraised before they are added to the question bank. There is a standardised process for question selection and test construction. Standard setting for the AKT follows a modified Angoff process where a panel of experts make individual judgements on each question of the test estimating the likelihood of the 'just-passing candidate' answering correctly. In the three examinations delivered in 2011 (AKT 11 (January), 12 (May) and 13 (October)) Cronbach's alpha was 0.88, 0.92, 0.91, respectively. For pretested questions, the predicted alpha was 0.90, 0.93, 0.92 and for non-pretested questions 0.84, 0.91, 0.92, respectively adjusting for test length using the Spearman-Brown formula. Pretesting of questions is unnecessary provided there is a systematic process of question and test construction which quality assures the AKT. This ensures that pretesting does not delay the use of questions to examine current knowledge and guidelines. [ABSTRACT FROM AUTHOR]

Aims To reassess the prognostic validity of immunohistochemical markers and algorithms identified in the CHOP era in immunochemotherapy-treated diffuse large B cell lymphoma patients. Methods and results The prognostic significance of immunohistochemical markers ( CD10, Bcl-6, Bcl-2, MUM1, Ki-67, CD5, GCET1, Fox P1, LMO2) and algorithms ( Hans, Hans*, Muris, Choi, Choi*, Nyman, Visco- Young, Tally) was assessed using clinical diagnostic blocks taken from an unselected, population-based cohort of 190 patients treated with R- CHOP. Dichotomizing expression, low CD10 (<10%), low LMO2 (<70%) or high Bcl-2 (≥80%) predicted shorter overall survival ( OS; P = 0.033, P = 0.010 and P = 0.008, respectively). High Bcl-2 (≥80%), low Bcl-6 (<60%), low GCET1 (<20%) or low LMO2 (<70%) predicted shorter progression-free survival ( PFS; P = 0.001, P = 0.048, P = 0.045 and P = 0.002, respectively). The Hans, Hans* and Muris classifiers predicted OS ( P = 0.022, P = 0.037 and P = 0.011) and PFS ( P = 0.021, P = 0.020 and P = 0.004). The Choi, Choi* and Tally were associated with PFS ( P = 0.049, P = 0.009 and P = 0.023). In multivariate analysis, the International Prognostic Index ( IPI) was the only independent predictor of outcome ( OS; HR: 2.60, P < 0.001 and PFS; HR: 2.91, P < 0.001). Conclusions Results highlight the controversy surrounding immunohistochemistry-based algorithms in the R- CHOP era. The need for more robust markers, applicable to the clinic, for incorporation into improved prognostic systems is emphasized. [ABSTRACT FROM AUTHOR]

The article reports a study which was conducted to identify the organisational cultural dimensions in two general practices and their relationship to the development of Medical Leadership Competency Framework (MLCF) competencies. The two practices studied demonstrated features of rational outcomes-based culture; and a developmental culture, characterized as adaptive, flexible, and with an external focus. General practices need to take account of existing culture(s) before implementing the MLCF.

Background A new computer-based Applied Knowledge Test (AKT) has been developed for the licensing examination for general practice administered by the Royal College of General Practitioners. Aim The aim of this evaluation was to assess the acceptability, feasibility, and validity of the test as well as its transfer to a computerised format at local test centres. Design of study Computer-based test and postal questionnaire. Participants and setting Panel of examiners, Membership of the Royal College of General Practitioners (MRCGP) examination, UK. Method Self-administered postal questionnaires were sent to examiners not involved with the development of the test after completing it. Their performance scores were compared with those of candidates. Results The majority of participants (80.9%) were satisfied with the new computer-based test. Responses relating to content and attitudes to the test were also positive overall, but some problems with content were highlighted. Fewer examiners (61.9%) were positive about the physical comfort of the test centre, including seating, heating, and lighting. Examiners had significantly higher scores (mean 83.3%, range 69 to 93%, 95% confidence interval [CI] = 81.9 to 84.7%) than 'real' candidates (mean 75.0%, range 45 to 94%, 95% CI = 74.6 to 75.5%), who subsequently took an identical test. Conclusion The new computer-based licensing test (the AKT) was found to be acceptable to the majority of examiners. The pass-fail standard, determined by routine methods including an Angoff procedure, was supported by the higher success rate of examiners compared with candidates. The use of selected groups to assess high-stakes (licensing) examinations can be useful for assessing test validity. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the performance of a sample of general practitioner (GP) trainers in the multiple choice paper (MCP) of the Membership Examination of the Royal College of General Practitioners (MRCGP) and to obtain their views of the content of the paper and its relevance to general practice using a written knowledge test and self-administered questionnaire. The participants were volunteer GP trainers in the Northern, Wessex, Kent, Surrey and Sussex (KSS) and Northwest deaneries of the UK. The trainers completed a shortened version of an MRCGP MCP paper under examination conditions and provided feedback immediately afterwards. Of 191 trainers invited to participate, 86 (45%) sat the paper and of these, 81 completed the questionnaire. Most trainers believed that the paper assessed knowledge of common or important topics relevant to general practice, that the majority of questions were appropriate, clear and unambiguous and that time pressure was not a problem. Trainers performed significantly better compared to registrars overall, and in questions on medicine related to general practice and practice administration but not research methodology or critical appraisal. They did so without making prior preparation. The findings from this group of trainers lend support to the face validity and content validity of the MRCGP MCP examination as an assessment of applied knowledge of general practice. [ABSTRACT FROM AUTHOR]

This paper presents a work-based management development programme for practice managers working in the north west of England. The paper explains that the programme is a response to the changing nature of the role of the practice manager, particularly in the light of organisational change and policy reform in the primary care sector. It is designed to help practice managers to make the transition to a more strategically focused managerial role. The paper outlines the programme design, based on a partnership approach between a university and teaching PCT. It also describes the programme content, aligned to developing competency and skills development; and delivery, based on a ‘blended’ approach, utilising workshops and supported by e learning tools. The main features of the programme are described and several key issues that are likely to emerge with relevance to other developmental initiatives are suggested. These include the importance of flexibility, the emphasis on work based learning and reflective practice, personal support and mentoring, shared learning, and employer support. To date, the programme has been delivered to five groups of general practice managers and two groups of dental practice managers. [ABSTRACT FROM AUTHOR]

Background: The 313-variant polygenic risk score (PRS313) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Methods: We explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank. The mean PRS was calculated by country in the BCAC dataset and by country of birth in the UK Biobank. We explored different approaches to reduce the observed heterogeneity in the mean PRS across the countries, and investigated the implications of the distribution variability in risk prediction. Results: The mean PRS313 differed markedly across European countries, being highest in individuals from Greece and Italy and lowest in individuals from Ireland. Using the overall European PRS313 distribution to define risk categories, leads to overestimation and underestimation of risk in some individuals from these countries. Adjustment for principal components explained most of the observed heterogeneity in the mean PRS. The mean estimates derived when using an empirical Bayes approach were similar to the predicted means after principal component adjustment. Conclusions: Our results demonstrate that PRS distribution differs even within European ancestry populations leading to underestimation or overestimation of risk in specific European countries, which could potentially influence clinical management of some individuals if is not appropriately accounted for. Population-specific PRS distributions may be used in breast cancer risk estimation to ensure predicted risks are correctly calibrated across risk categories. [ABSTRACT FROM AUTHOR]

BACKGROUND: Microplastics are a pervasive contaminant cycling through food webs—leading to concerns regarding exposure and risk to humans. OBJECTIVES: We aimed to quantify and characterize anthropogenic particle contamination (including microplastics) in fish caught for human consumption from the Humber Bay region of Lake Ontario. We related quantities of anthropogenic particles to other factors (e.g., fish size) that may help in understanding accumulation of microplastics in fish. METHODS: A total of 45 samples of six fish species collected from Humber Bay in Lake Ontario near Toronto, Ontario, Canada, were examined for anthropogenic particles in their gastrointestinal (GI) tracts and fillets. Using microscopy and spectroscopy, suspected anthropogenic particles were identified and characterized. RESULTS: We observed anthropogenic particles in the GI tracts and fillets of all species. Individual fish had a mean±standard deviation of 138±231 anthropogenic particles, with a single fish containing up to 1,508 particles. GI tracts had 93±226 particles/fish (9.8±32.6 particles/gram), and fillets had 56±61 particles/fish (0.5±0.8 particles/gram). Based on a consumption rate of 2 servings/week, the average yearly human exposure through the consumption of these fish fillets would be 12,800±18,300 particles. DISCUSSION: Our findings suggest that consumption of recreationally caught freshwater fish can be a pathway for human exposure to microplastics. The elevated number of particles observed in fish from Humber Bay highlights the need for large-scale geographic monitoring, especially near sources of microplastics. Currently, it is unclear what the effects of ingesting microplastics are for humans, but given that recreationally caught freshwater fish are one pathway for human exposure, these data can be incorporated into future human health risk assessment frameworks for microplastics. [ABSTRACT FROM AUTHOR]

The article discusses a study which compared the differences for male and female candidates with respect to their knowledge relating to sex-specific questions in the Applied Knowledge Test (AKT). A cross-sectional design utilizing routinely collected performance and demographic data from the first three versions of the AKT was used. It notes that choice of doctors by patient is often related to interpersonal skills, clinical behaviour and expertise rather than the physician's sex.

In the last few decades, the word 'safety' has become silently but increasingly pervasive in educational policies and debates, gaining a new momentum with the pandemic. Our intention in this article is to problematise what is done in schools in the name of safety by delving into the safety policy discourses of a New Zealand school and the narratives of resistance employed by a group of female Pasifika students during the Covid-19 crisis. This critical ethnographic inquiry explores how safety at schools operates as a mechanism to oppress their fights and reproduce inequalities in an era of apparent 'racism without racists'. [ABSTRACT FROM AUTHOR]

Silicon nanowires (SiNWs) with good extinction performance achieve light capture larger than own cross-section. However, the isotropic response of the polarization angle and the narrow response spectrum of SiNWs limit their application in optoelectronic detectors. In this work, we designed a kind of oblate SiNWs with excellent anisotropic response and wide absorption spectrum, which is suitable for linear polarized light detection. According to the propagation characteristics of electromagnetic waves in the Si material medium, it is found that the induced current presents a vortex flow in the polarization plane of the incident light. Meanwhile, extending the scale of SiNWs in the polarization plane increases the number and mode of induced current to accelerate the attenuation of light in SiNWs for broadens the response spectrum. In addition, this scale extending changes the axial symmetry of SiNWs to achieve anisotropic response. Based on numerical simulation technology, it is obtained that when the incident light wavelength is 420 nm, the light absorption coefficient (Qabs) of oblate SiNWs is 11.42 higher than that of cylindrical SiNWs. The excellent Qabs anisotropy ratio (Qmax/Qmin) of oblate SiNWs can be achieved in the range of 400 nm to 650 nm, of which the maximum value is 74.18. This provides ideas for the design of semiconductor nanowires and their application in photodetectors. [ABSTRACT FROM AUTHOR]

This paper outlines the public health issues relating to the north-west region of England. The role of Primary Care Trusts in addressing the health and well-being issues is described and the development of Teaching Public Health Networks to support capacity and capability building in the public health workforce is outlined. Healthy weight management is used as a case study of how public health and primary care can be brought closer together by describing the role of the Food and Health Action Plan in addressing healthy weight management and its relationship with primary care. [ABSTRACT FROM PUBLISHER]

Chew, Teng Keat, BSH23-EP51. Ross, David M, BSH23-PO33, BSH23-PO35. B v b van de Donk, Niels WCJ, BSH23-EP162. van de Wetering, Gijs, BSH23-PO72, BSH23-PO78. van der Poel, Marjolein, BSH23-OR13. Tan, Sui Keat, BSH23-EP51. Peffault de Latour, R, BSH23-PO103. [Extracted from the article]

828 The use of digital platforms in the financial sector requires automated processes in order to collect the large volumes of data which will allow firms to create a shared understanding around rules through technological applications. The UK Financial Conduct Authority launched innovation programmes, i. e. a regulatory sandbox, to assess technologies and expedite the delivery of fintech products. This initiative has been followed by the European Digital Finance Package, which introduced the Pilot Regime for market infrastructure based on distributed ledger technology. Albeit a laudable initiative, the EU sandbox model may face obstacles on account of the different approaches taken by Member States in relieving regulatory requirements which can create a perverse incentive to circumvent prudential rules in the context of risk assessment. This article examines the impact of sandboxes on the operation of digital platforms and considers the extent to which decision-making processes are amenable to digital treatment, and what will be the implications for the quality of regulation and the exercise of judgement by the supervisory authority. It argues that the application of regulatory sandboxes can promote more effective compliance processes, while ensuring transparency and accuracy of enforcement actions. 829 [ABSTRACT FROM AUTHOR]

854 Despite a pandemic, crowdfunding continues to be a growing source of finance for small businesses across the EU. This article discusses nature and business typology of digital platforms that raise funds from the crowd. In the effort to support the ongoing uptake of new technologies in financial services, the first harmonised regime for the intermediation of financial instruments and loans to businesses via digital crowdfunding platforms has recently entered into application and promises to change the landscape of this financial service in the years to come. The new policy framework creates a robust EU-wide license, with requirements that support integration with social media, as well as the progressive creation of pan-European one-stop-shop platforms that offer multiple funding tools. Moreover, the regime also tests new boundaries in investor protection and behavioural finance, with the introduction of a system of warnings, targeted transparency on multiple levels and a conflict-of-interest framework to ensure that the platform acts as a risk neutral gatekeeper. The jury is still out and there are a number of unknowns, as this new framework will have to face the reality of well-established legal and supervisory national obstacles in its implementation. [ABSTRACT FROM AUTHOR]

In the Māori world, people move backwards into the future. The past is on the horizon, we can see it, we know it. The future remains uncertain, we must sharpen our senses and proceed with caution. This article contends that a change of perspective is the most powerful tool to identify multiple ethical implications when conducting research in settings characterized by unfolding processes that weave together human interventions and non-human agency. Walking backwards and based on ethnographic fieldwork in Māori lands, scientific laboratories, research nurseries, and healthy and declining forest in the upper North Island of New Zealand, this paper reflects on the ethical issues that arise from meeting in the field with scientists, Indigenous experts, lethal microorganisms, and giant ancient trees, while also considering the evidence of past multispecies encounters and the uncertainty of future ones. Aware that most of the terrestrial biomass remains outside the field of vision of institutional review boards, this article argues for the adoption of a broader conception of ethics, not as a human construct associated with the production of knowledge, but rather as an essential component of all interdependencies that make life possible on Earth. [ABSTRACT FROM AUTHOR]