Inhibition of the glucocorticoid-activating enzyme 11ß-hydroxysteroid dehydrogenase type 1 drives concurrent 11-oxygenated androgen excess.

Aldo-keto reductase 1C3 (AKR1C3) is a key enzyme in the activation of both classic and 11-oxygenated androgens. In adipose tissue, AKR1C3 is co-expressed with 11ß-hydroxysteroid dehydrogenase type 1 (HSD11B1), which catalyzes not only the local activation of glucocorticoids but also the inactivation of 11-oxygenated androgens, and thus has the potential to counteract AKR1C3. Using a combination of in vitro assays and in silico modeling we show that HSD11B1 attenuates the biosynthesis of the potent 11-oxygenated androgen, 11-ketotestosterone (11KT), by AKR1C3. Employing ex vivo incubations of human female adipose tissue samples we show that inhibition of HSD11B1 results in the increased peripheral biosynthesis of 11KT. Moreover, circulating 11KT increased 2-3 fold in individuals with type 2 diabetes after receiving the selective oral HSD11B1 inhibitor AZD4017 for 35 days, thus confirming that HSD11B1 inhibition results in systemic increases in 11KT concentrations. Our findings show that HSD11B1 protects against excess 11KT production by adipose tissue, a finding of particular significance when considering the evidence for adverse metabolic effects of androgens in women. Therefore, when targeting glucocorticoid activation by HSD11B1 inhibitor treatment in women, the consequently increased generation of 11KT may offset beneficial effects of decreased glucocorticoid activation.

Reliability, validity and acceptability of an online clinical reasoning simulator for medical students: An international pilot.

INTRODUCTION: Clinical reasoning skills are essential for decision-making. Current assessment methods are limited when testing clinical reasoning and management of uncertainty. This study evaluates the reliability, validity and acceptability of Practicum Script, an online simulation-based programme, for developing medical students' clinical reasoning skills using real-life cases. METHODS: In 2020, we conducted an international, multicentre pilot study using 20 clinical cases with 2457 final-year medical students from 21 schools worldwide. Psychometric analysis was performed (n = 1502 students completing at least 80% of cases). Classical estimates of reliability for three test domains (hypothesis generation, hypothesis argumentation and knowledge application) were calculated using Cronbach's alpha and McDonald's omega coefficients. Validity evidence was obtained by confirmatory factor analysis (CFA) and measurement alignment (MA). Items from the knowledge application domain were analysed using cognitive diagnostic modelling (CDM). Acceptability was evaluated by an anonymous student survey. RESULTS: Reliability estimates were high with narrow confidence intervals. CFA revealed acceptable goodness-of-fit indices for the proposed three-factor model. CDM analysis demonstrated good absolute test fit and high classification accuracy estimates. Student survey responses showed high levels of acceptability. CONCLUSION: Our findings suggest that Practicum Script is a useful resource for strengthening students' clinical reasoning skills and ability to manage uncertainty.

Myeloid expression of the anti-apoptotic protein Mcl1 is required in anti-myeloperoxidase vasculitis but myeloperoxidase inhibition is not protective.

Antibodies to neutrophil and monocyte myeloperoxidase and proteinase 3 are a feature of anti-neutrophil cytoplasmic antibody vasculitis, a disease with significant morbidity for which new treatments are needed. Mice with a myeloid-specific deletion of the anti-apoptotic protein Mcl1 have reduced numbers of circulating neutrophils. Here, we assessed if myeloid-specific Mcl1 was required in murine anti-myeloperoxidase vasculitis and whether inhibition of myeloperoxidase was protective. In a murine model of anti-neutrophil cytoplasmic antibody vasculitis, induced by anti-myeloperoxidase antibody, mice with a myeloid-specific deletion of Mcl1 were protected from disease. They had fewer crescents, neutrophils, and macrophages in the glomeruli, lower serum creatinine levels and reduced albuminuria compared with controls. At baseline and day six after disease induction they had fewer circulating neutrophils than controls. At day six there were also fewer circulating monocytes. Myeloperoxidase inhibition with AZD5904 had no effect on histological or biochemical parameters of disease, and there was also no reduction in albuminuria at day one, two, five or seven after disease induction. These findings persisted when disease was induced without granulocyte-colony stimulating factor, which increases disease severity. A second myeloperoxidase inhibitor, AZM198, also showed no evidence of an effect, although both AZD5904 and AZM198 inhibited human neutrophil extracellular trap formation in vitro. Thus, our results show that while myeloid-specific Mcl1 is required in this model of anti-myeloperoxidase vasculitis, myeloperoxidase inhibition is not protective.

Examiner perceptions of the MRCGP recorded consultation assessment for general practice licensing during COVID-19: cross-sectional study.

BACKGROUND: The Recorded Consultation Assessment (RCA) was developed rapidly during the COVID-19 pandemic to replace the Clinical Skills Assessment (CSA) for UK general practice licensing. Our aim was to evaluate examiner perceptions of the RCA. METHODS: We employed a cross-sectional design using a questionnaire survey of RCA examiners with attitudinal (relating to examiners thoughts and perceptions of the RCA) and free text response options. We conducted statistical descriptive and factor analysis of quantitative data with qualitative thematic analysis of free text responses. RESULTS: Overall, 182 of 260 (70%) examiners completed the questionnaire. Responders felt that consultations submitted were representative of the work of a typical GP during the pandemic and provided a good sample across the curriculum. They were also generally positive about the logistic, advisory and other support provided as well as the digital platform. Despite responders generally agreeing there was sufficient information available in video or audio consultations to judge candidates' data gathering, clinical management, and interpersonal skills, they were less confident about their ability to make judgments of candidates' performance compared with the CSA. The qualitative analysis of free text responses detailed the problems of case selection and content, explained examiners' difficulties when making judgments, and detailed the generally positive views about support, training and information technology. Responders also provided helpful recommendations for improving the assessment. CONCLUSION: The RCA was considered by examiners to be feasible and broadly acceptable, although they experienced challenges from candidate case selection, case content and judgments leading to suggested areas for improvement.

Candidate perceptions of the UK Recorded Consultation Assessment: cross-sectional data linkage study.

The Recorded Consultation Assessment (RCA) was rapidly developed to replace the Clinical Skills Assessment (CSA) for UK general practice licencing during COVID-19. We aimed to evaluate candidate perceptions of the RCA and relationships with performance. We conducted a cross-sectional survey of RCA candidates with attitudinal, demographic, and free text response options, undertaking descriptive and factor analysis of quantitative data with qualitative thematic analysis of free text. Binomial regression was used to estimate associations between RCA pass, candidate characteristics and questionnaire responses.645 of 1551 (41.6%) candidates completed a questionnaire; 364 (56.4%) responders permitted linkage with performance and demographic data. Responders and non-responders were similar in exam performance, gender and declared disability but were significantly more likely to be UK graduates (UKG) or white compared with international medical (IMG) or ethnic minority graduates. Responders were positive about the digital platform and support resources. A small overall majority regarded the RCA as a fair assessment; a larger majority reported difficulty collecting, selecting, and submitting cases or felt rushed during recording.Logistic regression showed that ethnicity (white vs minority ethnic: odds ratio [OR] 2.99,95% confidence interval [CI] 1.23, 7.30, p = 0.016), training (UK vs IMG: OR 6.88, 95% CI 2.79, 16.95, p < 0.001), and English as first language (OR 5.11, 0% CI 2.08, 12.56, p < 0.001) were associated with exam success but questionnaire subscales, consultation type submitted, or extent of trainer review were not. The RCA was broadly acceptable but experiences were variable. Candidates experienced challenges and suggested areas for improvement.

Ottawa 2020 consensus statement for programmatic assessment - 1. Agreement on the principles.

INTRODUCTION: In the Ottawa 2018 Consensus framework for good assessment, a set of criteria was presented for systems of assessment. Currently, programmatic assessment is being established in an increasing number of programmes. In this Ottawa 2020 consensus statement for programmatic assessment insights from practice and research are used to define the principles of programmatic assessment. METHODS: For fifteen programmes in health professions education affiliated with members of an expert group (n = 20), an inventory was completed for the perceived components, rationale, and importance of a programmatic assessment design. Input from attendees of a programmatic assessment workshop and symposium at the 2020 Ottawa conference was included. The outcome is discussed in concurrence with current theory and research. RESULTS AND DISCUSSION: Twelve principles are presented that are considered as important and recognisable facets of programmatic assessment. Overall these principles were used in the curriculum and assessment design, albeit with a range of approaches and rigor, suggesting that programmatic assessment is an achievable education and assessment model, embedded both in practice and research. Knowledge on and sharing how programmatic assessment is being operationalized may help support educators charting their own implementation journey of programmatic assessment in their respective programmes.

Ottawa 2020 consensus statements for programmatic assessment - 2. Implementation and practice.

INTRODUCTION: Programmatic assessment is a longitudinal, developmental approach that fosters and harnesses the learning function of assessment. Yet the implementation, a critical step to translate theory into practice, can be challenging. As part of the Ottawa 2020 consensus statement on programmatic assessment, we sought to provide descriptions of the implementation of the 12 principles of programmatic assessment and to gain insight into enablers and barriers across different institutions and contexts. METHODS: After the 2020 Ottawa conference, we surveyed 15 Health Profession Education programmes from six different countries about the implementation of the 12 principles of programmatic assessment. Survey responses were analysed using a deductive thematic analysis. RESULTS AND DISCUSSION: A wide range of implementations were reported although the principles remained, for the most part, faithful to the original enunciation and rationale. Enablers included strong leadership support, ongoing faculty development, providing students with clear expectations about assessment, simultaneous curriculum renewal and organisational commitment to change. Most barriers were related to the need for a paradigm shift in the culture of assessment. Descriptions of implementations in relation to the theoretical principles, across multiple educational contexts, coupled with explanations of enablers and barriers, provided new insights and a clearer understanding of the strategic and operational considerations in the implementation of programmatic assessment. Future research is needed to further explore how contextual and cultural factors affect implementation.

Cut-scores revisited: feasibility of a new method for group standard setting.

BACKGROUND: Standard setting is one of the most contentious topics in educational measurement. Commonly-used methods all have well reported limitations. To date, there is not conclusive evidence suggesting which standard setting method yields the highest validity. METHODS: The method described and piloted in this study asked expert judges to estimate the scores on a real MCQ examination that they consider indicated a clear pass, clear fail, and pass mark for the examination as a whole. The mean and SD of the judges responses to these estimates, Z scores and confidence intervals were used to derive the cut-score and the confidence in it. RESULTS: In this example the new method's cut-score was higher than the judges' estimate. The method also yielded estimates of statistical error which determine the range of the acceptable cut-score and the estimated level of confidence one may have in the accuracy of that cut-score. CONCLUSIONS: This new standard-setting method offers some advances, and possibly advantages, in that the decisions being asked of judges are based on firmer constructs, and it takes into account variation among judges.

Automated quantification of 3D wound morphology by machine learning and optical coherence tomography in type 2 diabetes.

Background: Driven by increased prevalence of type 2 diabetes and ageing populations, wounds affect millions of people each year, but monitoring and treatment remain limited. Glucocorticoid (stress hormones) activation by the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) also impairs healing. We recently reported that 11ß-HSD1 inhibition with oral AZD4017 improves acute wound healing by manual 2D optical coherence tomography (OCT), although this method is subjective and labour-intensive. Objectives: Here, we aimed to develop an automated method of 3D OCT for rapid identification and quantification of multiple wound morphologies. Methods: We analysed 204 3D OCT scans of 3 mm punch biopsies representing 24 480 2D wound image frames. A u-net method was used for image segmentation into 4 key wound morphologies: early granulation tissue, late granulation tissue, neo-epidermis, and blood clot. U-net training was conducted with 0.2% of available frames, with a mini-batch accuracy of 86%. The trained model was applied to compare segment area (per frame) and volume (per scan) at days 2 and 7 post-wounding and in AZD4017 compared to placebo. Results: Automated OCT distinguished wound tissue morphologies, quantifying their volumetric transition during healing, and correlating with corresponding manual measurements. Further, AZD4017 improved epidermal re-epithelialisation (by manual OCT) with a corresponding trend towards increased neo-epidermis volume (by automated OCT). Conclusion: Machine learning and OCT can quantify wound healing for automated, non-invasive monitoring in real-time. This sensitive and reproducible new approach offers a step-change in wound healing research, paving the way for further development in chronic wounds.

Performance of ethnic minority versus White doctors in the MRCGP assessment 2016-2021: a cross-sectional study.

BACKGROUND: Differential attainment has previously been suggested as being due to subjective bias because of racial discrimination in clinical skills assessments. AIM: To investigate differential attainment in all UK general practice licensing tests comparing ethnic minority with White doctors. DESIGN AND SETTING: Observational study of doctors in GP specialty training in the UK. METHOD: Data were analysed from doctors' selection in 2016 to the end of GP training, linking selection, licensing, and demographic data to develop multivariable logistic regression models. Predictors of pass rates were identified for each assessment. RESULTS: A total of 3429 doctors entering GP specialty training in 2016 were included, with doctors of different sex (female 63.81% versus male 36.19%), ethnic group (White British 53.95%, minority ethnic 43.04%, and mixed 3.01%), country of primary medical qualification (UK 76.76% versus non-UK 23.24%), and declared disability (disability declared 11.98% versus not declared 88.02%). Multi-Specialty Recruitment Assessment (MSRA) scores were highly predictive for GP training end-point assessments, including the Applied Knowledge Test (AKT), Clinical Skills Assessment (CSA), Recorded Consultation Assessment (RCA), and Workplace-Based Assessment (WPBA) and Annual Review of Competency Progression (ARCP). Ethnic minority doctors did significantly better compared with White British doctors in the AKT (odds ratio [OR] 2.05, 95% confidence interval [CI] = 1.03 to 4.10, P = 0.042). There were no significant differences on other assessments: CSA (OR 0.72, 95% CI = 0.43 to 1.20, P = 0.201), RCA (OR 0.48, 95% CI = 0.18 to 1.32, P = 0.156), or WPBA-ARCP (OR 0.70, 95% CI = 0.49 to 1.01, P = 0.057). CONCLUSION: Ethnic background did not reduce the chance of passing GP licensing tests once sex, place of primary medical qualification, declared disability, and MSRA scores were accounted for.

A systemic framework for the progress test: strengths, constraints and issues: AMEE Guide No. 71.

There has been increasing use and significance of progress testing in medical education. It is used in many ways and with several formats to reflect the variety of curricula and assessment purposes. These developments have occurred alongside a recognised sensitivity for error variance inherent in multiple choice tests from which challenges to its validity and reliability have arisen. This Guide presents a generic, systemic framework to help identify and explore improvements in the quality and defensibility of progress test data. The framework draws on the combined experience of the Dutch consortium, an individual medical school in the United Kingdom, and the bulk of the progress test literature to date. It embeds progress testing as a quality-controlled assessment tool for improving learning, teaching and the demonstration of educational standards. The paper describes strengths, highlights constraints and explores issues for improvement. These may assist in the establishment of potential or new progress testing in medical education programmes. They can also guide the evaluation and improvement of existing programmes.

StarGazer: A Hybrid Intelligence Platform for Drug Target Prioritization and Digital Drug Repositioning Using Streamlit.

Target prioritization is essential for drug discovery and repositioning. Applying computational methods to analyze and process multi-omics data to find new drug targets is a practical approach for achieving this. Despite an increasing number of methods for generating datasets such as genomics, phenomics, and proteomics, attempts to integrate and mine such datasets remain limited in scope. Developing hybrid intelligence solutions that combine human intelligence in the scientific domain and disease biology with the ability to mine multiple databases simultaneously may help augment drug target discovery and identify novel drug-indication associations. We believe that integrating different data sources using a singular numerical scoring system in a hybrid intelligent framework could help to bridge these different omics layers and facilitate rapid drug target prioritization for studies in drug discovery, development or repositioning. Herein, we describe our prototype of the StarGazer pipeline which combines multi-source, multi-omics data with a novel target prioritization scoring system in an interactive Python-based Streamlit dashboard. StarGazer displays target prioritization scores for genes associated with 1844 phenotypic traits, and is available via https://github.com/AstraZeneca/StarGazer.

An organ-on-chip model of pulmonary arterial hypertension identifies a BMPR2-SOX17-prostacyclin signalling axis.

Pulmonary arterial hypertension (PAH) is an unmet clinical need. The lack of models of human disease is a key obstacle to drug development. We present a biomimetic model of pulmonary arterial endothelial-smooth muscle cell interactions in PAH, combining natural and induced bone morphogenetic protein receptor 2 (BMPR2) dysfunction with hypoxia to induce smooth muscle activation and proliferation, which is responsive to drug treatment. BMPR2- and oxygenation-specific changes in endothelial and smooth muscle gene expression, consistent with observations made in genomic and biochemical studies of PAH, enable insights into underlying disease pathways and mechanisms of drug response. The model captures key changes in the pulmonary endothelial phenotype that are essential for the induction of SMC remodelling, including a BMPR2-SOX17-prostacyclin signalling axis and offers an easily accessible approach for researchers to study pulmonary vascular remodelling and advance drug development in PAH.

Non-covalent inhibitors of rhinovirus 3C protease.

The first known non-covalent inhibitors of rhinovirus 3C protease (3CP) have been identified through fragment based screening and hit identification activities.

Public-Private Partnerships: Compound and Data Sharing in Drug Discovery and Development.

Collaborative efforts between public and private entities such as academic institutions, governments, and pharmaceutical companies form an integral part of scientific research, and notable instances of such initiatives have been created within the life science community. Several examples of alliances exist with the broad goal of collaborating toward scientific advancement and improved public welfare. Such collaborations can be essential in catalyzing breaking areas of science within high-risk or global public health strategies that may have otherwise not progressed. A common term used to describe these alliances is public-private partnership (PPP). This review discusses different aspects of such partnerships in drug discovery/development and provides example applications as well as successful case studies. Specific areas that are covered include PPPs for sharing compounds at various phases of the drug discovery process-from compound collections for hit identification to sharing clinical candidates. Instances of PPPs to support better data integration and build better machine learning models are also discussed. The review also provides examples of PPPs that address the gap in knowledge or resources among involved parties and advance drug discovery, especially in disease areas with unfulfilled and/or social needs, like neurological disorders, cancer, and neglected and rare diseases.

Choosing and designing knowledge assessments: experience at a new medical school.

BACKGROUND: Curriculum developers have a wide choice of assessment methods in all aspects of medical education including the specific area of medical knowledge. When selecting the appropriate tool, there is an increasing literature to provide a robust evidence base for developments or decisions. AIM: As a new medical school, we wished to select the most appropriate method for knowledge assessment. METHODS: This article describes how a new medical school came to choose progress testing as its only method of summative assessment of undergraduate medical knowledge. RESULTS: The rationale, implementation, development and performance of the assessment are described. The position after the first cohort of students qualified is evaluated. CONCLUSION: Progress testing has worked well in a new school. Opportunities for further study and development exist. It is to be hoped that our experiences and evidence will assist and inform others as they consider developments for their own schools.

Can we share questions? Performance of questions from different question banks in a single medical school.

BACKGROUND: To use progress testing, a large bank of questions is required, particularly when planning to deliver tests over a long period of time. The questions need not only to be of good quality but also balanced in subject coverage across the curriculum to allow appropriate sampling. Hence as well as creating its own questions, an institution could share questions. Both methods allow ownership and structuring of the test appropriate to the educational requirements of the institution. METHOD: Peninsula Medical School (PMS) has developed a mechanism to validate questions written in house. That mechanism can be adapted to utilise questions from an International question bank International Digital Electronic Access Library (IDEAL) and another UK-based question bank Universities Medical Assessment Partnership (UMAP). These questions have been used in our progress tests and analysed for relative performance. RESULTS: Data are presented to show that questions from differing sources can have comparable performance in a progress testing format. CONCLUSION: There are difficulties in transferring questions from one institution to another. These include problems of curricula and cultural differences. Whilst many of these difficulties exist, our experience suggests that it only requires a relatively small amount of work to adapt questions from external question banks for effective use. The longitudinal aspect of progress testing (albeit summatively) may allow more flexibility in question usage than single high stakes exams.

Beyond assessment: feedback for individuals and institutions based on the progress test.

BACKGROUND: Progress testing is used at Peninsula Medical School to test applied medical knowledge four times a year using a 125-item multiple choice test. Items within each test are classified and matched to the curriculum blueprint. AIM: To examine the use of item classifications as part of a quality assurance process and to examine the range of available feedback provided after each test or group of tests. METHODS: The questions were classified using a single best classification method. These were placed into a simplified version of the progress test assessment blueprint. Average item facilities for individuals and cohorts were used to provide feedback to individual students and curriculum designers. RESULTS: The analysis shows that feedback can be provided at a number of levels, and inferences about various groups can be made. It demonstrates that learning mostly occurs in the early years of the course, but when examined longitudinally, it shows how different patterns of learning exist in different curriculum areas. It also shows that the effect of changes in the curriculum may be monitored through these data. CONCLUSIONS: Used appropriately, progress testing can provide a wide range of feedback to every individual or group of individuals in a medical school.

Adaptation of medical progress testing to a dental setting.

Although progress testing (PT) is well established in several medical schools, it is new to dentistry. Peninsula College of Medicine and Dentistry has recently established a Bachelor of Dental Surgery programme and has been one of the first schools to use PT in a dental setting. Issues associated with its development and of its adaption to the specific needs of the dental curriculum are considered.