Investigating the physiological role of PYY-expressing cells in the gut and pancreas

Peptide YY (PYY) is a hormone produced by the enteroendocrine L cells in the gut. It is also expressed in the pancreatic islets and brainstem. PYY is secreted from the L cells in proportion to caloric intake and is involved in the regulation of satiety and energy homeostasis. The physiological role of PYY in the pancreatic islets and brainstem is not clear. In order to investigate the physiological role of PYY-expressing cells, I used a transgenic mouse model in which diphtheria toxin receptor (DTR) is expressed downstream of the PYY promoter. This enabled ablation of the PYY-expressing cells following administration of diphtheria toxin (DT) in adult mice. Intraperitoneal administration of DT at a dose of 40ng/g resulted in a significant loss of colonic, pancreatic and brainstem PYY (> 95%). Interestingly, ablation of PYY-expressing cells resulted in a significant loss of pancreatic insulin and hence severe hyperglycaemia in adult mice. In vitro administration of DT in cultured islets resulted in a significant dose-dependent loss of insulin, PYY and glucagon content. Immunohistochemical distribution of DTR was shown to be limited to the periphery of the islet, where PYY is also expressed. These experiments suggest that a product of the PYY-expressing cells may provide a paracrine factor essential for beta cell viability. Replacement of PYY using twice-daily subcutaneous injection of a long-acting PYY analogue (X-PYY) prevented the development of diabetes and reduced the loss of pancreatic insulin content. Administration of the analogue also reduced insulin loss in streptozotocin-treated mice. These studies suggest that PYY may be an important signal for beta cell maintenance. These findings have important implications for identifying novel therapies for prevention of beta cell loss in diabetes mellitus

Rimonabant: From RIO to Ban

Endocannabinoid antagonism as a treatment for obesity and the metabolic syndrome became a hugely anticipated area of pharmacology at the start of the century. The CB1 receptor antagonist Rimonabant entered the European mass market on the back of several trials showing weight loss benefits alongside improvements in numerous other elements of the metabolic syndrome. However, the drug was quickly withdrawn due to the emergence of significant side effects—notably severe mood disorders. This paper provides a brief overview of the Rimonabant story and places the recent spate of FDA rejections of other centrally acting weight loss drugs entering Phase 3 trials in this context

Assessing the predictive validity of the UCAT — a systematic review and narrative synthesis

Background: The University Clinical Aptitude Test (UCAT) is an admissions assessment used by a consortium of universities across the UK, Australia, and New Zealand, to aid the selection of applicants to medical and dental degree programmes. The UCAT aims to measure the mental aptitude and professional behaviours required to become successful doctors and dentists. We conducted a systematic review to establish the predictive value of the UCAT across measures of performance at undergraduate and post-graduate levels. Methods: A literature search was conducted in April 2020 using eight electronic databases: MEDLINE, APA PsycInfo, SCOPUS, Web of Science, EThOS, OpenGrey, PROSPERO, and the UCAT website. Data were extracted from selected studies and tabulated as results matrices. A narrative synthesis was performed. Results: Twenty-four studies satisfied our inclusion criteria, 23 of which were deemed to be of good quality (using the Newcastle-Ottawa Scale). For over 70% of univariate data points, the UCAT exerted no statistically significant predictive validity; for the remainder, predictive power was weak. The cognitive total and verbal reasoning subtests had the largest evidence base as weakly positive predictors of academic performance. The SJT subtest was a weak predictor of professional behaviour during medical school. Studies specific to dental schools demonstrated variable findings across the five studies. Only 1 study looked at post-graduate outcome measures and demonstrated that the UCAT was not a predictor of health- or conduct-related fitness to practice declarations at GMC registration. Conclusions: These data provide some support for the use of cognitive total and verbal reasoning subtests as part of medical school selection. Further research is needed to investigate outcomes beyond professional registration and for dental students

National inter-rater agreement of standardised simulated-patient-based assessments.

PURPOSE: The forthcoming UK Medical Licensing Assessment will require all medical schools in the UK to ensure that their students pass an appropriately designed Clinical and Professional Skills Assessment (CPSA) prior to graduation and registration with a licence to practice medicine. The requirements for the CPSA will be set by the General Medical Council, but individual medical schools will be responsible for implementing their own assessments. It is therefore important that assessors from different medical schools across the UK agree on what standard of performance constitutes a fail, pass or good grade. METHODS: We used an experimental video-based, single-blinded, randomised, internet-based design. We created videos of simulated student performances of a clinical examination at four scripted standards: clear fail (CF), borderline (BD), clear pass (CPX) and good (GD). Assessors from ten regions across the UK were randomly assigned to watch five videos in 12 different combinations and asked to give competence domain scores and an overall global grade for each simulated candidate. The inter-rater agreement as measured by the intraclass correlation coefficient (ICC) based on a two-way random-effects model for absolute agreement was calculated for the total domain scores. RESULTS: 120 assessors enrolled in the study, with 98 eligible for analysis. The ICC was 0.93 (95% CI 0.81-0.99). The mean percentage agreement with the scripted global grade was 74.4% (range 40.8-96.9%). CONCLUSIONS: The inter-rater agreement amongst assessors across the UK when rating simulated candidates performing at scripted levels is excellent. The level of agreement for the overall global performance level for simulated candidates is also high. These findings suggest that assessors from across the UK viewing the same simulated performances show high levels of agreement of the standards expected of students at a 'clear fail,' 'borderline,' 'clear pass' and 'good' level.Cambridge NIHR Biomedical Research Centr

Advances in Robotic In-Orbit Assembly of Large Aperture Space Telescopes

Modular Large Aperture Space Telescopes (LAST) hold the key to future astronomical missions in search of the origin of the cosmos. Robotics and Autonomous Systems technology would be required to meet the challenges associated with the assembly of such high value infrastructure in orbit. In this paper an End-Over-End walking robot is selected to assemble a 25m LAST. The dynamical model, control architecture and gait pattern of the E-Walker are discussed. The key mission requirements are stated along with the strategies for scheduling the assembly process. A mission concept of operations (ConOps) is proposed for assembling the 25m LAST. Simulation results show the precise trajectory tracking of the EWalker for the chosen mission scenario

Using very short answer errors to guide teaching.

Funder: National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) West MidlandsFunder: National Institute for Health Research Cambridge Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100018956Funder: Medical Schools Council Assessment AllianceBACKGROUND: Student performance in examinations reflects on both teaching and student learning. Very short answer questions require students to provide a self-generated response to a question of between one and five words, which removes the cueing effects of single best answer format examinations while still enabling efficient machine marking. The aim of this study was to pilot a method of analysing student errors in an applied knowledge test consisting of very short answer questions, which would enable identification of common areas that could potentially guide future teaching. METHODS: We analysed the incorrect answers given by 1417 students from 20 UK medical schools in a formative very short answer question assessment delivered online. FINDINGS: The analysis identified four predominant types of error: inability to identify the most important abnormal value, over or unnecessary investigation, lack of specificity of radiology requesting and over-reliance on trigger words. CONCLUSIONS: We provide evidence that an additional benefit to the very short answer question format examination is that analysis of errors is possible. Further assessment is required to determine if altering teaching based on the error analysis can lead to improvements in student performance

Comparing single-best-answer and very-short-answer questions for the assessment of applied medical knowledge in 20 UK medical schools: Cross-sectional study.

OBJECTIVES: The study aimed to compare candidate performance between traditional best-of-five single-best-answer (SBA) questions and very-short-answer (VSA) questions, in which candidates must generate their own answers of between one and five words. The primary objective was to determine if the mean positive cue rate for SBAs exceeded the null hypothesis guessing rate of 20%. DESIGN: This was a cross-sectional study undertaken in 2018. SETTING: 20 medical schools in the UK. PARTICIPANTS: 1417 volunteer medical students preparing for their final undergraduate medicine examinations (total eligible population across all UK medical schools approximately 7500). INTERVENTIONS: Students completed a 50-question VSA test, followed immediately by the same test in SBA format, using a novel digital exam delivery platform which also facilitated rapid marking of VSAs. MAIN OUTCOME MEASURES: The main outcome measure was the mean positive cue rate across SBAs: the percentage of students getting the SBA format of the question correct after getting the VSA format incorrect. Internal consistency, item discrimination and the pass rate using Cohen standard setting for VSAs and SBAs were also evaluated, and a cost analysis in terms of marking the VSA was performed. RESULTS: The study was completed by 1417 students. Mean student scores were 21 percentage points higher for SBAs. The mean positive cue rate was 42.7% (95% CI 36.8% to 48.6%), one-sample t-test against ≤20%: t=7.53, p<0.001. Internal consistency was higher for VSAs than SBAs and the median item discrimination equivalent. The estimated marking cost was £2655 ($3500), with 24.5 hours of clinician time required (1.25 s per student per question). CONCLUSIONS: SBA questions can give a false impression of students' competence. VSAs appear to have greater authenticity and can provide useful information regarding students' cognitive errors, helping to improve learning as well as assessment. Electronic delivery and marking of VSAs is feasible and cost-effective

Standard setting Very Short Answer Questions (VSAQs) relative to Single Best Answer Questions (SBAQs): does having access to the answers make a difference?

Background: We investigated whether question format and access to the correct answers affect the pass mark set by standard-setters on written examinations. Methods: Trained educators used the Angoff method to standard set two 50-item tests with identical vignettes, one in a single best answer question (SBAQ) format (with five answer options) and the other in a very short answer question (VSAQ) format (requiring free text responses). Half the participants had access to the correct answers and half did not. The data for each group were analysed to determine if the question format or having access to the answers affected the pass mark set. Results: A lower pass mark was set for the VSAQ test than the SBAQ test by the standard setters who had access to the answers (median difference of 13.85 percentage points, Z = -2.82, p = 0.002). Comparable pass marks were set for the SBAQ test by standard setters with and without access to the correct answers (60.65% and 60.90% respectively). A lower pass mark was set for the VSAQ test when participants had access to the correct answers (difference in medians -13.75 percentage points, Z = 2.46, p = 0.014). Conclusions: When given access to the potential correct answers, standard setters appear to appreciate the increased difficulty of VSAQs compared to SBAQs

Is the assumption of equal distances between global assessment categories used in borderline regression valid?

Background Standard setting for clinical examinations typically uses the borderline regression method to set the pass mark. An assumption made in using this method is that there are equal intervals between global ratings (GR) (e.g. Fail, Borderline Pass, Clear Pass, Good and Excellent). However, this assumption has never been tested in the medical literature to the best of our knowledge. We examine if the assumption of equal intervals between GR is met, and the potential implications for student outcomes. Methods Clinical finals examiners were recruited across two institutions to place the typical ‘Borderline Pass’, ‘Clear Pass’ and ‘Good’ candidate on a continuous slider scale between a typical ‘Fail’ candidate at point 0 and a typical ‘Excellent’ candidate at point 1. Results were analysed using one-sample t-testing of each interval to an equal interval size of 0.25. Secondary data analysis was performed on summative assessment scores for 94 clinical stations and 1191 medical student examination outcomes in the final 2 years of study at a single centre. Results On a scale from 0.00 (Fail) to 1.00 (Excellent), mean examiner GRs for ‘Borderline Pass’, ‘Clear Pass’ and ‘Good’ were 0.33, 0.55 and 0.77 respectively. All of the four intervals between GRs (Fail-Borderline Pass, Borderline Pass-Clear Pass, Clear Pass-Good, Good-Excellent) were statistically significantly different to the expected value of 0.25 (all p-values < 0.0125). An ordinal linear regression using mean examiner GRs was performed for each of the 94 stations, to determine pass marks out of 24. This increased pass marks for all 94 stations compared with the original GR locations (mean increase 0.21), and caused one additional fail by overall exam pass mark (out of 1191 students) and 92 additional station fails (out of 11,346 stations). Conclusions Although the current assumption of equal intervals between GRs across the performance spectrum is not met, and an adjusted regression equation causes an increase in station pass marks, the effect on overall exam pass/fail outcomes is modest

Elevated Cocaine-and Amphetamine-Regulated Transcript Immunoreactivity in the Circulation of Patients with Neuroendocrine Malignancy

Context: Cocaine-and amphetamine-regulated transcript (CART) codes for a peptide widely distributed in nervous and endocrine tissues. CART immunoreactivity (CART-LI) has been detected in human insulinomas. Objective: The objective of the study was to investigate the measurement of plasma CART-LI as a tumor marker of neuroendocrine malignancy. Design and Subjects: Plasma CART-LI levels were measured in 401 patients with a range of diagnoses: neuroendocrine malignancy (n ϭ 131), after removal of neuroendocrine malignancy (n ϭ 27), without any form of tumor or renal impairment (n ϭ 192), with renal impairment (n ϭ 17) and with nonneuroendocrine tumors (n ϭ 34). Chromatography methods were used to investigate CART-LI circulating in human plasma. Results: The upper limit of normal calculated for CART-LI was 150 pmol/liter. Mean circulating plasma CART-LI among neuroendocrine tumor patients was 440 pmol/liter, 56% of subjects having levels greater than 150 pmol/liter. Measuring CART-LI in addition to chromogranin (Cg)-A improved the sensitivity for neuroendocrine malignancy from 85 to 91%, whereas combined use of CgA and CgB had a joint sensitivity of 89%. Of 38 patients with pancreatic neuroendocrine tumors, 71% had plasma CART-LI levels greater than 150 pmol/liter, increasing to 95% in those classified with progressive disease (n ϭ 20, mean CART-LI 625 pmol/liter), compared with 80% for CgA. Chromatographic analysis suggests that circulating CART-LI is present as one major form, which may correspond to CART (62-102) or another unknown form. Conclusions: We demonstrate CART-LI as a specific tumor marker in patients with a range of neuroendocrine tumors. Used in combination with CgA, CART-LI measurement has the potential to improve sensitivity in diagnosis and follow-up of neuroendocrine tumors, in particular progressive pancreatic neuroendocrine tumors