Broadly sampled assessment reduces ethnicity-related differences in clinical grades.

CONTEXT: Ethnicity-related differences in clinical grades exist. Broad sampling in assessment of clinical competencies involves multiple assessments used by multiple assessors across multiple moments. Broad sampling in assessment potentially reduces irrelevant variances and may therefore mitigate ethnic disparities in clinical grades. OBJECTIVES: Research question 1 (RQ1): to assess whether the relationship between students' ethnicity and clinical grades is weaker in a broadly sampled versus a global assessment. Research question 2 (RQ2): to assess whether larger ethnicity-related differences in grades occur when supervisors are given the opportunity to deviate from the broadly sampled assessment score. METHODS: Students' ethnicity was classified as Turkish/Moroccan/African, Surinamese/Antillean, Asian, Western, and native Dutch. RQ1: 1667 students (74.3% native Dutch students) were included, who entered medical school between 2002 and 2004 (global assessment, 818 students) and between 2008 and 2010 (broadly sampled assessment, 849 students). The main outcome measure was whether or not students received ≥3 times a grade of 8 or higher on a scale from 1 to 10 in five clerkships. RQ2: 849 students (72.4% native Dutch students) were included, who were assessed by broad sampling. The main outcome measure was the number of grade points by which supervisors had deviated from broadly sampled scores. Both analyses were adjusted for gender, age, (im)migration status and average bachelor grade. RESULTS: Research question 1: ethnicity-related differences in clinical grades were smaller in broadly sampled than in global assessment, and this was also seen after adjustments. More specifically, native Dutch students had reduced probabilities (0.87-0.65) in broadly sampled as compared with global assessment, whereas Surinamese (0.03-0.51) and Asian students (0.21-0.30) had increased probabilities of having ≥3 times a grade of 8 or higher in five clerkships. Research question 2: when supervisors were allowed to deviate from original grades, ethnicity-related differences in clinical grades were reintroduced. CONCLUSIONS: Broadly sampled assessment reduces ethnicity-related differences in grades.

Integrity situational judgement test for medical school selection: judging 'what to do' versus 'what not to do'.

CONTEXT: Despite their widespread use in medical school selection, there remains a lack of clarity on exactly what situational judgement tests (SJTs) measure. OBJECTIVES: We aimed to develop an SJT that measures integrity by combining critical incident interviews (inductive approach) with an innovative deductive approach. The deductive approach guided the development of the SJT according to two established theoretical models, of which one was positively related to integrity (honesty-humility [HH]) and one was negatively related to integrity (cognitive distortions [CD]). The Integrity SJT covered desirable (HH-based) and undesirable (CD-based) response options. We examined the convergent and discriminant validity of the Integrity SJT and compared the validity of the HH-based and CD-based subscores. METHODS: The Integrity SJT was administered to 402 prospective applicants at a Dutch medical school. The Integrity SJT consisted of 57 scenarios, each followed by four response options, of which two represented HH facets and two represented CD categories. Three SJT scores were computed, including a total, an HH-based and a CD-based score. The validity of these scores was examined according to their relationships with external integrity-related measures (convergent validity) and self-efficacy (discriminant validity). RESULTS: The three SJT scores correlated significantly with all integrity-related measures and not with self-efficacy, indicating convergent and discriminant validity. In addition, the CD-based SJT score correlated significantly more strongly than the HH-based SJT score with two of the four integrity-related measures. CONCLUSIONS: An SJT that assesses the ability to correctly recognise CD-based response options as inappropriate (i.e. what one should not do) seems to have stronger convergent validity than an SJT that assesses the ability to correctly recognise HH-based response options as appropriate (i.e. what one should do). This finding might be explained by the larger consensus on what is considered inappropriate than on what is considered appropriate in a challenging situation. It may be promising to focus an SJT on the ability to recognise what one should not do.

Influence of response instructions and response format on applicant perceptions of a situational judgement test for medical school selection.

BACKGROUND: This study examined the influence of two Situational Judgement Test (SJT) design features (response instructions and response format) on applicant perceptions. Additionally, we investigated demographic subgroup differences in applicant perceptions of an SJT. METHODS: Medical school applicants (N = 372) responded to an online survey on applicant perceptions, including a description and two example items of an SJT. Respondents randomly received one of four SJT versions (should do-rating, should do-pick-one, would do-rating, would do-pick-one). They rated overall favourability and items on four procedural justice factors (face validity, applicant differentiation, study relatedness and chance to perform) and ease-of-cheating. Additionally, applicant perceptions were compared for subgroups based on gender, ethnic background and first-generation university status. RESULTS: Applicants rated would-do instructions as easier to cheat than should-do instructions. Rating formats received more favourable judgements than pick-one formats on applicant differentiation, study-relatedness, chance to perform and ease of cheating. No significant main effect for demographic subgroup on applicant perceptions was found, but significant interaction effects showed that certain subgroups might have more pronounced preferences for certain SJT design features. Specifically, ethnic minority applicants - but not ethnic majority applicants - showed greater preference for should-do than would-do instructions. Additionally, first-generation university students - but not non-first-generation university students - were more favourable of rating formats than of pick-one formats. CONCLUSIONS: Findings indicate that changing SJT design features may positively affect applicant perceptions by promoting procedural justice factors and reducing perceived ease of cheating and that response instructions and response format can increase the attractiveness of SJTs for minority applicants.

Sex difference in cold perception and shivering onset upon gradual cold exposure.

To maintain a thermal balance when experiencing cold, humans reduce heat loss and enhance heat production. A potent and rapid mechanism for heat generation is shivering. Research has shown that women prefer a warmer environment and feel less comfortable than men in the same thermal condition. Using the Blanketrol® III, a temperature management device commonly used to study brown adipose tissue activity, we tested whether the experimental temperature (TE) at which men and women start to shiver differs. Twenty male and 23 female volunteers underwent a cooling protocol, starting at 24 °C and gradually decreasing by 1-2 °C every 5 min until an electromyogram detected the shivering or the temperature reached 9 °C. Women started shivering at a higher TE than men (11.3 ±â€¯1.8 °C for women vs 9.6 ±â€¯1.8 °C for men, P = 0.003). In addition, women felt cool, scored by a visual analogue scale, at a higher TE than men (18.3 ±â€¯3.0 °C for women vs 14.6 ±â€¯2.6 °C for men, P < 0.001). This study demonstrates a sex difference in response to cold exposure: women require shivering as a source of heat production earlier than men. This difference could be important and sex should be considered when using cooling protocols in physiological studies.

The relationship between extracurricular activities assessed during selection and during medical school and performance.

Several medical schools include candidates' extracurricular activities in their selection procedure, with promising results regarding their predictive value for achievement during the clinical years of medical school. This study aims to reveal whether the better achievement in clinical training of students selected on the basis of their extracurricular activities could be explained by persistent participation in extracurricular activities during medical school (msECAs). Lottery-admitted and selected student admission groups were compared on their participation in three types of msECAs: (1) research master, (2) important board positions or (3) additional degree programme. Logistic regression was used to measure the effect of admission group on participation in any msECA, adjusted for pre-university GPA. Two-way ANCOVA was used to examine the inter-relationships between admission group, participation in msECAs and clerkship grade, with pre-university GPA as covariate. Significantly more selected students compared to lottery-admitted students participated in any msECA. Participation in msECAs was associated with a higher pre-university GPA for lottery-admitted students only, whereas participation in msECAs was associated with higher clerkship grades for selected students only. These results suggest that persistent participation in extracurricular activities of selected students favours better clinical achievement, supporting the inclusion of ECAs in the selection procedure. More insight in the rationale behind participation in extracurricular activities during medical school may explain differences found between lottery-admitted and selected students.

Participation and selection effects of a voluntary selection process.

Many different medical school selection processes are used worldwide. In this paper, we examine the effect of (1) participation, and (2) selection in a voluntary selection process on study performance. We included data from two cohorts of medical students admitted to Erasmus MC, Rotterdam and VUmc, Amsterdam, The Netherlands and compared them to previously published data from Groningen medical school, The Netherlands. All included students were admitted based on either (1) a top pre-university grade point average, or (2) a voluntary selection process, or (3) weighted lottery. We distinguished between lottery-admitted students who had participated in the voluntary selection process and had been rejected, and lottery-admitted students who had not participated. Knowledge test scores, study progress, and professionalism scores were examined using ANCOVA modelling, logistic regression, and Bonferroni post hoc multiple-comparison tests, controlling for gender and cohort. For written test grades, results showed a participation effect at Groningen medical school and Erasmus MC (p < 0.001), and a selection effect at VUmc (p < 0.05). For obtained course credits, results showed a participation effect at all universities (p < 0.01) and a selection effect at Groningen medical school (p < 0.005). At Groningen medical school, a participation effect seemed apparent in on time first-year completion (p < 0.05). Earlier reported selection and participation effects in professionalism scores at Groningen medical school were not apparent at VUmc. Top pre-university students performed well on all outcome measures. For both the participation effect and the selection effect, results differed between universities. Institutional differences in curricula and in the design of the selection process seem to mediate relations between the different admissions processes and performance. Further research is needed for a deeper understanding of the influence of institutional differences on selection outcomes.

Participation in a scientific pre-university program and medical students' interest in an academic career.

BACKGROUND: The proportion of medical doctors involved in research activities is declining. Undergraduate medical research programs are positively associated with medical students' research interest. Scientific pre-university programs (SPUPs) outside the medical domain are also positively associated with research interest, but have not been related to the shortage of clinician-scientists. This study examined the effect of an SPUP on medical students' research interest. METHODS: This study was conducted at a Dutch medical school. Medical students in all years who had participated in an SPUP and first-year master students who had not participated in an SPUP were invited to fill out an online survey on extracurricular activities and future career interests. SPUP participants were compared with three groups of non-participants: (i) an unmatched group, (ii) a group matched on gender and pre-university Grade Point Average (pu-GPA) and (iii) a group matched on gender and first-year GPA, one to five years after finishing the SPUP. Participants evaluated the SPUP through ratings of statements about the program. RESULTS: Two-hundred forty medical students, including 71 SPUP participants responded to the survey. SPUP participants participated significantly more often in the Honors class (i.e., extracurricular educational program for high-performing students), gained significantly more often extracurricular research experience, enrolled significantly more often in the Research master (i.e., research training program parallel to the clinical master program) and obtained significantly more often a scholarship than unmatched non-SPUP participants. Using a non-SPUP group matched on gender and pu-GPA reduced the effect size of the significant differences in Honors class participation, Research master participation and scholarship obtainment. Using a non-SPUP group matched on gender and first-year GPA rendered the significant difference in Research master participation and scholarship obtainment insignificant. Significantly more SPUP participants than unmatched non-SPUP participants preferred a combination of clinical care and research in their future career. Using a non-SPUP group matched on gender and either pu-GPA or first-year GPA did not change the effect size of this significant difference. CONCLUSIONS: These findings demonstrate the potential value of an SPUP in increasing the number of medical students with research interest and as a policy measure to help to alleviate the shortage of clinician-scientists.

Hormonal evaluation in relation to phenotype and genotype in 286 patients with a disorder of sex development from Indonesia.

OBJECTIVE: The objective of this study was to determine the aetiological spectrum of disorders of sex development (DSD) in a large cohort of underprivileged and undiagnosed patients from Indonesia. METHODS: A total of 286 patients with atypical external and/or internal genitalia were evaluated using clinical, hormonal, molecular genetic and histological parameters. RESULTS: The age (years) at presentation was 0-0·5 in 41 (14·3%), >0·5-12 in 181 (63·3%) and >12 in 64 cases (22·4%). 46,XY DSD was most common (68·2%, n = 195), 46,XX DSD was found in 23·4% (n = 67) and sex chromosomal DSD in 8·4% (n = 24). In 61·2% of 46,XX DSD patients, 17·9% of 46,XY DSD patients and all sex chromosome DSD patients (29·4% in total), a final diagnosis was reached based on genetic or histological gonadal tissue evaluation. 17-hydroxyprogesterone and androstenedione levels were the most distinctive parameters in 46,XX DSD patients. In 46,XY DSD, diagnostic groups were identified based on the external masculinization score: androgen action disorder (AAD), unknown male undermasculinization (UMU), and gonadal dysgenesis (GD). LH, FSH and testosterone levels were most informative especially in the older age group. HCG tests were of no additional value as no patients with androgen synthesis disorders were found. Hormonal profiles of patients with sex chromosome DSD and a Y-chromosome sequence containing karyotype showed high levels of LH and FSH, and low levels of AMH, inhibin B and testosterone compared with the normal male range. Gene mutations were found in all patients with CAH, but in only 24·5% and 1·8% of patients with AAD and UMU. In 32% of 46,XY GD patients, copy number variants of different genes were found. CONCLUSION: A stepwise diagnostic approach led to a molecularly or histologically proven final diagnosis in 29·4% of the patients. The most informative parameters were serum levels of 17-hydroxyprogesterone and androstenedione in 46,XX DSD patients, and serum LH, FSH and testosterone levels in 46,XY DSD patients.

Non-cognitive selected students do not outperform lottery-admitted students in the pre-clinical stage of medical school.

Medical schools all over the world select applicants using non-cognitive and cognitive criteria. The predictive value of these different types of selection criteria has however never been investigated within the same curriculum while using a control group. We therefore set up a study that enabled us to compare the academic performance of three different admission groups, all composed of school-leaver entry students, and all enrolled in the same Bachelor curriculum: students selected on non-cognitive criteria, students selected on cognitive criteria and students admitted by lottery. First-year GPA and number of course credits (ECTS) at 52 weeks after enrollment of non-cognitive selected students (N = 102), cognitive selected students (N = 92) and lottery-admitted students (N = 356) were analyzed. In addition, chances of dropping out, probability of passing the third-year OSCE, and completing the Bachelor program in 3 years were compared. Although there were no significant differences between the admission groups in first-year GPA, cognitive selected students had obtained significantly more ECTS at 52 weeks and dropped out less often than lottery-admitted students. Probabilities of passing the OSCE and completing the bachelor program in 3 years did not significantly differ between the groups. These findings indicate that the use of only non-cognitive selection criteria is not sufficient to select the best academically performing students, most probably because a minimal cognitive basis is needed to succeed in medical school.

The development of self-regulated learning during the pre-clinical stage of medical school: a comparison between a lecture-based and a problem-based curriculum.

Society expects physicians to always improve their competencies and to be up to date with developments in their field. Therefore, an important aim of medical schools is to educate future medical doctors to become self-regulated, lifelong learners. However, it is unclear if medical students become better self-regulated learners during the pre-clinical stage of medical school, and whether students develop self-regulated learning skills differently, dependent on the educational approach of their medical school. In a cross-sectional design, we investigated the development of 384 medical students' self-regulated learning skills with the use of the Self-Regulation of Learning Self-Report Scale. Next, we compared this development in students who enrolled in two distinct medical curricula: a problem-based curriculum and a lectured-based curriculum. Analysis showed that more skills decreased than increased during the pre-clinical stage of medical school, and that the difference between the curricula was mainly caused by a decrease in the skill evaluation in the lecture-based curriculum. These findings seem to suggest that, irrespective of the curriculum, self-regulated learning skills do not develop during medical school.

Self-regulated learning and academic performance in medical education.

CONTENT: Medical schools aim to graduate medical doctors who are able to self-regulate their learning. It is therefore important to investigate whether medical students' self-regulated learning skills change during medical school. In addition, since these skills are expected to be helpful to learn more effectively, it is of interest to investigate whether these skills are related to academic performance. METHODS: In a cross-sectional design, the Self-Regulation of Learning Self-Report Scale (SRL-SRS) was used to investigate the change in students' self-regulated learning skills. First and third-year students (N = 949, 81.7%) SRL-SRS scores were compared with ANOVA. The relation with academic performance was investigated with multinomial regression analysis. RESULTS: Only one of the six skills, reflection, significantly, but positively, changed during medical school. In addition, a small, but positive relation of monitoring, reflection, and effort with first-year GPA was found, while only effort was related to third-year GPA. CONCLUSIONS: The change in self-regulated learning skills is minor as only the level of reflection differs between the first and third year. In addition, the relation between self-regulated learning skills and academic performance is limited. Medical schools are therefore encouraged to re-examine the curriculum and methods they use to enhance their students' self-regulated learning skills. Future research is required to understand the limited impact on performance.

The acylated (AG) to unacylated (UAG) ghrelin ratio in esterase inhibitor-treated blood is higher than previously described.

CONTEXT: The acylated/unacylated ghrelin (AG/UAG) ratio has been reported to range from 0·02 to 0·3, suggesting biologically relevant independent regulation of each ghrelin isoform. However, AG is deacylated to UAG by esterases in blood samples, and esterase inhibition is critical for their accurate measurement. Our hypothesis is that at least part of the variation in reported AG and UAG values is due to inconsistent sample preparation. DESIGN: A non-interventional study. Quantification with two different, commercially available, ELISA formats of AG and UAG in venous plasma stabilized or not with 4-(2-aminoethyl) benzenesulphonyl fluoride (AEBSF) and stored for 0-6 months at -20 or -80 °C. PARTICIPANTS: Healthy, non-obese, adults (n = 8; 4 women), age 26-42 yrs, after an overnight fast. MEASUREMENTS: AG and UAG stability following different methods of sample treatment and storage. RESULTS: Non-AEBSF plasma contained low AG and high UAG (>270 pg/ml) indicating rapid conversion of AG to UAG. However, AEBSF plasma, stored at -80 °C and measured at 0, 1, 3 and 6 months contained AG and UAG ranges of 12-350 and 17-170 pg/ml, respectively. Mean (SEM) AG/UAG ratios were 1·7(0·3), 1·2(0·2), 1·5(0·3) and 1·8(0·5) at each time point with no significant effect of storage period. CONCLUSIONS: AG and UAG levels measured in AEBSF-stabilized plasma indicate that the AG/UAG ratio is markedly higher than previously described and that UAG is a physiological component of the circulation. This highlights the importance of immediately stabilizing blood samples on collection for determination of both AG and UAG concentrations and provides a valuable tool for their measurement in physiological and interventional studies.

Direct activating effects of adrenocorticotropic hormone (ACTH) on brown adipose tissue are attenuated by corticosterone.

Brown adipose tissue (BAT) and brown-like cells in white adipose tissue (WAT) can dissipate energy through thermogenesis, a process mediated by uncoupling protein 1 (UCP1). We investigated whether stress hormones ACTH and corticosterone contribute to BAT activation and browning of WAT. ACTH and corticosterone were studied in male mice exposed to 4 or 23°C for 24 h. Direct effects were studied in T37i mouse brown adipocytes and primary cultured murine BAT and inguinal WAT (iWAT) cells. In vivo effects were studied using (18)F-deoxyglucose positron emission tomography. Cold exposure doubled serum ACTH concentrations (P=0.03) and fecal corticosterone excretion (P=0.008). In T37i cells, ACTH dose-dependently increased Ucp1 mRNA (EC50=1.8 nM) but also induced Ucp1 protein content 88% (P=0.02), glycerol release 32% (P=0.03) and uncoupled respiration 40% (P=0.003). In cultured BAT and iWAT, ACTH elevated Ucp1 mRNA by 3-fold (P=0.03) and 3.7-fold (P=0.01), respectively. In T37i cells, corticosterone prevented induction of Ucp1 mRNA and Ucp1 protein by both ACTH and norepinephrine in a glucocorticoid receptor (GR)-dependent fashion. ACTH and GR antagonist RU486 independently doubled BAT (18)F-deoxyglucose uptake (P=0.0003 and P=0.004, respectively) in vivo. Our results show that ACTH activates BAT and browning of WAT while corticosterone counteracts this.

Ethnic and social disparities in performance on medical school selection criteria.

CONTEXT: Medical schools in Western societies seek measures to increase the diversity of their student bodies with respect to ethnicity and social background. Currently, little is known about the effects of different selection procedures on student diversity. OBJECTIVES: This prospective cohort study aimed to determine performance differences between traditional and non-traditional (i.e. ethnic minority and first-generation university candidates) medical school applicants in academic and non-academic selection criteria. METHODS: Applicants in 2013 (n = 703) were assessed on academic and non-academic selection criteria. They also completed a questionnaire on ethnicity and social background. Main outcome measures were 'not selected' (i.e. failure on any criteria), 'failure on academic criteria' and 'failure on non-academic criteria'. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by logistic regression analysis for ethnic subgroups (Surinamese/Antillean, Turkish/Moroccan/African, Asian, Western) compared with Dutch applicants, adjusted for age, gender, additional socio-demographic variables (first-generation immigrant, first-generation university applicant, first language, medical doctor as parent) and pre-university grade point average (pu-GPA). Similar analyses were performed for first-generation university applicants. RESULTS: Compared with Dutch applicants, Surinamese/Antillean applicants underperformed in the selection procedure (failure rate: 78% versus 57%; adjusted OR 2.52, 95% CI 1.07-5.94), in particular on academic criteria (failure rate: 66% versus 34%; adjusted OR 3.00, 95% CI 1.41-6.41). The higher failure rate of first-generation university applicants on academic criteria (50% versus 37%; unadjusted OR 1.66, 95% CI 1.18-2.33) was partly explained by additional socio-demographic variables and pu-GPA. The outcome measure 'failure on non-academic criteria' showed no significant differences among the ethnic or social subgroups. CONCLUSIONS: The absence of differences on non-academic criteria was promising with reference to increasing social and ethnic diversity; however, the possibility that self-selection instigated by the selection procedure is stronger in applicants from non-traditional backgrounds cannot be ruled out. Further research should also focus on why cognitive tests might favour traditional applicants.

Predicting performance: relative importance of students' background and past performance.

CONTEXT: Despite evidence for the predictive value of both pre-admission characteristics and past performance at medical school, their relative contribution to predicting medical school performance has not been thoroughly investigated. OBJECTIVES: This study was designed to determine the relative importance of pre-admission characteristics and past performance in medical school in predicting student performance in pre-clinical and clinical training. METHODS: This longitudinal prospective study followed six cohorts of students admitted to a Dutch, 6-year, undergraduate medical course during 2002-2007 (n = 2357). Four prediction models were developed using multivariate logistic regression analysis. Main outcome measures were 'Year 1 course completion within 1 year' (models 1a, 1b), 'Pre-clinical course completion within 4 years' (model 2) and 'Achievement of at least three of five clerkship grades of ≥ 8.0' (model 3). Pre-admission characteristics (models 1a, 1b, 2, 3) and past performance at medical school (models 1b, 2, 3) were included as predictor variables. RESULTS: In model 1a - including pre-admission characteristics only - the strongest predictor for Year 1 course completion was pre-university grade point average (GPA). Success factors were 'selected by admission testing' and 'age > 21 years'; risk factors were 'Surinamese/Antillean background', 'foreign pre-university degree', 'doctor parent' and male gender. In model 1b, number of attempts and GPA at 4 months were the strongest predictors for Year 1 course completion, and male gender remained a risk factor. Year 1 GPA was the strongest predictor for pre-clinical course completion, whereas being male or aged 19-21 years were risk factors. Pre-clinical course GPA positively predicted clinical performance, whereas being non-Dutch or a first-generation university student were important risk factors for lower clinical grades. Nagelkerke's R(2) ranged from 0.16 to 0.62. CONCLUSIONS: This study not only confirms the importance of past performance as a predictor of future performance in pre-clinical training, but also reveals the importance of a student's background as a predictor in clinical training. These findings have important practical implications for selection and support during medical school.

Des-acyl ghrelin analogs prevent high-fat-diet-induced dysregulation of glucose homeostasis.

There is clinical evidence that des-acyl ghrelin (DAG) favorably modulates glucose and lipid metabolism, although its mode of action is unknown. A murine model of prediabetes was used to assess possible mechanisms of action for DAG and a newly developed bioactive analog, AZP531. C57BL/6J mice were infused with saline, DAG, or AZP531 continuously for 4 wk, and fed either normal diet (ND) or normal diet for 2 wk followed by a high-fat diet (HFD) for 2 wk. Compared with mice in the ND group, HFD increased body and fat mass, caused glucose intolerance and insulin resistance, had proinflammatory effects in white adipose tissue, and caused lipid accumulation in brown adipose tissue. DAG and AZP531 treatment prevented HFD-induced proinflammatory effects, stimulated expression of mitochondrial function markers in brown adipose tissue, and prevented development of a prediabetic metabolic state. AZP531 also prevented a HFD-induced increase in acyl ghrelin levels. Our data indicate DAG analogs as potential treatment for the prevention of metabolic syndrome.

Functional characterization of a new human melanocortin-4 receptor homozygous mutation (N72K) that is associated with early-onset obesity.

The melanocortin 4 receptor (MC4R) is expressed in the hypothalamus and is essential for regulation of appetite and energy expenditure. MC4R dysfunction in humans causes hyperphagia, impaired satiety and obesity. We have identified a novel c.216C>A (N72 K) homozygous mutation in MC4R in a girl with severe obesity. The patient presented with early-onset obesity and hyperphagia indicating an effect of the homozygous mutation on her phenotype. In silico analyses indicate a damaging effect on receptor function, and the mutation is unusual in occurring in the first intra-cellular loop of the receptor. Site-directed mutagenesis was used to generate plasmid constructs expressing wild-type and mutant MC4R. These were transfected into HEK293 cells and assessed for cAMP responsiveness to α-MSH. Cells expressing N-terminal HA and C-terminal GFP-tagged MC4R were assessed by immunofluorescence confocal microscopy and flow cytometry for correct cell-surface localization. The maximal response of the mutant MC4R to α-MSH was decreased to 20 ± 1 % of the wild type receptor response, and the EC50 was increased from 16.5 ± 5.4 nM to 37.0 ± 8.3 nM. Localization of N- and C-terminally tagged MC4R by confocal microscopy and flow cytometry showed aberrant retention of the mutant receptor in the cytoplasm. Our data describe a rare homozygous inactivating mutation in the first intra-cellular loop of MC4R that markedly impairs its function and is associated with early-onset obesity and hyperphagia.

The effect of a short integrated study skills programme for first-year medical students at risk of failure: a randomised controlled trial.

BACKGROUND: There is a need for outcome-based studies on strategies for supporting at-risk medical students that use long-term follow-up and contemporaneous controls. AIM: To measure the effect of a short integrated study skills programme (SSP) on the study progress of at-risk medical students. METHODS: First-year students identified as at-risk of academic failure at 7 months after enrolment were invited to participate in the randomised controlled trial. Participants were randomly assigned to the SSP group or to a control group receiving standard academic support. Effects of SSP were measured on the short (passed first exam after intervention), medium (obtained enough credits to proceed to second year) and long term (completed first-year curriculum within 2 years). RESULTS: SSP participants (n=43) more often passed the first exam after the intervention than controls (n=41; 30% versus 12%; X2(1)=4.06, p<0.005, effect size=0.22), in particular those who had previously passed at least one exam. No medium or long-term effect was found. Participants who had attended four or five SSP sessions outperformed those who had attended fewer sessions on all outcome measures. CONCLUSION: A short, integrated SSP benefited some, but not all students. Our advice is to focus support efforts on at-risk students who have demonstrated commitment and academic potential.

Academic and non-academic selection criteria in predicting medical school performance.

BACKGROUND: A two-step selection procedure, consisting of a non-academic and an academic step, was recently shown to select students with a 2.6 times lower risk of early dropout and a higher clerkship Grade Point Average (GPA) than lottery-admitted controls. AIM: To determine the relative contribution of the non-academic and academic steps to differences found in student performance. METHOD: Lottery-admitted students (n = 653) and three groups of selection procedure participants were compared on early dropout rate and clerkship GPA: (1) all participants (n = 1676), (2) participants who passed step 1, and (3) participants who passed step 2. RESULTS: Selection procedure participation resulted in a 4.4% lower dropout rate than lottery admission and this difference increased to 5.2% after step 1 and to 8.7% after step 2. Clerkship GPA was significantly higher for participants who passed step 1 than for their lottery-admitted controls. This difference remained significant after the rejection of students on academic criteria in step 2. CONCLUSION: The lower dropout rate of selected students is related to both self-selection of participants before the start of the selection procedure and the academic part of the selection procedure. The higher clerkship GPA of selected students is almost exclusively related to the non-academic selection criteria.