Morten Jensen

The effect of testing on skills learning

Objectives  In addition to the extrinsic effects of assessment and examinations on students’ study habits, testing can have an intrinsic effect on the memory of studied material. Whether this testing effect also applies to skills learning is not known. However, this is especially interesting in view of the need to maximise learning outcomes from costly simulation‐based courses. This study was conducted to determine whether testing as the final activity in a skills course increases learning outcome compared with an equal amount of time spent practising the skill.

Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives.

The American Heart Association (AHA) recommends family screening for hypertrophic cardiomyopathy (HCM). We assessed the outcome of family screening combining clinical evaluation and screening for sarcomere gene mutations in a cohort of 90 Danish HCM patients and their close relatives, in all 451 persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants was performed. In total, 297 adult relatives (>18 years) (51.2%) fulfilled one or more criteria for HCM. A total of 38 HCM‐causing mutations were detected in 32 index patients. Six patients carried two disease‐associated mutations. Twenty‐two mutations have only been identified in the present cohort. The genetic diagnostic yield was almost twice as high in familial HCM (53%) vs. HCM of sporadic or unclear inheritance (19%). The yield was highest in families with an additional history of HCM‐related clinical events. In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or more criteria was fulfilled. A total of 60% of family members had no mutation and could be reassured and further follow‐up ceased. Genetic diagnosis may be established in approximately 40% of families with the highest yield in familial HCM with clinical events. Mutation‐screening was superior to clinical investigation in identification of individuals not at increased risk, where follow‐up is redundant, but should be offered in all families with relatives at risk for developing HCM. Hum Mutat 0,1–8, 2008.

PICK1 Deficiency Impairs Secretory Vesicle Biogenesis and Leads to Growth Retardation and Decreased Glucose Tolerance

Two lipid membrane sculpting BAR domain proteins, PICK1 and ICA69, play a key role early in the biogenesis of peptide hormone secretory vesicles and are critical for normal growth and metabolic homeostasis.

The significance of clinical experience on learning outcome from resuscitation training-a randomised controlled study.

CONTEXT The impact of clinical experience on learning outcome from a resuscitation course has not been systematically investigated. AIM To determine whether half a year of clinical experience before participation in an Advanced Life Support (ALS) course increases the immediate learning outcome and retention of learning. MATERIALS AND METHODS This was a prospective single blinded randomised controlled study of the learning outcome from a standard ALS course on a volunteer sample of the entire cohort of newly graduated doctors from Copenhagen University. The outcome measurement was ALS-competence assessed using a validated composite test including assessment of skills and knowledge. INTERVENTION The intervention was half a year of clinical work before an ALS course. The intervention group received the course after a half-year of clinical experience. The control group participated in an ALS course immediately following graduation. RESULTS Invitation to participate was accepted by 154/240 (64%) graduates and 117/154 (76%) completed the study. There was no difference between the intervention and control groups with regard to the immediate learning outcome. The intervention group had significantly higher retention of learning compared to the control group, intervention group mean 82% (CI 80-83), control group mean 78% (CI 76-80), P=0.002. The magnitude of this difference was medium (effect size=0.57). CONCLUSIONS Half a year of clinical experience, before participation in an ALS course had a small but statistically significant impact on the retention of learning, but not on the immediate learning outcome.

Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial.

BACKGROUND No medical treatment has been reliably shown to halt or reverse disease progression in hypertrophic cardiomyopathy, but the results of several pilot studies have suggested beneficial effects of angiotensin II receptor blockers on left ventricular hypertrophy and fibrosis, which are predictive of an adverse outcome. We aimed to assess the effect of the angiotensin II receptor blocker losartan on left ventricular hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. METHODS In this single-centre, randomised, double-blind, placebo-controlled trial, adult patients (aged 18 years and older) with obstructive or non-obstructive hypertrophic cardiomyopathy were randomly assigned via computer-based system to losartan (100 mg per day) or placebo for 12 months. Patients and investigators were masked to assigned treatment. The primary endpoint was change in left ventricular mass as assessed by cardiac magnetic resonance imaging (CMR) or CT. Efficacy analyses were done in the modified intention-to-treat population (all patients with data available at the 12-month follow-up). The trial is registered with ClinicalTrials.gov, number NCT01447654. FINDINGS Between Dec 1, 2011, and May 1, 2013, 318 patients were screened. 133 patients (mean age 52 years [SD 13], 35% women) consented and were randomly assigned to placebo (n=69) or losartan (n=64). 124 (93%) patients completed the study and were included in the modified intention-to-treat analysis for the primary endpoint. After 12 months we noted no significant difference in the change in left ventricular mass between the placebo group and the losartan group (mean difference 1 g/m(2), 95% CI -3 to 6; p=0·60). A decrease in systolic blood pressure in the losartan group (from mean 127 mm Hg [SD 12] to 121 mm Hg [14]; p=0·0001) confirmed drug compliance; blood pressure did not decrease in the placebo group. Two (2%) patients, both in the placebo group, died from sudden cardiac death during follow-up. In the losartan group, one (1%) patient had angioedema, one (1%) had deterioration of renal function, and one (1%) had hyperkalaemia. Treatment was well tolerated by patients with left ventricular outflow obstruction at baseline. INTERPRETATION Our findings challenge the generally held view that angiotensin II receptor blockers reduce cardiac hypertrophy. Treatment with losartan was safe, suggesting that it can be used for other indications in patients with hypertrophic cardiomyopathy, irrespective of obstructive physiology. Additional studies are needed to assess the effect of angiotensin II receptor blockers in preclinical hypertrophic cardiomyopathy-eg, in genotype-positive but phenotype-negative individuals.

Neuropeptide Y Y5 receptor antagonism attenuates cocaine-induced effects in mice

RationaleSeveral studies suggest a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. However, the NPY receptors mediating addiction-related effects remain to be determined.ObjectivesTo explore the potential role of Y5 NPY receptors in cocaine-induced behavioural effects.MethodsThe Y5 antagonist L-152,804 and Y5-knockout (Y5-KO) mice were tested in two models of cocaine addiction-related behaviour: acute self-administration and cocaine-induced hyperactivity. We also studied effects of Y5 receptor antagonism on cocaine-induced c-fos expression and extracellular dopamine with microdialysis as well as dopamine transporter-mediated uptake of dopamine in vitro. Immunocytochemistry was used to determine whether dopamine neurons express Y5-like immunoreactivity.ResultsIn self-administration, L-152,804 prominently decreased nose-poking for the peak dose of cocaine and shifted the dose–response curve for cocaine downward. Y5-KO mice also showed modestly attenuated self-administration. Cocaine-induced hyperactivity was attenuated by L-152,804 and in Y5-KO mice. Cocaine failed to increase c-fos expression in the nucleus accumbens and striatum of L-152,804-treated mice, indicating that the Y5 antagonist could act by influencing neural activity in these regions. Accordingly, the cocaine-induced increase in accumbal extracellular dopamine was attenuated by L-152,804 and in Y5-KO mice, suggesting that Y5 antagonism influences cocaine-induced behaviour by regulating dopamine. Consistent with this concept, dopamine neurons in the ventral tegmental area appeared to contain Y5 receptors. In contrast, neither L-152,804 nor NPY influenced dopamine transporter-mediated dopamine uptake.ConclusionsThe present data indicate that Y5 antagonism may attenuate cocaine-induced behavioural effects, suggesting that Y5 receptors could be a potential therapeutic target in cocaine addiction.

Test-enhanced learning may be a gender-related phenomenon explained by changes in cortisol level

Medical Education 2011: 45: 192–199

Anxiolytic-Like Effects of Increased Ghrelin Receptor Signaling in the Amygdala.

Background: Besides the well-known effects of ghrelin on adiposity and food intake regulation, the ghrelin system has been shown to regulate aspects of behavior including anxiety and stress. However, the effect of virus-mediated overexpression of the ghrelin receptor in the amygdala has not previously been addressed directly. Methods: First, we examined the acute effect of peripheral ghrelin administration on anxiety- and depression-like behavior using the open field, elevated plus maze, forced swim, and tail suspension tests. Next, we examined the effect of peripheral ghrelin administration and ghrelin receptor deficiency on stress in a familiar and social environment using the Intellicage system. Importantly, we also used a novel approach to study ghrelin receptor signaling in the brain by overexpressing the ghrelin receptor in the amygdala. We examined the effect of ghrelin receptor overexpression on anxiety-related behavior before and after acute stress and measured the modulation of serotonin receptor expression. Results: We found that ghrelin caused an anxiolytic-like effect in both the open field and elevated plus maze tests. Additionally, it attenuated air-puff–induced stress in the social environment, while the opposite was shown in ghrelin receptor deficient mice. Finally, we found that overexpression of the ghrelin receptor in the basolateral division of the amygdala caused an anxiolytic-like effect and decreased the 5HT1a receptor expression. Conclusions: Ghrelin administration and overexpression of the ghrelin receptor in the amygdala induces anxiolytic-like behavior. Since the ghrelin receptor has high constitutive activity, ligand-independent signaling in vivo may be important for the observed anxiolytic-like effects. The anxiolytic effects seem to be mediated independently from the HPA axis, potentially engaging the central serotonin system.

Functional effects of losartan in hypertrophic cardiomyopathy—a randomised clinical trial

Objective There is a lack of disease-modifying treatments in hypertrophic cardiomyopathy (HCM). The aim of this randomised, placebo-controlled study was to assess if losartan could improve or ameliorate deterioration of cardiac function and exercise capacity. Methods Echocardiography, exercise test and MRI or CT were performed at baseline and after 12 months in 133 patients (52±13 years, 35% female) randomly allocated to losartan (100 mg/day) or placebo. Results Losartan had no effect on systolic function compared with placebo (mean difference for left ventricular ejection fraction (LVEF) 0% (95% CI −3% to 4%), p=0.84 or global longitudinal strain 0.7% (95% CI −0.2% to 1.6%), p=0.13). Neither Doppler measures of diastolic function, left atrial volume (mean difference 2 mL/m2 (95% CI −4 to 8 mL/m2) p=0.53) nor exercise capacity (mean difference −0.3 metabolic equivalents (METS) (95% CI −1.0 to 0.3 METS), p=0.28) differed between the treatment groups. At follow-up, there was further progression of disease, with the most prominent impairment being an increase in left atrial volume of 6 mL/m2 (95% CI 3 to 9 mL/m2, p<0.0001) in both groups combined. LVEF decreased (mean change −2%, (95% CI −3% to −1%), p=0.037) and 4% of patients had end-stage HCM with a LVEF of less than 50% at the end of the study. Conclusion Treatment with losartan had no effect on cardiac function or exercise capacity compared with placebo. Losartan fail to improve myocardial performance and failed to alter the progression of the disease. These findings do not support the use of angiotensin II receptor blockers as disease modifiers in adult patients with overt HCM. Trial registration number NCT01447654-results.

Stress and learning

1 Miller GA. The magical number seven, plus or minus two: some limits on our capacity for processing information. Psychol Rev 1956;63:81–97. 2 Lucas PJF, de Bruijn NC, Schurink K, Hoepelman A. A probabilistic and decision-theoretic approach to the management of infectious disease at the ICU. Artif Intell Med 2000;19 (3):251–79. 3 Wegwarth O, Gaissmaier W, Gigerenzer G. Smart strategies for doctors and doctors-in-training: heuristics in medicine. Med Educ 2009;43:721–8. 4 Marewski JN, Gaissmaier W, Gigerenzer G. Good judgements do not require complex cognition. Cogn Process 2010;11 (2):103–21. 5 Simon HA. Rational choice and the structure of the environment. Psychol Rev 1956;63:129–38. 6 Simon HA. Invariants of human behaviour. Annu Rev Psychol 1990;41:1–19. 7 Reyna VF, Lloyd FJ. Physician decision making and cardiac risk: effects of knowledge, risk perception, risk tolerance, and fuzzy processing. J Exp Psychol Appl 2006;12 (3):179–95. 8 Mazzocco K, Cherubini P. The effect of outcome information on health professionals’ spontaneous learning. Med Educ 2010;44:962–8. 9 Baron J, Hershey JC. Outcome bias in decision evaluation. J Pers Soc Psychol 1988;54:569–79. 10 Tversky A, Kahneman D. Availability: a heuristic for judging frequency and probability. Cogn Psychol 1973;5:207–32. 11 Mamede S, Schmidt HG, Rikers RMJP, Custers EJFM, Splinter TA, van Saase JLCM. Conscious thought beats deliberation without attention in diagnostic decision making: at least when you are an expert. Psychol Res (in press).