Self-explanation in learning clinical reasoning: the added value of examples and prompts

ContextRecent studies suggest that self-explanation (SE) while diagnosing cases fosters the development of clinical reasoning in medical students; however, the conditions that optimise the impact of SE remain unknown. The example-based learning framework justifies an exploration of students' use of their own SEs combined with the study of examples. This study aimed to assess the impact on medical students' diagnostic performance of: (i) combining students' SEs with their listening to examples of residents' SEs, and (ii) the addition of prompts (specific questions) while working with examples. MethodsThis study consisted of a training phase and an assessment phase conducted 1week later. In the training phase, 54 Year3 medical students were randomly assigned to one of three groups. In all groups, students first solved four clinical cases using SE. Subsequently, Group1 listened to examples of residents' SEs with prompts; Group2 listened to examples of residents' SEs without prompts, and the control group solved word puzzles. Then, all students again solved the same four cases. One week later, all students solved four similar and four different cases. Students' diagnostic performance and diagnostic accuracy scores were assessed for each case at each time-point. ResultsAlthough all groups' diagnostic accuracy scores on similar cases improved significantly between the training and the assessment phase, Group1 showed a significantly higher diagnostic performance score after 1week than the control group (p=0.037). On different cases, Group1 obtained significantly higher diagnostic accuracy (p=0.011) and diagnostic performance (p<0.001) scores than the control group and a significantly higher diagnostic performance score than Group2 (p=0.018). ConclusionsSelf-explanation seems to be an effective technique to help medical students learn clinical reasoning. Its impact is increased significantly by combining it with examples of residents' SEs and prompts. Although students' exposure to examples of clinical reasoning is important, their active processing' of these examples appears to be critical to their learning from them. Discuss ideas arising from the article at discuss

Cardiovascular diseases, risk factors and short-term heart rate variability in an elderly general population: the CARLA study 2002-2006

Background: A reduced heart rate variability (HRV) is associated with worse prognosis, increased incidence of cardiovascular disease (CVD) and mortality. There are conflicting results and a lack of population-based data regarding the association of HRV with CVD risk factors and its potential role as independent cause or mediator of CVD risk. Methods: Cross-sectional data of a population-based cohort including 1,779 women and men aged 45-83 years were used to analyse associations of time and frequency domain measures of HRV (derived from 5-min ECG segments) with age, behavioural and biomedical risk factors and disease in the whole sample and in a "healthy" subgroup. Results: Age was inversely associated with all measures of HRV (mean standard deviation of normal intervals across 10-year age-groups 32.1, 26.9, 27.1 and 24.8 ms in women, 29.3, 25.9, 23.8 and 25.7 ms in men). There was no association of physical activity, current smoking or alcohol with HRV. In age-adjusted models, triglycerides, glucose, waist-to-hip ratio and diabetes were inversely associated with HRV in men and women, and low/high density cholesterol and hypertension in men only (up to 43% difference across risk factor quartiles). Multivariable adjustment and restriction to the "healthy" subgroup attenuated the associations. Conclusions: We found only weak and inconsistent associations of HRV with cardiovascular risk factors. However, these results as well as those from previous studies are still compatible with the hypothesis that short-term HRV may be a marker of ill health or a mediator of the effect of selected biomedical risk factors on CVD

Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease

Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3'-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3'-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association

No association of ALOX5AP polymorphisms with risk of MRI-defined brain infarcts

The arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene has been associated with stroke. The majority of the reported ALOX5AP associations have considered non-radiologically confirmed infarcts as the stroke phenotype. We assessed the association of genetic variants in ALOX5AP with stroke defined by the presence infarcts on brain Magnetic Resonance Imaging (MRI). We studied 202 persons with MRI-defined brain infarcts cases and 487 healthy individuals of Caribbean Hispanic ancestry. Another sample of European ancestry comprised of 1,823 persons with MRI-defined brain infarct and 7,578 controls. Subjects were genotyped for the four SNPs that define ALOX5AP HapA haplotype. No association was found between SNPs and MRI-defined brain infarcts. Our data do not support the hypothesis that variants in ALOX5AP are associated with risk of MRI-defined brain infarcts

Association of Alzheimer's disease GWAS loci with MRI markers of brain aging

Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta +/- SE = -0.047 +/- 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons. (C) 2015 Elsevier Inc. All rights reserved

Genome-Wide Association Studies of MRI-Defined Brain Infarcts Meta-Analysis From the CHARGE Consortium

Background and Purpose-Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age-and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >= 1 MRI infarct). Results-The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P = 4.64 x 10(-7)). Highly suggestive associations (P 0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. Conclusions-This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed. (Stroke. 2010; 41: 210-217.

Genetic Variants Associated With Cardiac Structure and Function A Meta-analysis and Replication of Genome-wide Association Data

Context Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. Objective To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. Design, Setting, and Participants Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms ( SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. Main Outcome Measures Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. Results In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining < 1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). Conclusions We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease. JAMA. 2009;302(2):168-178 www.jama.co