A novel 6D-approach to radically transform undergraduate medical education: preliminary reflections from MBRU.

BACKGROUND: Designers of undergraduate medical education (UME) need to address the exponentially expanding volume and variability of scientific knowledge, where by didactic teaching techniques need to be augmented by innovative student-centric pedagogical strategies and implementation of milieus, where information, communication and technology-enabled tools are seamlessly integrated, and lifelong information gathering, assimilation, integration and implementation is the ultimate goal. In UME, the basic sciences provide a solid scaffold allowing students to develop their personal critical decisional framework as well as define the understanding of normal human physiology, pivotal for the identification, categorization and management of pathophysiology. However, most medical schools confine themselves to "stagnant curricula", with the implementation of traditional "teacher centered" pedagogical techniques in the dissemination of the courses pertaining to basic sciences in UME. METHOD: To tackle the above paucity, we present a novel "6D-Approach" for the dissemination of concepts in basic sciences through mentored journal-clubs. The approach is informed by a teaching principle derived from Constructivism. The technique in which the 6D-approach can be implemented in UME, is shown using an example from a first-year course of Molecular Biology and Principles of Genetics at our medical school. A reflection on the impact of 6D-Approach for students as well as instructors is also presented. RESULT: The 6D-approach was positively received by the students and the formal feedback for the course: Molecular Biology and Principles of Genetics, where the approach was repeatedly employed, indicated that students expressed satisfaction with the teaching strategies employed in the course, with ~ 89% of the students in the cohort strongly agreeing with the highest grading score "extremely satisfied". Further, the approach through the use of mentored journal clubs encourages retention of knowledge, critical thinking, metacognition, collaboration and leadership skills in addition to self-evaluation and peer feedback. CONCLUSION: Hence, through the 6D-Approach, our attempt is to initiate, advance and facilitate critical thinking, problem-solving and self-learning in UME, demonstrated by graduating accomplished, competent and safe medical practitioners.

Lipid and lipoprotein reference values from 133,450 Dutch Lifelines participants: Age- and gender-specific baseline lipid values and percentiles.

BACKGROUND: Lipids and lipoproteins are recognized as the most important modifiable risk factors for cardiovascular disease. Although reference values for the major lipoproteins, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides, have been collected in numerous studies and cohorts, complete contemporary percentile-based reference values are underreported. OBJECTIVE: We set out to provide such reference lipid data using a large contemporary population-based cohort study. STUDY DESIGN AND SETTING: Lifelines is a cross-sectional population-based Dutch cohort study. We analyzed 133,540 adult fasting participants without cardiovascular disease and without lipid-lowering drug use. Lipid levels were directly measured and selected percentiles of all lipid parameters were calculated. Friedewald LDL-C estimation was calculated as well. RESULTS: From 20 till 49 years of age, men were found to exhibit a steep 64% increase of LDL-C (median +54 mg/dL), while triglyceride levels increased almost two-fold. In women, LDL-C levels did not change from 18 till 35 years, followed by a steep 42% increase till 59 years (median +42 mg/dL). In contrast to men, triglycerides were stable in ageing women. Overall, Friedewald LDL-C levels are lower compared with the direct measurement, especially with increasing triglyceride levels. CONCLUSIONS: This observational study highlights striking gender- and age-related differences in plasma lipid profiles. The given reference ranges of plasma lipids can assist in early identification of individuals with hypocholesterolemia and hypercholesterolemia, especially familial hypercholesterolemia. These reference ranges are available for physicians and patients at www.my-cholesterol.care/.

International Developments in the Care of Familial Hypercholesterolemia: Where Now and Where to Next?

Several international guidelines and consensus statements have recently been published on the care of familial hypercholesterolemia (FH)(1-3)). They agree on approaches to case detection and cascade testing, protocols in children, lifestyle and drug treatment strategies, and indications for lipoprotein apheresis. However, most countries in the world still do not have integrated, systematic FH screening programs to adequately detect and treat cases in the community. This study provides a comprehensive overview of recent and future international initiatives for closing the gaps in the care of FH.

Expanding the Evidence Base: Comparing Randomized Controlled Trials and Observational Studies of Statins.

It is widely accepted that randomized controlled trials (RCTs) are the gold standard for demonstrating the efficacy of a given therapy (results under ideal conditions). Observational studies, on the other hand, can complement this by demonstrating effectiveness (results under real-world conditions). To examine the role that observational studies can play in complementing data from RCTs, we reviewed published studies for statins, a class of drugs that have been widely used to reduce the risk of cardiovascular (CV) events by lowering low-density lipoprotein cholesterol levels. RCTs have consistently demonstrated the benefits of statin treatment in terms of CV risk reduction and have demonstrated that more intensive statin therapy has incremental benefits over less intensive treatment. Observational studies of statin use in 'real-world' populations have served to augment the evidence base generated from statin RCTs in preselected populations of patients who are often at high CV risk and have led to similar safety and efficacy findings. They have also raised questions about factors affecting medication adherence, under-treatment, switching between statins, and failure to reach low-density lipoprotein cholesterol target levels, questions for which the answers could lead to improved patient care.

Efficacy of statins in familial hypercholesterolaemia: a long term cohort study.

OBJECTIVE: To determine the efficacy of statin treatment on risk of coronary heart disease in patients with familial hypercholesterolaemia. DESIGN: Cohort study with a mean follow-up of 8.5 years. SETTING: 27 outpatient lipid clinics. SUBJECTS: 2146 patients with familial hypercholesterolaemia without prevalent coronary heart disease before 1 January 1990. MAIN OUTCOME MEASURES: Risk of coronary heart disease in treated and "untreated" (delay in starting statin treatment) patients compared with a Cox regression model in which statin use was a time dependent variable. RESULTS: In January 1990, 413 (21%) of the patients had started statin treatment, and during follow-up another 1294 patients (66%) started after a mean delay of 4.3 years. Most patients received simvastatin (n=1167, 33 mg daily) or atorvastatin (n=211, 49 mg daily). We observed an overall risk reduction of 76% (hazard ratio 0.24 (95% confidence interval 0.18 to 0.30), P<0.001). In fact, the risk of myocardial infarction in these statin treated patients was not significantly greater than that in an age-matched sample from the general population (hazard ration 1.44 (0.80 to 2.60), P=0.23). CONCLUSION: Lower statin doses than those currently advised reduced the risk of coronary heart disease to a greater extent than anticipated in patients with familial hypercholesterolaemia. With statin treatment, such patients no longer have a risk of myocardial infarction significantly different from that of the general population.

Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing.

BACKGROUND: The plasma total and low-density lipoprotein-cholesterol (LDL-C) levels that are used as diagnostic criteria for familial hypercholesterolaemia (FH) probands in the general population are too stringent for use in relatives, given the higher prior probability of a first-degree relative being FH (50% vs. 1/500). Our objective was therefore to develop more appropriate LDL-C cutoffs to identify "affected" first-degree relatives found by cascade testing, to test their accuracy and utility in case identification, and to compare them with the published "Make early diagnosis to prevent disease" (MEDPED) cutoffs from the US. METHODS: Using a large, anonymised sample of genetically tested first-degree relatives of Netherlands FH probands (mutation carriers/non-carriers, n=825/2,469), age- and gender-specific LDL-C diagnostic cutoffs for first-degree relatives were constructed. These were used to test similar data from Denmark (n=160/161) and Norway (n=374/742). RESULTS: Gender-specific LDL-C diagnostic cutoffs were established for six different age groups, which achieved an overall accuracy (measured as Youden's index) of 0.53 in the Netherlands data, and performed significantly better amongst younger (<25 years) compared to older first-degree relatives (0.68 vs. 0.42 Youden's index, p<0.001). Compared with the Netherlands data, age- and gender-adjusted mean LDL-C levels were significantly higher (approximately 0.5 mmol/L) in the Denmark and Norway subjects for both mutation carriers and non-carriers. After adjusting for this difference, the LDL-C cut-offs showed a similar accuracy in identifying mutation carriers from Denmark (81%, range 78%-86%) and Norway (84%, range 82%-86%). Although the MEDPED cutoffs performed significantly worse than these for the Netherlands data (p<0.001), they performed equally well in overall accuracy for the Norwegian and Danish data, although the LDL-C cutoffs had a significantly higher sensitivity but lower specificity for all three countries. CONCLUSIONS: The cutoffs developed here are designed to give the greatest overall accuracy when testing relatives of FH patients in the absence of a genetic diagnosis. They have a more balanced specificity and sensitivity than the MEDPED cutoffs that are designed to achieve higher specificity, which is more appropriate for cascade testing purposes. The data suggest that country-specific LDL-C cutoffs may lead to greater accuracy for identifying FH patients, but should be used with caution and only when a genetic diagnosis (DNA) is not available.

Familial hypercholesterolemia: current treatment and advances in management.

Heterozygous familial hypercholesterolemia is associated with elevated levels of LDL-cholesterol and the development of premature cardiovascular disease. The condition is considerably under-diagnosed and under-treated. Statins are the first choice treatment for all patients with heterozygous familial hypercholesterolemia. For those patients who do not reach their treatment target or who are unable to use adequate statin dose, several alternative treatment modalities can be used, either as add-on therapy or as monotherapy. In this review the various treatment options are discussed.

Diagnosing familial hypercholesterolaemia: the relevance of genetic testing.

AIMS: We assembled a cohort of patients with familial hypercholesterolaemia (FH) for both basic and clinical research. We used a set of established diagnostic criteria to define FH. Some put forward that a definite diagnosis of FH is made when a mutation in the LDL-receptor (LDLR) gene is identified. We therefore set out to determine in these patients whether patients with a DNA diagnosis would differ significantly from those diagnosed clinically. METHODS AND RESULTS: We randomly selected 4000 hypercholesterolaemic patients from the Dutch Lipid Clinic network database. Phenotypical data were acquired by reviewing medical records. After review of medical records, 2400 patients could be defined as having FH. An LDLR mutation was identified in 52.3% of these patients. Patients with and without an LDLR mutation demonstrated different clinical and laboratory characteristics. Low-density lipoprotein cholesterol was higher in patients with an LDLR mutation, whereas triglycerides were higher in patients without an LDLR mutation. The phenotypic differences between the groups remained even after stratification for the presence or absence of tendon xanthomas. CONCLUSION: Despite the use of stringent clinical criteria to define FH patients, two cohorts could be identified within our study population, namely those patients with and those without an LDLR mutation. Our findings suggest that among those without an LDLR mutation, patients with other causes of dyslipidaemia may be present. These observations underline the relevance of genetic testing in FH for clinical practice, for screening purposes, and for research involving these patients.

Advanced method for the identification of patients with inherited hypercholesterolemia.

Familial hypercholesterolemia (FH) has a prevalence of 1 in 500 in Western society and predisposes for premature cardiovascular disease. Lipid-lowering treatment of affected individuals is widely advocated. Maximum health benefit can be obtained in FH if treatment is started as early as possible, as the World Health Organization has recently recommended. In 1994 we initiated an active case-finding program for individuals with FH, based on family investigation and DNA-testing. In an initial pilot study we established that active family screening supported by DNA diagnostics resulted in the identification of substantial numbers of FH heterozygotes and determined that diagnosis by DNA analysis was superior to conventional cholesterol measurement. Since its initiation, the program has led to the identification of more than 6000 individuals with FH, of whom the greatest part was not adequately treated at the time of identification. Our findings indicate not only that this case-finding approach is effective in identifying FH patients who otherwise would not have been identified but also that the vast majority of these patients seek treatment and are successfully started on cholesterol-lowering therapy to reduce their risk of premature cardiovascular disease. Here we describe an effective model to identify and bring under treatment large numbers of individuals affected by FH.

Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery.

BACKGROUND: Patients undergoing major vascular surgery are at increased risk of perioperative mortality due to underlying coronary artery disease. Inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (statins) may reduce perioperative mortality through the improvement of lipid profile, but also through the stabilization of coronary plaques on the vascular wall. METHODS AND RESULTS: To evaluate the association between statin use and perioperative mortality, we performed a case-controlled study among the 2816 patients who underwent major vascular surgery from 1991 to 2000 at the Erasmus Medical Center. Case subjects were all 160 (5.8%) patients who died during the hospital stay after surgery. From the remaining patients, 2 controls were selected for each case and were stratified according to calendar year and type of surgery. For cases and controls, information was obtained regarding statin use before surgery, the presence of cardiac risk factors, and the use of other cardiovascular medication. A vascular complication during the perioperative phase was the primary cause of death in 104 (65%) case subjects. Statin therapy was significantly less common in cases than in controls (8% versus 25%; P<0.001). The adjusted odds ratio for perioperative mortality among statin users as compared with nonusers was 0.22 (95% confidence interval 0.10 to 0.47). Similar results were obtained in subgroups of patients according to the use of cardiovascular therapy and the presence of cardiac risk factors. CONCLUSIONS: This case-controlled study provides evidence that statin use reduces perioperative mortality in patients undergoing major vascular surgery.

Measurement of subclinical atherosclerosis: beyond risk factor assessment.

PURPOSE OF REVIEW: Assessment of subclinical atherosclerosis using the current available noninvasive imaging modalities holds promise for individual cardiovascular risk management and monitoring efficacy of therapeutic interventions (i.e. surrogate end-points). The present review addresses benefits and limitations of flow-mediated dilatation, intima-media thickness, electron-beam computed tomography and magnetic resonance coronary angiography. RECENT FINDINGS: Both carotid intima-media thickness and peripheral flow-mediated dilatation correlate inversely with cardiovascular risk factors and coronary artery disease. They have been shown to carry predictive value for future cardiovascular events, but clinical application of both intima-media thickness and flow-mediated dilatation demands further methodological maturation of these techniques. Intima thickening has been successfully targeted in numerous intervention trials, but determination of an explicit threshold value beyond which cardiovascular risk significantly increases will facilitate its utility as a routine clinical tool. Electron-beam computed tomography can accurately detect and quantify coronary artery calcification (an established marker of the total coronary plaque burden). However, lack of evidence of its additional predictive power for future coronary events warrants for further research. Finally, magnetic resonance coronary angiography appears to be a promising technique, integrating both functional and anatomical aspects of coronary artery disease. Properly designed studies are needed to determine its value in clinical practice. SUMMARY: Various noninvasive imaging techniques have recently emerged that may find applications in clinical research. However, before widespread clinical utilization, further technical refinement of all of the cited imaging modalities is mandatory. It will be a challenge over the coming few years to clarify whether improvements in surrogate end-points can directly be translated into improved outcomes.