Pharmacogenetic Testing or Therapeutic Drug Monitoring: A Quantitative Framework.

BACKGROUND: Pharmacogenetic profiling and therapeutic drug monitoring (TDM) have both been proposed to manage inter-individual variability (IIV) in drug exposure. However, determining the most effective approach for estimating exposure for a particular drug remains a challenge. This study aimed to quantitatively assess the circumstances in which pharmacogenetic profiling may outperform TDM in estimating drug exposure, under three sources of variability (IIV, inter-occasion variability [IOV], and residual unexplained variability [RUV]). METHODS: Pharmacokinetic models were selected from the literature corresponding to drugs for which pharmacogenetic profiling and TDM are both clinically considered approaches for dose individualization. The models were used to simulate relevant drug exposures (trough concentration or area under the curve [AUC]) under varying degrees of IIV, IOV, and RUV. RESULTS: Six drug cases were selected from the literature. Model-based simulations demonstrated that the percentage of patients for whom pharmacogenetic exposure prediction is superior to TDM differs for each drug case: tacrolimus (11.0%), tamoxifen (12.7%), efavirenz (49.2%), vincristine (49.6%), risperidone (48.1%), and 5-fluorouracil (5-FU) (100%). Generally, in the presence of higher unexplained IIV in combination with lower RUV and IOV, exposure was best estimated by TDM, whereas, under lower unexplained IIV in combination with higher IOV or RUV, pharmacogenetic profiling was preferred. CONCLUSIONS: For the drugs with relatively low RUV and IOV (e.g., tamoxifen and tacrolimus), TDM estimated true exposure the best. Conversely, for drugs with similar or lower unexplained IIV (e.g., efavirenz or 5-FU, respectively) combined with relatively high RUV, pharmacogenetic profiling provided the most accurate estimate for most patients. However, genotype prevalence and the relative influence of genotypes on the PK, as well as the ability of TDM to accurately estimate AUC with a limited number of samples, had an impact. The results could be used to support clinical decision making when considering other factors, such as the probability for severe side effects.

Cardiovascular disease in transgender people: a systematic review and meta-analysis.

OBJECTIVE: Hormone therapy in transgender people might be associated with an increased risk of cardiovascular disease (CVD). We aimed to investigate whether the risk of CVD is increased in transgender people compared with people of the same birth sex. DESIGN AND METHODS: PubMed, Cochrane, Embase, and Google Scholar were searched until July 2022. Studies evaluating cardiovascular events in transgender women or men were included. Primary outcomes were stroke, myocardial infarction (MI), and venous thromboembolism (VTE). The risk for transgender women versus cisgender men and for transgender men versus cisgender women was analysed through random-effects meta-analysis. RESULTS: Twenty-two studies involving 19 893 transgender women, 14 840 transgender men, 371 547 cisgender men, and 434 700 cisgender women were included. The meta-analysis included 10 studies (79% of transgender women and 76% of transgender men). In transgender women, incidence of stroke was 1.8%, which is 1.3 (95% confidence interval [CI], 1.0-1.8) times higher than in cisgender men. Incidence of MI was 1.2%, with a pooled relative risk of 1.0 (95% CI, 0.8-1.2). Venous thromboembolism incidence was 1.6%, which is 2.2 (95% CI, 1.1-4.5) times higher. Stroke occurred in 0.8% of transgender men, which is 1.3 (95% CI, 1.0-1.6) times higher compared with cisgender women. Incidence of MI was 0.6%, with a pooled relative risk of 1.7 (95% CI, 0.8-3.6). For VTE, this was 0.7%, being 1.4 (95% CI, 1.0-2.0) times higher. CONCLUSIONS: Transgender people have a 40% higher risk of CVD compared with cisgender people of the same birth sex. This emphasizes the importance of cardiovascular risk management. Future studies should assess the potential influence of socio-economic and lifestyle factors.

The efficacy of aspirin to inhibit platelet aggregation in patients hospitalised with a severe infection: a multicentre, open-label, randomised controlled trial.

Patients with severe infection have an increased risk of cardiovascular events. A possible underlying mechanism is inflammation-induced platelet aggregation. We investigated whether hyperaggregation occurs during infection, and whether aspirin inhibits this. In this multicentre, open-label, randomised controlled trial, patients hospitalised due to acute infection were randomised to receive 10 days of aspirin treatment (80 mg 1dd or 40 mg 2dd) or no intervention (1:1:1 allocation). Measurements were performed during infection (T1; days 1-3), after intervention (T2; day 14) and without infection (T3; day > 90). The primary endpoint was platelet aggregation measured by the Platelet Function Analyzer® closure time (CT), and the secondary outcomes were serum and plasma thromboxane B2 (sTxB2 and pTxB2). Fifty-four patients (28 females) were included between January 2018 and December 2020. CT was 18% (95%CI 6;32) higher at T3 compared with T1 in the control group (n = 16), whereas sTxB2 and pTxB2 did not differ. Aspirin prolonged CT with 100% (95%CI 77; 127) from T1 to T2 in the intervention group (n = 38), while it increased with only 12% (95%CI 1;25) in controls. sTxB2 decreased with 95% (95%CI - 97; - 92) from T1 to T2, while it increased in the control group. pTxB2 was not affected compared with controls. Platelet aggregation is increased during severe infection, and this can be inhibited by aspirin. Optimisation of the treatment regimen may further diminish the persisting pTxB2 levels that point towards remaining platelet activity. This trial was registered on 13 April 2017 at EudraCT (2016-004303-32).

Optimization of blood pressure measurement practices for pharmacodynamic analyses of tyrosine-kinase inhibitors.

Blood pressure measurements form a critical component of adverse event monitoring for tyrosine kinase inhibitors, but might also serve as a biomarker for dose titrations. This study explored the impact of various sources of within-individual variation on blood pressure readings to improve measurement practices and evaluated the utility for individual- and population-level dose selection. A pharmacokinetic-pharmacodynamic modeling framework was created to describe circadian blood pressure changes, inter- and intra-day variability, changes from dipper to non-dipper profiles, and the relationship between drug exposure and blood pressure changes over time. The framework was used to quantitatively evaluate the influence of physiological and pharmacological aspects on blood pressure measurements, as well as to compare measurement techniques, including office-based, home-based, and ambulatory 24-h blood pressure readings. Circadian changes, as well as random intra-day and inter-day variability, were found to be the largest sources of within-individual variation in blood pressure. Office-based and ambulatory 24-h measurements gave rise to potential bias (>5 mmHg), which was mitigated by model-based estimations. Our findings suggest that 5-8 consecutive, home-based, measurements taken at a consistent time around noon, or alternatively within a limited time frame (e.g., 8.00 a.m. to 12.00 p.m. or 12.00 p.m. to 5.00 p.m.), will give rise to the most consistent blood pressure estimates. Blood pressure measurements likely do not represent a sufficiently accurate method for individual-level dose selection, but may be valuable for population-level dose identification. A user-friendly tool has been made available to allow for interactive blood pressure simulations and estimations for the investigated scenarios.

[Guidelines: leash or walking stick?] / Richtlijnen: leiband of wandelstok?

Guidelines are undeniably of great value to practicing physicians, but there are also objections. Due to the multitude of guidelines, it is sometimes difficult to find the most appropriate and it is not always clear how well-founded recommendations are. In addition, guidelines can limit the freedom of action. Also, in individual patients - especially in the case of multimorbidity - recommendations from different guidelines can conflict with each other. Finally, drawing up guidelines takes a lot of time, which is at the expense of patient care, and conflicts of interest are difficult to avoid completely. It is therefore important to put the recommendations from guidelines into perspective: they are an aid to individual patient care, not a law. This perspective is also important in education, so that students are taught to use guidelines in a wise way. Finally, it is important to regularly evaluate recommendations and revise them if necessary.

The effect of low-dose aspirin on platelet function during pregnancy compared to placebo: An explorative study.

OBJECTIVES: To evaluate the effect of aspirin 80 mg compared to placebo on platelet function tests in the second and third trimester of pregnancy. STUDY DESIGN: An explorative study was performed to assess laboratory platelet function in a subpopulation of the APRIL trial: a randomized double-blind trial comparing aspirin 80 mg once daily to placebo for the prevention of recurrent preterm birth. Platelet function was measured between 18 and 22, and between 28 and 32 weeks gestational age with three platelet function tests: VerifyNow®, Chronolog light transmission aggregometry (Chronolog LTA) and serum thromboxane B2 (TxB2). Medication adherence was evaluated by pill counts, self-reported diaries and structured interviews. RESULTS: We included 11 women, six in the aspirin and five in the placebo group. In women receiving aspirin, platelet function was significantly lower compared to women receiving placebo for all three tests: VerifyNow® Aspirin Reaction Units (450.5 vs 648.0, p = 0.017); Chronolog LTA (9.5% vs 94.5%, p = 0.009); serum TxB2 levels (11.9 ng/mL versus 175.9 ng/mL, p = 0.030). For all three tests, platelet function did not differ between the second and third trimester of pregnancy in the aspirin group. In the placebo group, serum TxB2 levels were significantly higher in the third trimester. One non-adherent participant in the aspirin group showed results similar to the placebo group. CONCLUSION: Aspirin 80 mg has a clear inhibitory effect on laboratory platelet function during pregnancy compared to placebo. This effect is similar in the second and third trimester of pregnancy.

The effect of transdermal gender-affirming hormone therapy on markers of inflammation and hemostasis.

BACKGROUND: Cardiovascular risk is increased in transgender persons using gender-affirming hormone therapy. To gain insight into the mechanism by which sex hormones affect cardiovascular risk in transgender persons, we investigated the effect of hormone therapy on markers of inflammation and hemostasis. METHODS: In this exploratory study, 48 trans women using estradiol patches plus cyproterone acetate (CPA) and 47 trans men using testosterone gel were included. They were between 18 and 50 years old and did not have a history of cardiovascular events. Measurements were performed before and after 3 and 12 months of hormone therapy. RESULTS: After 12 months, in trans women, systemic and endothelial inflammatory markers decreased (hs-CRP -66%, (95% CI -76; -53), VCAM-1-12%, (95% CI -16; -8)), while platelet activation markers increased (PF-4 +17%, (95% CI 4; 32), ß-thromboglobulin +13%, (95% CI 2; 24)). The coagulation marker fibrinogen increased transiently, after 3 months (+15%, (95% CI 1; 32)). In trans men, hs-CRP increased (+71%, (95% CI 19; 145)); platelet activation and coagulation markers were not altered. In both trans women and trans men, leptin and adiponectin changed towards reference values of the experienced gender. CONCLUSIONS: Platelet activation and coagulation marker concentrations increased in trans women using transdermal estradiol plus CPA, but not in trans men using testosterone. Also, concentrations of inflammatory markers decreased in trans women, while hs-CRP increased in trans men. Our results indicate that hormone therapy may affect hemostasis in transgender persons, which could be an underlying mechanism explaining the increased cardiovascular risk in this population.

[Research into diagnostic reasoning: significant, but also relevant?] / Onderzoek naar diagnostisch redeneren.

Research into diagnostic reasoning often focuses on diagnostic errors, while ignoring the also important concepts of overdiagnosis and cost of the diagnostic process. A popular theoretic model guiding studies on the subject is the dual process model in which cognitive errors play an important role. This paradigm is also used in the study of Mamede and colleagues, who studied the effect of disease specific knowledge on the occurrence of diagnostic errors due to availability bias in internal medicine residents. The study, which used case vignettes, is well set up but its experimental design cannot account for the influence of clinical context which limits its clinical value. Further research into this topic should be performed in actual clinical situations to provide more insight in how to improve diagnostic reasoning in medicine.

Erythrocytosis in a Large Cohort of Trans Men Using Testosterone: A Long-Term Follow-Up Study on Prevalence, Determinants, and Exposure Years.

CONTEXT: Erythrocytosis is a known side effect of testosterone therapy that can increase the risk of thromboembolic events. OBJECTIVES: To study the prevalence and determinants in the development of erythrocytosis in trans men using testosterone. METHODS: A 20-year follow-up study in adult trans men who started testosterone therapy and had monitoring of hematocrit at our center (n = 1073). RESULTS: Erythrocytosis occurred in 11% (hematocrit > 0.50 L/L), 3.7% (hematocrit > 0.52 L/L), and 0.5% (hematocrit > 0.54 L/L) of trans men. Tobacco use (odds ratio [OR] 2.2; 95% CI, 1.6-3.3), long-acting undecanoate injections (OR 2.9; 95% CI, 1.7-5.0), age at initiation of hormone therapy (OR 5.9; 95% CI, 2.8-12.3), body mass index (BMI) (OR 3.7; 95% CI, 2.2-6.2), and pulmonary conditions associated with erythrocytosis and polycythemia vera (OR 2.5; 95% CI, 1.4-4.4) were associated with hematocrit > 0.50 L/L. In the first year of testosterone therapy hematocrit increased most: 0.39 L/L at baseline to 0.45 L/L after 1 year. Although there was only a slight continuation of this increase in the following 20 years, the probability of developing erythrocytosis still increased (10% after 1 year, 38% after 10 years). CONCLUSION: Erythrocytosis occurs in trans men using testosterone. The largest increase in hematocrit was seen in the first year, but also after the first years a substantial number of people present with hematocrit > 0.50 L/L. A reasonable first step in the care for trans men with erythrocytosis while on testosterone is to advise them to quit smoking, to switch to a transdermal administration route, and if BMI is high, to lose weight.

[Uncertainty in medical decision-making]. / Onzekerheid in medisch handelen.

Disciplinary law originally intends to promote quality in individual health care. One could argue on the basis of empirical data that the current practice of medical disciplinary law does not demonstrably contribute to 'defensive medicine', a putative adverse effect of this form of jurisdiction. However, the practice and perception of disciplinary law should demonstrate that the possible other side effects (e.g. time consuming, emotionally distressful, impeding transparency to patients and colleagues, increasing the burden of uncertainty in medicine) of this form of case law dwarfs the yield: this postulated quality improvement. The words 'discipline' and 'law' are in themselves barriers in catalyzing an open attitude towards discussing suboptimal processes in health care with both patients and colleagues. Further reflection on the scope of practice and the perception of disciplinary law is necessary in order to further shape a cultural shift towards such an attitude and an dialogue. We have to move from the disciplinary law to a learning portal.

The relationship of a Prothrombin G20210A mutation or a factor V Leiden mutation and on-aspirin platelet (re-)activity.

INTRODUCTION: The interplay between platelets and pro-thrombotic factors may have been under-investigated in the identification of aspirin users at high risk for cardiovascular event reoccurrences. There is growing evidence that a Prothrombin G20210A (FII) or a Factor V Leiden (FVL) mutation might increase platelet activity. Subsequently, this study assessed on-aspirin platelet (re-)activity in non-pregnant participants with a FII - or a FVL mutation in comparison with non-pregnant data derived from controls. METHODS: This study was conducted with data derived from the follow-up FRUIT-RCT. This is a unique cohort namely, participants without a history of cardiovascular disease or thrombotic events, but who are a carrier of a pro-thrombotic mutation. All participants were instructed to ingest aspirin once daily for 10 days. Platelet (re-)activity was measured by the PFA Closure Time (PFA-CT), the VerifyNow (VN-ARU), and serum Thromboxane B2 (sTxB2) levels. RESULTS: In total, eight participants with a FII-, 15 with a FVL mutation, and 21 controls were included. The FII mutation carriers demonstrated significantly higher on-aspirin platelet (re)-activity (PFA-CT, -92 sec.; VN-ARU, +37 ARU) vs. controls. The FVL carriers demonstrated similar on-aspirin platelet (re-)activity vs. controls. The sTxB 2 levels were similar in either of the carrier groups vs. controls. CONCLUSION: We feel these data are suggestive of increased on-aspirin platelet (re-)activity, as measured by the PFA-200 and the VerifyNow, in non-pregnant carriers of a FII-mutation, but not in carriers of FVL-mutation. Interestingly, this increased on-aspirin platelet (re-)activity is present in spite of low sTxB2 levels.

Resistance of aspirin during and after pregnancy: A longitudinal cohort study.

OBJECTIVES: The objective of this study is to investigate possible changes in aspirin resistance during and after pregnancy over time. STUDY DESIGN: A longitudinal cohort study in obstetric high risk women with an indication for aspirin usage during pregnancy to prevent placenta mediated pregnancy complications. MAIN OUTCOME MEASURES: Aspirin resistance measured in the first, second and third trimester of pregnancy and at least three months postpartum by four complementary test: PFA-200, VerifyNow®, Chronolog light transmission aggregometry (Chronolog LTA) and serum thromboxane B2 (TxB2) level measurements. Correlation between the devices was investigated. RESULTS: In total, 23 pregnant women participated in the present study. Aspirin resistance according to the PFA-200, VerifyNow®, Chronolog LTA and serum TxB2, was 30.4%, 17.4%, 26.1% and 23.8% respectively. Resistance by any device was 69.6%. Aspirin resistance measured by the VerifyNow®, Chronolog LTA, serum TxB2 and aspirin resistance by any device during pregnancy was demonstrated more frequently than aspirin resistance after pregnancy. Correlation between the different devices was weak. CONCLUSION: Aspirin resistance was found in a considerable part of the participants. Considerable variation between participants, within participants over time and between the different devices was found. Prevalence of aspirin resistance during pregnancy differs from after pregnancy. More research on aspirin resistance and clinical obstetric outcome is needed.

Circadian Rhythm of Cardiovascular Disease: The Potential of Chronotherapy With Aspirin.

Almost all the systems in our body adhere to a daily 24 h rhythm. The cardiovascular system is also affected by this 24 h rhythm. In the morning there is a change in various cardiovascular processes, including platelet aggregability. These changes may play a role in the relative excess of early morning cardiovascular events. The number of recurrent cardiovascular diseases (CVD) could, in theory, be reduced by responding to this 24 h rhythm with timed medication intake (chronotherapy), which also applies to aspirin. Multiple studies on chronotherapy with low-dose aspirin are promising, showing a decrease in early morning platelet activity with evening intake compared with morning intake. However, in order to further demonstrate its clinical impact, randomized trials with cardiovascular events as a primary outcome are needed. This review discusses the available evidence of the effects of circadian rhythm on CVD and the potential positive effect of chronotherapy with aspirin.

Cardiometabolic Effects of Testosterone in Transmen and Estrogen Plus Cyproterone Acetate in Transwomen.

CONTEXT: The impact of gender-affirming hormone therapy (HT) on cardiometabolic parameters is largely unknown. OBJECTIVE: The effects of 1 year of treatment with oral or transdermal administration of estrogen (plus cyproterone) and transdermal or IM application of testosterone on serum lipid levels and blood pressure (BP) were assessed in transgender persons. DESIGN AND METHODS: In this prospective, observational substudy of the European Network for the Investigation of Gender Incongruence, measurements were performed before and after 12 months of HT in 242 transwomen and 188 transmen from 2010 to 2017. RESULTS: Mean values are reported. In transmen, HT increased diastolic BP (2.5%; 95% CI, 0.6 to 4.4) and levels of total cholesterol (TC; 4.1%; 95% CI, 1.5 to 6.6), low-density lipoprotein-cholesterol (LDL-C; 13.0%; 95% CI, 9.2 to 16.8), and triglycerides (36.9%; 95% CI, 29.8 to 44.1); high-density lipoprotein-cholesterol levels decreased (HDL-C; 10.8%; 95% CI, -14.0 to -7.6). In transwomen, HT slightly decreased BP (systolic BP, -2.6%, 95% CI, -4.2 to -1.0; diastolic BP, -2.2%, 95% CI, -4.0 to -0.4) and decreased levels of TC (-9.7%; 95% CI, -11.3 to -8.1), LDL-C (-6.0%; 95% CI, -8.6 to 3.6), HDL-C (-9.3%; 95% CI, -11.4 to -7.3), and triglycerides (-10.2%; 95% CI, -14.5 to -5.9). CONCLUSION: Unfavorable changes in lipid profile were observed in transmen; a favorable effect was noted in transwomen. HT effects on BP were negligible. Long-term studies are warranted to assess whether and to what extent HT in trans individuals results in a differential effect on cardiovascular disease outcomes.

Aspirin intake in the morning is associated with suboptimal platelet inhibition, as measured by serum Thromboxane B2, during infarct-prone early-morning hours.

Aspirin is traditionally taken once daily in the morning and considered to be effective throughout the 24h interval. Cardiovascular events occur most frequently in the early morning, suggesting that these hours are critical in terms of adequate platelet inhibition. This study therefore assed platelet function in the early morning-8.00 AM-in healthy volunteers, during a once-daily (OD) 80 mg morning in comparison with an OD evening regimen and a twice-daily (BID) 40 mg regimen. It was an open-label randomized cross-over study, comprising 12 healthy subjects. Subjects were allocated to three sequential dosage regimens: 80 mg OD at 8.00 AM, 80mg OD at 8.00 PM, and 40 mg BID at 8.00 AM and PM. Platelet function 12 and 24 hours after aspirin intake was measured by means of serum thromboxane B2 (sTxB2) levels, the collagen/epinephrine closure time (Platelet Function Analyzer(PFA)-200®) and the Aspirin Reaction Units (ARU, VerifyNow®). The results demonstrated that early morning sTxB2 concentrations were 5843pg in the morning regimen, 2877pg in the evening OD regimen, and 3343pg in the BID regimen (morning- vs evening regimen p = < 0.01; morning- vs BID regimen p = < 0.01). Early morning PFA-closure time (p = 0.12)) as well as VerifyNow ARU (p = 0.17) mean values were similar for all three regimens. In conclusion, the OD-morning regimen seems to acquire the lowest level of platelet inhibition during the critical early morning window. Switching to an OD-evening or BID intake seems prudent, although further research on clinical cardiovascular outcome in patients with stable cardiovascular disease is needed.

Fertility in adult women with classic galactosemia and primary ovarian insufficiency.

OBJECTIVE: To study pregnancy chance in adult women with classic galactosemia and primary ovarian insufficiency. Despite dietary treatment, >90% of women with classic galactosemia develop primary ovarian insufficiency, resulting in impaired fertility. For many years, chance of spontaneous conception has not been considered, leading to counseling for infertility. But an increasing number of reports on pregnancies in this group questions whether current counseling approaches are correct. DESIGN: Multicenter retrospective observational study. SETTING: Metabolic centers. PATIENT(S): Adult women (aged >18 y) with confirmed classic galactosemia and primary ovarian insufficiency were included. INTERVENTION(S): Participants and medical records were consulted to obtain study data in a standardized manner with the use of a questionnaire. MAIN OUTCOME MEASURE(S): Conception opportunities, time to pregnancy, pregnancy outcome, hormone replacement therapy use, fertility counseling, and the participants' vision of fertility were evaluated. Potential predictive factors for increased pregnancy chance were explored. RESULT(S): Eighty-five women with classic galactosemia and primary ovarian insufficiency participated. Twenty-one women actively attempted to conceive or did not take adequate contraceptive precautions. Of these 21 women, nine became pregnant spontaneously (42.9%). This was higher than reported in primary ovarian insufficiency due to other causes (5%-10%). After a period of 12 months, a cumulative proportion of 27.8% of couples had conceived, which increased to 48.4% after 24 months and 61.3% after 27 months. Predictive factors could not be identified. A considerable miscarriage rate of 30% was observed (6 of 20 pregnancies). Although a substantial proportion of women expressed a child-wish (n = 28/53; 52.8%), the vast majority of participants (n = 43/57; 75.4%) considered conceiving to be highly unlikely, owing to negative counseling in the past. CONCLUSION(S): The pregnancy rate in women with classic galactosemia and primary ovarian insufficiency was higher than for women with primary ovarian insufficiency of any cause. This shifting paradigm carries significant implications for fertility counseling and potential application of fertility preservation techniques.

Motivation and competence of participants in a learner-centered student-run clinic: an exploratory pilot study.

BACKGROUND: The Learner-Centered Student-run Clinic (LC-SRC) was designed to teach and train prescribing skills grounded in a real-life context, to provide students with early clinical experience and responsibility. The current studies' theoretical framework was based on the Self-determination Theory. According to the Self-determination Theory, early involvement in clinical practice combined with a high level of responsibility makes the LC-SRC an environment that can stimulate intrinsic motivation. We investigated the different types of motivation and the proficiency in CanMEDS competencies of the participating students. METHOD: Type of motivation was measured using the Academic Motivation Scale and Intrinsic Motivation Inventory. CanMEDS competencies were evaluated by faculty using a mini-clinical examination and by the students themselves using a post-participation questionnaire. RESULTS: The 29 participating students were highly intrinsic motivated for this project on all subscales of the Intrinsic Motivation Inventory. Motivation for medical school on the Academic Motivation Scale was high before and was not significantly changed after participation. Students considered that their CanMEDS competencies "Collaborator", "Communicator", "Academic", and "Medical expert" had improved. Their actual clinical team competence was judged by faculty to be at a junior doctor level. CONCLUSION: Students showed a high level of intrinsic motivation to participate in the LC-SRC and perceived an improvement in competence. Furthermore their actual clinical competence was at junior doctor level in all CanMEDS competencies. The stimulating characteristics of the LC-SRC, the high levels of intrinsic motivation and the qualitative comments of the students in this study makes the LC-SRC an attractive place for learning.