The Dutch list of essential drugs for undergraduate medical education: A modified Delphi study.

AIMS: Prescribing errors among junior doctors are common in clinical practice because many lack prescribing competence after graduation. This is in part due to inadequate education in clinical pharmacology and therapeutics (CP&T) in the undergraduate medical curriculum. To support CP&T education, it is important to determine which drugs medical undergraduates should be able to prescribe safely and effectively without direct supervision by the time they graduate. Currently, there is no such list with broad-based consensus. Therefore, the aim was to reach consensus on a list of essential drugs for undergraduate medical education in the Netherlands. METHODS: A two-round modified Delphi study was conducted among pharmacists, medical specialists, junior doctors and pharmacotherapy teachers from all eight Dutch academic hospitals. Participants were asked to indicate whether it was essential that medical graduates could prescribe specific drugs included on a preliminary list. Drugs for which ≥80% of all respondents agreed or strongly agreed were included in the final list. RESULTS: In all, 42 (65%) participants completed the two Delphi rounds. A total of 132 drugs (39%) from the preliminary list and two (3%) newly proposed drugs were included. CONCLUSIONS: This is the first Delphi consensus study to identify the drugs that Dutch junior doctors should be able to prescribe safely and effectively without direct supervision. This list can be used to harmonize and support the teaching and assessment of CP&T. Moreover, this study shows that a Delphi method is suitable to reach consensus on such a list, and could be used for a European list.

The impact of a summative national prescribing assessment and curriculum type on the development of the prescribing competence of junior doctors.

PURPOSE: The primary aim of this study was to investigate the effect of including the Dutch National Pharmacotherapy Assessment (DNPA) in the medical curriculum on the level and development of prescribing knowledge and skills of junior doctors. The secondary aim was to evaluate the relationship between the curriculum type and the prescribing competence of junior doctors. METHODS: We re-analysed the data of a longitudinal study conducted in 2016 involving recently graduated junior doctors from 11 medical schools across the Netherlands and Belgium. Participants completed three assessments during the first year after graduation (around graduation (+ / - 4 weeks), and 6 months, and 1 year after graduation), each of which contained 35 multiple choice questions (MCQs) assessing knowledge and three clinical case scenarios assessing skills. Only one medical school used the DNPA in its medical curriculum; the other medical schools used conventional means to assess prescribing knowledge and skills. Five medical schools were classified as providing solely theoretical clinical pharmacology and therapeutics (CPT) education; the others provided both theoretical and practical CPT education (mixed curriculum). RESULTS: Of the 1584 invited junior doctors, 556 (35.1%) participated, 326 (58.6%) completed the MCQs and 325 (58.5%) the clinical case scenarios in all three assessments. Junior doctors whose medical curriculum included the DNPA had higher knowledge scores than other junior doctors (76.7% [SD 12.5] vs. 67.8% [SD 12.6], 81.8% [SD 11.1] vs. 76.1% [SD 11.1], 77.0% [12.1] vs. 70.6% [SD 14.0], p < 0.05 for all three assessments, respectively). There was no difference in skills scores at the moment of graduation (p = 0.110), but after 6 and 12 months junior doctors whose medical curriculum included the DNPA had higher skills scores (both p < 0.001). Junior doctors educated with a mixed curriculum had significantly higher scores for both knowledge and skills than did junior doctors educated with a theoretical curriculum (p < 0.05 in all assessments). CONCLUSION: Our findings suggest that the inclusion of the knowledge focused DNPA in the medical curriculum improves the prescribing knowledge, but not the skills, of junior doctors at the moment of graduation. However, after 6 and 12 months, both the knowledge and skills were higher in the junior doctors whose medical curriculum included the DNPA. A curriculum that provides both theoretical and practical education seems to improve both prescribing knowledge and skills relative to a solely theoretical curriculum.

Do we become better prescribers after graduation: A 1-year international follow-up study among junior doctors.

AIM: The aim of this study was to investigate how the prescribing knowledge and skills of junior doctors in the Netherlands and Belgium develop in the year after graduation. We also analysed differences in knowledge and skills between surgical and nonsurgical junior doctors. METHODS: This international, multicentre (n = 11), longitudinal study analysed the learning curves of junior doctors working in various specialties via three validated assessments at about the time of graduation, and 6 months and 1 year after graduation. Each assessment contained 35 multiple choice questions (MCQs) on medication safety (passing grade ≥85%) and three clinical scenarios. RESULTS: In total, 556 junior doctors participated, 326 (58.6%) of whom completed the MCQs and 325 (58.5%) the clinical case scenarios of all three assessments. Mean prescribing knowledge was stable in the year after graduation, with 69% (SD 13) correctly answering questions at assessment 1 and 71% (SD 14) at assessment 3, whereas prescribing skills decreased: 63% of treatment plans were considered adequate at assessment 1 but only 40% at assessment 3 (P < .001). While nonsurgical doctors had similar learning curves for knowledge and skills as surgical doctors (P = .53 and P = .56 respectively), their overall level was higher at all three assessments (all P < .05). CONCLUSION: These results show that junior doctors' prescribing knowledge and skills did not improve while they were working in clinical practice. Moreover, their level was under the predefined passing grade. As this might adversely affect patient safety, educational interventions should be introduced to improve the prescribing competence of junior doctors.

Improving membrane based multiplex immunoassays for semi-quantitative detection of multiple cytokines in a single sample.

BACKGROUND: Inflammatory mediators can serve as biomarkers for the monitoring of the disease progression or prognosis in many conditions. In the present study we introduce an adaptation of a membrane-based technique in which the level of up to 40 cytokines and chemokines can be determined in both human and rodent blood in a semi-quantitative way. The planar assay was modified using the LI-COR (R) detection system (fluorescence based) rather than chemiluminescence and semi-quantitative outcomes were achieved by normalizing the outcomes using the automated exposure settings of the Odyssey readout device. The results were compared to the gold standard assay, namely ELISA. RESULTS: The improved planar assay allowed the detection of a considerably higher number of analytes (n = 30 and n = 5 for fluorescent and chemiluminescent detection, respectively). The improved planar method showed high sensitivity up to 17 pg/ml and a linear correlation of the normalized fluorescence intensity with the results from the ELISA (r = 0.91). CONCLUSIONS: The results show that the membrane-based technique is a semi-quantitative assay that correlates satisfactorily to the gold standard when enhanced by the use of fluorescence and subsequent semi-quantitative analysis. This promising technique can be used to investigate inflammatory profiles in multiple conditions, particularly in studies with constraints in sample sizes and/or budget.

Pressure overload-induced right ventricular failure is associated with re-expression of myocardial tenascin-C and elevated plasma tenascin-C levels.

BACKGROUND: We investigated whether (1) monocrotaline(MCT)-induced right ventricular (RV) dilatation is associated with re-expression of myocardial tenascin-C (TNC), (2) elevated plasma TNC levels can be used as a marker of ventricular dilatation, and (3) MCT-induced RV dilatation is associated with alterations of other remodeling-related proteins. METHODS: Rats were treated with MCT in low dose (30 mg/kg, MCT30, n=10) to induce compensated RV hypertrophy, in high dose (80 mg/kg, MCT80, n=11) to induce RV failure, and with saline as control (CONT, n=9). After 4 weeks, RV function was assessed. TNC gene expression, protein levels, and plasma levels were assayed. Myocardial gene expression of integrin subunit alpha6 and beta1, and myocardial proMMP2 and proMMP9 levels were assessed. RESULTS: TNC gene expression in the RV of MCT80 rats was significantly upregulated compared with RV of CONT (4-fold, p<0.001) and MCT30 rats (3-fold, p<0.01), whereas TNC gene expression was very low in LV and IVS of MCT80 rats, and absent in those of CONT and MCT30 rats. Myocardial TNC protein levels were only observed in MCT80 rats, and were higher in RV (0.62+/-0.64 ng/mg) than in LV (0.21+/-0.44 ng/mg) or IVS (0.21+/-0.09 ng/mg) (p<0.01, RV vs LV and IVS). Plasma levels of TNC were significantly elevated in MCT80 rats compared with CONT (p<0.05). RV volumes correlated positively with TNC plasma levels and RV ejection fraction correlated negatively with TNC plasma levels. MCT-induced RV failure was also associated with a significant downregulation of integrin alpha6 gene expression (by 48%, p<0.01). CONCLUSIONS: MCT-induced RV failure is associated with an upregulation of TNC gene expression, resulting in re-expression of myocardial TNC protein levels, and elevated TNC plasma levels. As RV ejection fraction correlated significantly with TNC plasma levels, TNC plasma levels may serve as a marker of ventricular failure. De-adhesive properties of TNC in combination with a downregulation of integrin alpha6 may have caused cardiomyocyte slippage, leading to adverse ventricular remodeling.

Myocardial collagen metabolism in failing hearts before and during cardiac resynchronization therapy.

BACKGROUND: In patients with heart failure cardiac resynchronization therapy (CRT) leads to reverse ventricular remodelling. AIM: To evaluate whether myocardial collagen metabolism in patients with heart failure is implicated in adverse ventricular remodelling and response to CRT. METHODS: Collagen synthesis and degradation were assessed from the concentrations of aminoterminal propeptides of type I and type III collagen (PINP and PIIINP) and carboxyterminal telopeptide of type I collagen (ICTP), respectively, in serum of 64 patients with heart failure before and after 6 months of CRT. Forty-six patients (72%) showed a > 10% reduction in LV end-systolic volume at follow-up and were classified as responders to CRT, the other 18 patients (28%) were classified as non-responders. RESULTS: Responders demonstrated a mean (+/-SEM) increase of serum PINP and PIIINP during follow-up, from 32.9+/-2.2 to 46.7+/-4.0 microg/L (p < 0.001) and from 4.59+/-0.24 to 5.13+/-0.36 microg/L (p < 0.05), respectively. In non-responders, serum PINP and PIIINP remained unchanged during follow-up. At baseline, responders had significantly lower serum PINP than non-responders (32.9+/-2.2 vs. 41.8+/-4.3 microg/L; p < 0.05). ICTP levels of responders at baseline tended to be higher than in non-responders (3.54+/-0.56 vs. 2.08+/-0.37 microg/L, p = ns), and in both groups ICTP levels did not change upon CRT. CONCLUSION: Reverse LV remodelling following CRT is associated with increased collagen synthesis rate in the first 6 months of follow-up.

Reverse ventricular remodelling after cardiac resynchronization therapy is associated with a reduction in serum tenascin-C and plasma matrix metalloproteinase-9 levels.

BACKGROUND: In heart failure patients, cardiac resynchronization therapy (CRT) leads to reverse ventricular remodelling. AIM: The aim of this study was to evaluate whether changes in levels of circulating biomarkers of extracellular matrix metabolism correlate with the response to CRT. METHODS AND RESULTS: Clinical parameters, left ventricular (LV) volumes, and circulating levels of tenascin-C (TNC), matrix metalloproteinase-2 (MMP-2), MMP-9, and amino-terminal propeptide of brain natriuretic peptide (NT-proBNP) were assessed in 64 patients at baseline and 6 months follow-up. The majority of patients (72%) showed a >10% reduction in LV end-systolic volume at follow-up, and were classified as responders to CRT. The remaining patients were classified as non-responders. In responders, a significant decrease in circulating levels of TNC (from 60+/-40 ng/mL to 47+/-30 ng/mL, p<0.01), MMP-9 (from 55+/-30 AU to 44+/-27 AU, p<0.01), and NT-proBNP (from 2106+/-1805 pg/mL to 1132+/-1289 pg/mL, p<0.001) were observed at follow-up; MMP-2 levels were unchanged. In non-responders TNC, NT-proBNP, MMP-9 and MMP-2 levels remained unchanged. CONCLUSION: At 6 months follow-up, CRT was associated with reverse LV remodelling, and a significant decrease in TNC, MMP-9, and NT-proBNP levels. This suggests an important role of ECM modulation in the process of reverse ventricular remodelling in patients responding to CRT.

Activation of signaling molecules and matrix metalloproteinases in right ventricular myocardium of rats with pulmonary hypertension.

Pulmonary hypertension induces right ventricular (RV) overload, which is transmitted to cardiomyocytes via integrins that activate intracellular messengers, including focal adhesion kinase (FAK) and neuronal nitric oxide synthase (NOS1). We investigated whether RV hypertrophy (RVH) and RV failure (RVF) were associated with activation of FAK, NOS1, and matrix metalloproteinases (MMPs). Rats were treated without (RVC) or with a low dose of monocrotaline (30mg/kg) to induce RVH, and with a high dose (80mg/kg) to induce RVF. After approximately 30 days, RV function was determined using a combined pressure-conductance catheter. After sacrifice, FAK, NOS1, their phosphorylated forms (FAK-P and NOS1-P), MMP-2, and MMP-9 were quantified in RV myocardium by immunohistochemistry. In RVH and RVF, RV weight/ body weight increased by 36% and 109%, whereas RV ejection fraction decreased by 23% and 57% compared to RVC, respectively. FAK-P and FAK-P/FAK were highest in RVH (2.87+/-0.12 and 2.52+/-0.23 fold compared to RVC, respectively) and slightly elevated in RVF (1.76+/-0.17 and 1.15+/-0.13 fold compared to RVC, respectively). NOS1-P and NOS1-P/NOS1 were increased in RVH (1.63+/-0.12 and 3.06+/-0.80 fold compared to RVC, respectively) and RVF (2.16+/-0.03 and 3.30+/-0.38 fold compared to RVC, respectively). MMP-2 was highest in RVH and intermediate in RVF (3.50+/-0.12 and 1.84+/-0.22 fold compared to RVC, respectively). MMP-9 was elevated in RVH and RVF (2.39+/-0.35 and 2.92+/-0.68 fold compared to RVC, respectively). Activation of FAK in RVH points to an integrin-dependent hypertrophic response of the myocardium. Activation of NOS1 in failing RV suggests a role of excessive NO in the development of failure and activation of MMPs leading to ventricular remodeling.

CXCL10 Is a Circulating Inflammatory Marker in Patients with Advanced Heart Failure: a Pilot Study.

Chemokines are involved in the remodeling of the heart; however, their significance as biomarkers in heart failure is unknown. We observed that circulating CXCR3 receptor chemokines CXCL9 and CXCL10 in a rat model of heart failure were increased 1 week after myocardial infarction. CXCL10 was also increased in both remote and infarcted regions of the heart and remained elevated at 16 weeks; CXCL9 was elevated in the remote area at 1 week. In humans, hierarchical clustering and principal component analysis revealed that circulating CXCL10, MIP-1α, and CD40 ligand were the best indicators for differentiating healthy and heart failure subjects. Serum CXCL10 levels were increased in patients with symptomatic heart failure as indexed by NYHA classification II through IV. The presence of CXCL10, MIP-1α, and CD40 ligand appears to be dominant in patients with advanced heart failure. These findings identify a distinct profile of inflammatory mediators in heart failure patients.

Characterization of right ventricular function after monocrotaline-induced pulmonary hypertension in the intact rat.

We characterized hemodynamics and systolic and diastolic right ventricular (RV) function in relation to structural changes in the rat model of monocrotaline (MCT)-induced pulmonary hypertension. Rats were treated with MCT at 30 mg/kg body wt (MCT30, n = 15) and 80 mg/kg body wt (MCT80, n = 16) to induce compensated RV hypertrophy and RV failure, respectively. Saline-treated rats served as control (Cont, n = 13). After 4 wk, a pressure-conductance catheter was introduced into the RV to assess pressure-volume relations. Subsequently, rats were killed, hearts and lungs were rapidly dissected, and RV, left ventricle (LV), and interventricular septum (IVS) were weighed and analyzed histochemically. RV-to-(LV + IVS) weight ratio was 0.29 +/- 0.05 in Cont, 0.35 +/- 0.05 in MCT30, and 0.49 +/- 0.10 in MCT80 (P < 0.001 vs. Cont and MCT30) rats, confirming MCT-induced RV hypertrophy. RV ejection fraction was 49 +/- 6% in Cont, 40 +/- 12% in MCT30 (P < 0.05 vs. Cont), and 26 +/- 6% in MCT80 (P < 0.05 vs. Cont and MCT30) rats. In MCT30 rats, cardiac output was maintained, but RV volumes and filling pressures were significantly increased compared with Cont (all P < 0.05), indicating RV remodeling. In MCT80 rats, RV systolic pressure, volumes, and peak wall stress were further increased, and cardiac output was significantly decreased (all P < 0.05). However, RV end-systolic and end-diastolic stiffness were unchanged, consistent with the absence of interstitial fibrosis. MCT-induced pressure overload was associated with a dose-dependent development of RV hypertrophy. The most pronounced response to MCT was an overload-dependent increase of RV end-systolic and end-diastolic volumes, even under nonfailing conditions.

Partial and delayed release of troponin-I compared with the release of lactate dehydrogenase from necrotic cardiomyocytes.

Although the troponins are the serum proteins most frequently used nowadays to diagnose myocardial infarction, controversy continues about whether troponins are released later from infarcted myocardium than the cytoplasmic enzymes used previously, like lactate dehydrogenase (LDH). The present study compared the release kinetics of troponin-I (TnI) and LDH from necrotic cardiomyocytes in vitro. Cardiomyocytes prepared from neonatal rat ventricles were grown for 3 days. A total of 126 cultures were subjected to metabolic inhibition to induce cell necrosis. At various time intervals cells and media were collected for quantitative analysis of LDH activity and TnI concentration. Mean (+/-SD) LDH activity and TnI content of nine cultures at time t=0 were 2.07+/-0.30 U and 1.52+/-0.30 micro g per culture, respectively. Release of LDH from necrotic cardiomyocytes preceded release of TnI by about 60 min. The quantity of LDH released from the cultures after 210 min was 83.2+/-10.0%, whereas that of TnI released after 210 min was always less (33.8+/-22.2%). Cytochemical assessment of necrotic cardiomyocytes showed TnI-positive cells that were poor in LDH. The delay of TnI release relative to LDH release may be explained by slow dissociation of TnI molecules from myofilaments and/or formation of TnI degradation products that are undetected by the currently used ELISA assay.