Critical appraisal of RCTs by 3rd year undergraduates after short courses in EBM compared to expert appraisal.

Introduction: An essential aim of courses in evidence-based medicine (EBM) is to improve the skills for reading and interpreting medical literature adequately. Regarding the conceptual framework, it is important to consider different educational levels. Aim: Our primary aim was to investigate the applicability of different instruments for the assessment of methodological study quality by 3rd grade students after short courses in EBM. Our secondary outcomes were agreement with expert assessments and student's knowledge and competences. Methods: We conducted four short courses in EBM of 90 minutes each for health care management and medical students focused on critical appraisal of the literature. At the end, the students assessed five publications about randomized controlled trials (RCTs) using five different instruments; the results were compared to expert assessments. Results: In total, 167 students participated in our EBM courses. Students' assessments showed a non-systematic over- and underestimation of risk of bias compared to expert assessments with no clear direction. Agreement with expert assessments ranged between 66% to over 80%. Across RCTs, evidence was found that the choice of instrument had an impact on agreement rates between expert and student assessments (p=0.0158). Three RCTs showed an influence of the instrument on the agreement rate (p<0.05 each). Discussion: Our results contrast sharply with those of many other comparable evaluations. Reasons may be a lack of students' motivation due to the compulsory courses, and the comparison to a reference standard in addition to self-ratings causing objectivity. Conclusion: Undergraduates should become familiar with the principles of EBM, including research methods, and the reading of scientific papers as soon as possible. For a deeper understanding, clinical experience seems to be an indispensable precondition. Based on our results, we would recommend an integration of lectures about EBM and critical appraisal at least twice during studies and with greater intensity shortly before graduation.

Gadobutrol for contrast-enhanced magnetic resonance imaging in elderly patients: review of the safety profile from clinical trial, post-marketing surveillance, and pharmacovigilance data.

AIM: To assess the safety of gadobutrol administration in elderly patients (≥65 years) by comparing the incidence of adverse drug reactions (ADRs) following gadobutrol-enhanced magnetic resonance imaging (MRI) procedures in elderly patients with that in adults aged 18-64 years. MATERIALS AND METHODS: Safety data on gadobutrol administration from clinical trials, post-marketing surveillance (PMS) studies, and pharmacovigilance reports were collected in three databases. In each dataset, absolute and relative frequencies of ADRs between age groups were analysed, along with odds ratios and 95% confidence intervals. Logistic regression was used to identify significant influencing factors on ADRs in the PMS and pharmacovigilance data. RESULTS: Rates of reported ADRs were lower in elderly patients versus adults aged <65 years due to a reduced incidence of non-serious ADRs; this was statistically significant for the clinical trials and pharmacovigilance populations, with a trend in the PMS database. Serious ADRs occurred infrequently in the clinical trials and PMS populations (too low for statistical comparison), and pharmacovigilance data demonstrated a low incidence (<0.005%) in both age groups. CONCLUSIONS: This evaluation involving three large databases demonstrated no greater incidence of ADRs following gadobutrol-enhanced MRI in elderly patients (≥65 years) compared with younger adults, with gadobutrol having a favourable safety profile in both age groups.

Diffusion-weighted imaging of focal renal lesions: a meta-analysis.

OBJECTIVES: Contrast-enhanced MRI can only distinguish to a limited extent between malignant and benign focal renal lesions. The aim of this meta-analysis is to review renal diffusion-weighted imaging (DWI) to compare apparent diffusion coefficient (ADC) values for different renal lesions that can be applied in clinical practice. METHODS: A PubMed search was performed to identify relevant articles published 2004-2011 on renal DWI of focal renal lesions. ADC values were extracted by lesion type to determine whether benign or malignant. The data table was finalised in a consensus read. ADC values were evaluated statistically using meta-regression based on a linear mixed model. Two-sided P value <5 % indicated statistical significance. RESULTS: The meta-analysis is based on 17 studies with 764 patients. Renal cell carcinomas have significant lower ADC values than benign tissue (1.61 ± 0.08 × 10(-3) mm(2)/s vs 2.10 ± 0.09 × 10(-3) mm(2)/s; P < 0.0001). Uroepithelial malignancies can be differentiated by lowest ADC values (1.30 ± 0.11 × 10(-3) mm(2)/s). There is a significant difference between ADC values of renal cell carcinomas and oncocytomas (1.61 ± 0.08 × 10(-3) mm(2)/s vs 2.00 ± 0.08 × 10(-3) mm(2)/s; P < 0.0001). CONCLUSIONS: Evaluation of ADC values can help to determine between benign and malignant lesions in general but also seems able to differentiate oncocytomas from malignant tumours, hence potentially reducing the number of unnecessarily performed nephrectomies. KEY POINTS: • This meta-analysis assesses the role of diffusion-weighted MRI in renal lesions. • ADC values obtained by DW MRI have been compared for different renal lesions. • ADC values can help distinguish between benign and malignant tumours. • Differentiating oncocytomas from malignant tumours can potentially reduce inappropriate nephrectomies.

Intra-individual, randomised comparison of the MRI contrast agents gadobutrol versus gadoteridol in patients with primary and secondary brain tumours, evaluated in a blinded read.

OBJECTIVE: To prove that 1.0 M gadobutrol provides superior contrast enhancement and MRI image characteristics of primary and secondary brain tumours compared with 0.5 M gadoteridol, thereby providing superior diagnostic information. METHODS: Brain MRI was performed in two separate examinations in patients scheduled for neurosurgery. Independent injections of 1.0 M gadobutrol and 0.5 M gadoteridol at doses of 0.1 mmol Gd/kg body weight were administered per patient in randomised order. Evaluation was performed in an off-site blinded read. RESULTS: Fifty-one patients in the full analysis set (FAS) were eligible for efficacy analysis and 44 for the per-protocol analysis. For the primary efficacy variable "preference in contrast enhancement for one contrast agent or the other", the rate of "gadobutrol preferred" was estimated at 0.73 (95 % confidence interval 0.61; 0.83), showing significant superiority of gadobutrol over gadoteridol. Calculated lesion-to-brain contrast and the results of all qualitative secondary efficacy variables were also in favour of gadobutrol. Keeping a sufficient time delay after contrast application proved to be essential to get optimal image quality. CONCLUSION: Compared with 0.5 M gadoteridol, 1.0 M gadobutrol was proven to have significantly superior contrast enhancement characteristics in a routine MRI protocol of primary and secondary brain tumours.

ECG-gated imaging of the left atrium and pulmonary veins: Intra-individual comparison of CTA and MRA.

AIM: To compare electrocardiography (ECG)-gated computed tomography angiography (CTA) with ECG-gated magnetic resonance angiography (MRA) for assessment of the left atrium (LA) and pulmonary veins (PVs). MATERIAL AND METHODS: Twenty-nine consecutive patients who underwent both cardiac CTA and MRA were evaluated. Contrast-enhanced CTA was performed with prospective ECG-gating using a 320 detector row CT system. Contrast-enhanced MRA was performed with prospective ECG-gating using a 1.5 T MRI system equipped with a 32 channel cardiac coil. MRA was acquired during free-breathing with a navigator-gated inversion-recovery prepared steady-state free precession sequence. Two readers independently assessed the CTA and MRA images for vascular definition of the PVs (from 0, not visualized, to 4, excellent definition) and ostial PV diameters. Variants of LA anatomy were assessed in consensus. RESULTS: CTA was successfully performed in all patients with a mean radiation exposure of 5.1 ± 2.2 mSv. MRA was successfully performed in 27 of 29 patients (93 %). Visual definition of PVs was rated significantly higher on CTA compared to MRA (p < 0.0001; reader 1: excellent/good ratings of CTA versus MRA: 100% versus 86%; reader 2: excellent/good ratings of CTA versus MRA: 99% versus 89%). Assessment of ostial PV diameters showed good correlation between CTA and MRA (reader 1: Pearson r = 0.91; reader 2: Pearson r = 0.82). Moreover, agreement between both imaging methods for evaluation of variants of LA anatomy was high (agreement rate of 95% (95% CI: 92-99%). CONCLUSION: ECG-gated CTA provides higher image quality compared to ECG-gated MRA. Nevertheless, both CTA and MRA provided similar information of LA anatomy and ostial PV diameters.

Dynamic contrast enhanced MRI of the prostate: comparison of gadobutrol and Gd-DTPA.

PURPOSE: To evaluate the enhancement profile of the macrocyclic contrast medium (CM) gadobutrol in comparison to linear CM Gd-DTPA in DCE-MRI of the prostate. MATERIALS AND METHODS: In total 53 patients with prostata cancer (PCa) were included, who received a radical prostatectomy after multiparametric MRI of the prostate including DCE-MRI. Using circular regions of interests normal peripheral zone (PZ) and PCa foci > 5 mm in diameter (42 and 34 foci in Gd-DTPA and gadobutrol group, respectively) were analysed in DCE-MRI. Enhancement curves (Type I, II and III) and pharmacokinetic parameters were analyzed qualitatively and quantitatively and compared using mixed linear models (two sided p-values < 0.05 were regarded significant). RESULTS: There was no significant difference in frequencies of curve types I, II or III in the normal PZ (p = 0.63) or in PCa foci (p = 0.75). PCa with a Gleason score ≥ 7 had in comparison to Gleason ≤ 6 significantly more often a Wash-Out-curve (Type III) with both CM (p = 0.02). The relative peak enhancement was in the PZ (Gd-DTPA 1.4 a. u. [1.20; 1.59], gadobutrol 1.58 a. u. [1.37; 1.78]) and in PCa foci (Gd-DTPA 1.56 a. u. [1.41; 1.71], gadobutrol 1.76 a. u. [1.59; 1.94]) significantly higher with gadobutrol (p = 0.04). The pharmacokinetic parameters Ktrans und kep were higher in PCa foci than in PZ (p < 0.0001 and p = 0.002, respectively) without significant difference of the parameter values between both CM (p = 0.65). CONCLUSION: [corrected] This study is the first systematic comparison of gadobutrol and Gd-DTPA in DCE-MRI of the prostate. The relative peak enhancement is higher using gadobutrol compared to Gd-DTPA in DCE-MRI. There was no statistically significant difference in curve types or the pharmacokinetic parameters in PCa or normal PZ between both CM.

Intra-individual randomised comparison of gadobutrol 1.0 M versus gadobenate dimeglumine 0.5 M in patients scheduled for preoperative breast MRI.

OBJECTIVE: To demonstrate non-inferiority of gadobutrol versus gadobenate dimeglumine by intra-individually comparing 0.1 mmol/kg body weight doses for contrast-enhanced breast magnetic resonance imaging (MRI) and prospectively evaluating lesion detection and characterisation in a multicentre trial. METHODS: Two identical breast MRI examinations were performed in 72 patients with biopsy-proven breast cancer, separated by 1-7 days. Gadobutrol 1.0 M or gadobenate 0.5 M were administered in a randomised order. Lesion detection and characterisation were performed by two independent blinded readers. Lesion tracking, which compared on-site readings and histology from surgery or biopsy, was performed by a third reader. Differences in lesion detection and characterisation were compared between the two contrast agents. RESULTS: Among 103 lesions, 96 were malignant and 7 were benign. No difference in lesion detection was identified between the contrast agents (82.33 % for gadobutrol, 81.60 % for gadobenate). Assessment of sensitivity in lesion characterisation and Breast Imaging Reporting and Data Systems showed no difference between gadobutrol (92.63 %) and gadobenate (90.53 %). Regarding morphology, there was more non-focal enhancement for gadobutrol than for gadobenate (P = 0.0057). CONCLUSION: Non-inferiority of gadobutrol compared with gadobenate was demonstrated for breast lesion detection and sensitivity in lesion characterisation in breast MRI.

Contrast-enhanced magnetic resonance angiography (MRA): evaluation of three different contrast agents at two different doses (0.05 and 0.1 mmol/kg) in pigs at 1.5 Tesla.

OBJECTIVE: To compare the image quality of contrast-enhanced magnetic resonance angiography (CE-MRA) of the supra-aortic vessels at 0.05 mmol/kg bw and 0.1 mmol/kg bw, between gadobutrol, Gd-DTPA and Gd-BOPTA quantitatively and qualitatively a total of eight pigs were evaluated intraindividually at 1.5 T. METHODS: Each pig was examined using 0.1 mmol/kg gadobutrol, Gd-DTPA and Gd-BOPTA on day one and 0.05 mmol/kg on day two. MRA datasets for the carotid artery and the infraorbital artery were qualitatively assessed regarding overall image quality on an ordinal four-point scale (4-excellent, 1-non-diagnostic). The signal-to noise-ratio (SNR) was measured. RESULTS: The qualitative assessment of the carotid artery showed a higher median image quality for the 0.1 mmol dose than for the 0.05 mmol dose for all three compounds. No difference was found for the infraorbital artery. Mean SNR of Gd-BOPTA, Gd-DTPA, gadobutrol at 0.05 mmol/kg were 36.0 ± 13.4/37.9 ± 16.3/43.7 ± 0.4 and at 0.1 mmol/kg they were 50.1 ± 12.4/46.6 ± 6.5 / 54.6 ± 10.2. Gd-BOPTA 0.05 revealed a significantly lower SNR than all other agents at normal dose. CONCLUSIONS: Full-dose gadolinium MRA results in higher image quality and significantly higher SNR compared with the half dose. Gadobutrol and Gd-BOPTA have similar enhancement properties at full dose but at half dose, gadobutrol appears superior.

"Number needed to read"--how to facilitate clinical trials in MR-angiography.

PURPOSE: To evaluate the effect of the number of readers on the statistical results in peripheral MRA. MATERIALS AND METHODS: 40 patients with peripheral arterial occlusive disease were included as a sample dataset in this study, randomly separated into two matched groups with n = 20 patients (group 1--gadobutrol, group 2--gadoterate meglumine) who underwent a continuous table movement MRA of the peripheral vessels at 3 T. Image quality (IQ) of 17 vessel segments was evaluated by 5 independent readers. The effect of the number of readers on significance and statistical power was statistically analyzed. RESULTS: Image quality in group 1 (gadobutrol) ranks significantly higher compared to group 2 (gadoterade meglumine) with a diagnostic IQ in 97% vs. 78% (p < 0.0001). For the diagnostic/non-diagnostic IQ assessment significance was reached with one reader 1/5 times (20%), with two readers in 4/10 (40%), with three readers in 6/10 (60%), with four readers in 4/5 (80%), with five readers in 1/1 (100%). Power considerations showed considerable gain when increasing the number of readers. CONCLUSION: Increasing the number of readers in a diagnostic MRA-study can be used to achieve a higher power or to decrease the number of subjects included with maintained statistical validity.

Analysis of differences in proportions from clustered data with multiple measurements in diagnostic studies.

OBJECTIVES: In diagnostic studies, proportions such as sensitivities are often to be calculated and to be compared between different diagnostic procedures. As statistical unit of analysis, multiple observational units may be assessed within each patient, i.e., multiple lesions in an organ. As a requirement, these are to be assessed by multiple blinded readers. In this paper we propose a method to cover correlations between units within patients, correlations between procedures and correlations between different raters assessing each observational unit. METHODS: The proposed approach is a two-step method to analyze clustered data with multiple measurements to compare diagnostic procedures in a paired modality design and the correlation between the readers in a paired reader design. The performance of the approach was compared to a generalized estimation equations model (GEEs) by power simulations. RESULTS: Power simulations suggest, that the two-step approach is not inferior to GEEs with regard to the single readers as well as with regard to the average reader. CONCLUSIONS: An intuitive approach was developed next to established methods to analyze "paired modality, paired reader" and "unpaired modality, paired reader" studies with binary endpoints when estimating proportions and differences in proportions for clustered data with multiple measurements. This two-step approach is an alternative method to cover routine designs of diagnostic studies where the difference of proportions is to be estimated directly along with confidence intervals.

Analysis of proportions from clustered data with missing observations in a matched-pair design.

OBJECTIVES: Typically, methods for the estimation of differences in proportions from clustered data are based on complete cases with no missing information. In this paper we propose an extension to the method of Rao and Scott and Obuchowski to allow for the explicit computation of the variance of the estimator for the difference in presence of incomplete cases. METHODS: We divided the full analysis set into a set of complete cases and a set of incomplete cases. The differences in proportions of correct diagnoses were estimated for each set by taking into consideration the clustering effect for both sets and the correlation between the procedures in the set with complete cases. Then the estimates of the two parts were combined by appropriate weights, which then allowed the explicit calculation of the variance. The performance of the extension as compared to the original method and generalized estimation equations model (GEEs) was examined by simulations. RESULTS: The results of the examples suggest that the extended approach is superior to the complete-case method and is therefore appropriate when all data are to be used. In comparison to GEEs, the extended method appears to be slightly inferior, when the number of observations per patient is high, but of similar efficiency with a low number of observations per patient. CONCLUSIONS: With the extension of the method by Rao and Scott and Obuchowski we make use of all available data. Therefore, we follow the intent-to-treat principle as close as possible.

[Combined vaccine against tetanus, diphtheria and polio. A randomized controlled study of immunogenicity and tolerance]. / Kombinationsimpfstoff gegen Tetanus, Diphtherie und Polio. Eine randomisierte kontrollierte Studie zu Immunogenität und Verträglichkeit.

UNLABELLED: BACKGROUND, METHOD: Given the worldwide distribution of infection and the mobility of large parts of the population immunizations against tetanus, diphtheria and polio remain a challenge. This is especially true for adolescents and adults since antibodies tend to wane once immunized children enter adolescence and adulthood. A new combination vaccine against tetanus, diphtheria and polio (Td-IPV) for booster immunizations was subjected to a randomized, controlled and single-blind trial. Non-inferiority had to be demonstrated with regard to efficacy (immunogenicity) and safety in comparison to separate Td and IPV injections. RESULTS: Almost 500 subjects from community practices and occupational/immunization clinics took part. Antibody titres were equivalent for all antigens. Local and systemic reactions were equal or even less marked in the intervention group. CONCLUSION: From a public health perspective the new vaccine can make an important contribution to ensure adequate protection against tetanus, diphtheria and polio in adolescent and adult populations.

Preservative-free influenza vaccine.

OBJECTIVE: To investigate the immunogenicity of and tolerance towards the preservative-free inactivated influenza vaccine Begrivac. METHODS: In this prospective, single-centre, non-controlled study, efficacy was evaluated by the change in influenza antibody titre from baseline to 21 days following vaccination. The safety variables included post-injection reactions and adverse events. Blood samples were taken on day 21 and the antibody titre assayed by haemagglutination inhibition test. RESULTS: All three of the European efficacy requirements for influenza vaccines are satisfied by the new preservative-free vaccine described in this report. The mean geometric increase in titre and the proportion of vaccination responders were greater in patients of the adult group than in the elderly. Thus for strain A/Beijing/262/95 66% of subjects seroconverted and 28% showed a significant increase in antibody titre (total 94%), compared to a total of 45 patients (76%) in the elderly group. For strain A/Sydney/5/97 the corresponding figures were total 55 (90%) adult and 47 (80%) elderly, and for B/Beijing/184/93 46 (75%) adult and 31 (53%) elderly. Sixty four subjects (53%) reported adverse events, mainly local reactions at the injection site such as pain, erythema and induration, and systemic reactions such as headache and fatigue. CONCLUSIONS: The absence of preservative in this novel vaccine preparation does not have any detectable impact on its efficacy or safety and tolerability profile.

Guillain-Barré syndrome: activated complement components C3a and C5a in CSF.

Plasma and spinal fluid levels of complement activation products C3a and C5a were quantitated by radioimmunoassay in a group of 16 patients suffering from acute monophasic Guillain-Barré syndrome (GBS). Median CSF levels of C3a (118 ng/ml) and of C5a (9.6 ng/ml) were significantly elevated when compared with samples from a control group of patients with noninflammatory neurologic diseases. Plasma concentrations of these anaphylotoxic peptides were not significantly different between the two populations. Our findings indicate that the complement system is activated in the CSF of patients with acute GBS. Complement activation products may contribute to the inflammatory changes observed in this disorder.