Comparison of nuisance parameters in pediatric versus adult randomized trials: a meta-epidemiologic empirical evaluation

BACKGROUND We wished to compare the nuisance parameters of pediatric vs. adult randomized-trials (RCTs) and determine if the latter can be used in sample size computations of the former. METHODS In this meta-epidemiologic empirical evaluation we examined meta-analyses from the Cochrane Database of Systematic-Reviews, with at least one pediatric-RCT and at least one adult-RCT. Within each meta-analysis of binary efficacy-outcomes, we calculated the pooled-control-group event-rate (CER) across separately all pediatric and adult-trials, using random-effect models and subsequently calculated the control-group event-rate risk-ratio (CER-RR) of the pooled-pediatric-CERs vs. adult-CERs. Within each meta-analysis with continuous outcomes we calculated the pooled-control-group effect standard deviation (CE-SD) across separately all pediatric and adult-trials and subsequently calculated the CE-SD-ratio of the pooled-pediatric-CE-SDs vs. adult-CE-SDs. We then calculated across all meta-analyses the pooled-CER-RRs and pooled-CE-SD-ratios (primary endpoints) and the pooled-magnitude of effect-sizes of CER-RRs and CE-SD-ratios using REMs. A ratio < 1 indicates that pediatric trials have smaller nuisance parameters than adult trials. RESULTS We analyzed 208 meta-analyses (135 for binary-outcomes, 73 for continuous-outcomes). For binary outcomes, pediatric-RCTs had on average 10% smaller CERs than adult-RCTs (summary-CE-RR: 0.90; 95% CI: 0.83, 0.98). For mortality outcomes the summary-CE-RR was 0.48 (95% CIs: 0.31, 0.74). For continuous outcomes, pediatric-RCTs had on average 26% smaller CE-SDs than adult-RCTs (summary-CE-SD-ratio: 0.74). CONCLUSIONS Clinically relevant differences in nuisance parameters between pediatric and adult trials were detected. These differences have implications for design of future studies. Extrapolation of nuisance parameters for sample-sizes calculations from adult-trials to pediatric-trials should be cautiously done

Reporting of euthanasia and physician-assisted suicide in the Netherlands: descriptive study

Background: An important principle underlying the Dutch Euthanasia Act is physicians' responsibility to alleviate patients' suffering. The Dutch Act states that euthanasia and physician-assisted suicide are not punishable if the attending physician acts in accordance with criteria of due care. These criteria concern the patient's request, the patient's suffering (unbearable and hopeless), the information provided to the patient, the presence of reasonable alternatives, consultation of another physician and the applied method of ending life. To demonstrate their compliance, the Act requires physicians to report euthanasia to a review committee. We studied which arguments Dutch physicians use to substantiate their adherence to the criteria and which aspects attract review committees' attention. Methods: We examined 158 files of reported euthanasia and physician-assisted suicide cases that were approved by the review committees. We studied the physicians' reports and the verdicts of the review committees by using a checklist. Results: Physicians reported that the patient's request had been well-considered because the patient was clear-headed (65%) and/or had repeated the request several times (23%). Unbearable suffering was often substantiated with physical symptoms (62%), function loss (33%), dependency (28%) or deterioration (15%). In 35%, physicians reported that there had been alternatives to relieve patients' suffering which were refused by the majority. The nature of the relationship with the consultant was sometimes unclear: the consultant was reported to have been an unknown colleague (39%), a known colleague (21%), otherwise (25%), or not clearly specified in the report (24%). Review committees relatively often scrutinized the consultation (41%) and the patient's (unbearable) suffering (32%); they had few questions about possible alternatives (1%). Conclusion: Dutch physicians substantiate their adherence to the criteria in a variable way with an emphasis on physical symptoms. The information they provide is in most cases sufficient to enable adequate review. Review committees' control seems to focus on (unbearable) suffering and on procedural issues

Two Decades of Research on Euthanasia from the Netherlands. What Have We Learnt and What Questions Remain?

Two decades of research on euthanasia in the Netherlands have resulted into clear insights in the frequency and characteristics of euthanasia and other medical end-of-life decisions in the Netherlands. These empirical studies have contributed to the quality of the public debate, and to the regulating and public control of euthanasia and physician-assisted suicide. No slippery slope seems to have occurred. Physicians seem to adhere to the criteria for due care in the large majority of cases. Further, it has been shown that the majority of physicians think that the euthanasia Act has improved their legal certainty and contributes to the carefulness of life-terminating acts. In 2005, eighty percent of the euthanasia cases were reported to the review committees. Thus, the transparency envisaged by the Act still does not extend to all cases. Unreported cases almost all involve the use of opioids, and are not considered to be euthanasia by physicians. More education and debate is needed to disentangle in these situations which acts should be regarded as euthanasia and which should not. Medical end-of-life decision-making is a crucial part of end-of-life care. It should therefore be given continuous attention in health care policy and medical training. Systematic periodic research is crucial for enhancing our understanding of end-of-life care in modern medicine, in which the pursuit of a good quality of dying is nowadays widely recognized as an important goal, in addition to the traditional goals such as curing diseases and prolonging life

Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (the SToP-BPD study): Statistical analysis plan

Background: Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth with short-term and long-term adverse consequences. Although the glucocorticoid dexamethasone has been proven to be beneficial for the prevention of BPD, there are concerns about an increased risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. The aim of the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (SToP-BPD) trial is to assess the efficacy and safety of postnatal hydrocortisone administration for the reduction of death or BPD in ventilator-dependent preterm infants. Methods/design: The SToP-BPD study is a multicentre, double-blind, placebo-controlled hydrocortisone trial in preterm infants at risk for BPD. After parental informed consent is obtained, ventilator-dependent infants are randomly allocated to hydrocortisone or placebo treatment during a 22-day period. The primary outcome measure is the composite outcome of death or BPD at 36 weeks postmenstrual age. Secondary outcomes are short-term effects on pulmonary condition and long-term neurodevelopmental sequelae assessed at 2 years corrected age. Complications of treatment, other serious adverse events and suspected unexpected serious adverse reactions are reported as safety outcomes. This pre-specified statistical analysis plan was written and submitted without knowledge of the unblinded data

Computer-aided detection in breast MRI: a systematic review and meta-analysis

To evaluate the additional value of computer-aided detection (CAD) in breast MRI by assessing radiologists' accuracy in discriminating benign from malignant breast lesions. A literature search was performed with inclusion of relevant studies using a commercially available CAD system with automatic colour mapping. Two independent researchers assessed the quality of the studies. The accuracy of the radiologists' performance with and without CAD was presented as pooled sensitivity and specificity. Of 587 articles, 10 met the inclusion criteria, all of good methodological quality. Experienced radiologists reached comparable pooled sensitivity and specificity before and after using CAD (sensitivity: without CAD: 89%; 95% CI: 78-94%, with CAD: 89%; 95%CI: 81-94%) (specificity: without CAD: 86%; 95% CI: 79-91%, with CAD: 82%; 95% CI: 76-87%). For residents the pooled sensitivity increased from 72% (95% CI: 62-81%) without CAD to 89% (95% CI: 80-94%) with CAD, however, not significantly. Concerning specificity, the results were similar (without CAD: 79%; 95% CI: 69-86%, with CAD: 78%; 95% CI: 69-84%). CAD in breast MRI has little influence on the sensitivity and specificity of experienced radiologists and therefore their interpretation remains essential. However, residents or inexperienced radiologists seem to benefit from CAD concerning breast MRI evaluation

The added value of quantitative multi-voxel MR spectroscopy in breast magnetic resonance imaging

To determine whether quantitative multivoxel MRS improves the accuracy of MRI in the assessment of breast lesions. Twenty-five consecutive patients with 26 breast lesions a parts per thousand yen1 cm assessed as BI-RADS 3 or 4 with mammography underwent quantitative multivoxel MRS and contrast-enhanced MRI. The choline (Cho) concentration was calculated using the unsuppressed water signal as a concentration reference. ROC analysis established the diagnostic accuracy of MRI and MRS in the assessment of breast lesions. Respective Cho concentrations in 26 breast lesions re-classified by MRI as BI-RADS 2 (n = 5), 3 (n = 8), 4 (n = 5) and 5 (n = 8) were 1.16 +/- 0.43 (mean +/- SD), 1.43 +/- 0.47, 2.98 +/- 2.15 and 4.94 +/- 3.10 mM. Two BI-RADS 3 lesions and all BI-RADS 4 and 5 lesions were malignant on histopathology and had Cho concentrations between 1.7 and 11.8 mM (4.03 +/- 2.72 SD), which were significantly higher (P = 0.01) than that in the 11 benign lesions (0.4-1.5 mM; 1.19 +/- 0.33 SD). Furthermore, Cho concentrations in the benign and malignant breast lesions in BI-RADS 3 category differed (P = 0.01). The accuracy of combined multivoxel MRS/breast MRI BI-RADS re-classification (AUC = 1.00) exceeded that of MRI alone (AUC = 0.96 +/- 0.03). These preliminary data indicate that multivoxel MRS improves the accuracy of MRI when using a Cho concentration cut-off a parts per thousand currency sign1.5 mM for benign lesions. Key Points aEuro cent Quantitative multivoxel MR spectroscopy can improve the accuracy of contrast-enhanced breast MRI. aEuro cent Multivoxel-MRS can differentiate breast lesions by using the highest Cho-concentration. aEuro cent Multivoxel-MRS can exclude patients with benign breast lesions from further invasive diagnostic procedures

'We knew it was a totally random thing': parents' experiences of being part of a trial

Background Studies exploring parents’ trial experiences generally relate to their understanding of the consent process and the development of researcher strategies to facilitate recruitment and retention. The aim was to better understand parents’ experience of being part of a trial at the time and their perceptions of trial participation in retrospect. Methods Data were collected in a number of ways: from recorded discussions between parents and clinicians about the MRI or ultrasound, in open-text responses to questionnaires and in qualitative interviews at 1 and 2 years after participation. Thematic analysis was undertaken using NVivo10. Results Key themes identified were ‘deciding to take part’, with subthemes associated with ‘benefitting self’, ‘benefitting others’ and ‘being prepared’; ‘the randomisation process’ with subthemes relating to ‘acceptance’ and ‘understanding’ and ‘actual engagement’ with subthemes of ‘practicalities’ and ‘care from responsive staff’. Conclusion Parents’ perspectives on the trial and the processes and information received reflect their understanding and experience of the trial and the value of parent-friendly information-giving about participation, randomisation and follow-up. The practical and logistical points raised confirm the key issues and parents’ need for sensitive care and support in the course of a trial. Looking back, almost all parents were positive about their experience and felt that the family had benefitted from participation in the trial and follow-up studies, even when the developmental outcomes were poor

Bioethical implications of end-of-life decision-making in patients with dementia:a tale of two societies

End-of-life decision-making in patients with dementia is a complex topic. Belgium and the Netherlands have been at the forefront of legislative advancement and progressive societal changes concerning the perspectives toward physician-assisted death (PAD). Careful consideration of clinical and social aspects is essential during the end-of-life decision-making process in patients with dementia. Geriatric assent provides the physician, the patient and his family the opportunity to end life with dignity. Unbearable suffering, decisional competence, and awareness of memory deficits are among the clinical considerations that physicians should incorporate during the end-of-life decision-making process. However, as other societies introduce legislature granting the right of PAD, new social determinants should be considered; Mexico City is an example. Current perspectives regarding advance euthanasia directives (AED) and PAD in patients with dementia are evolving. A new perspective that hinges on the role of the family and geriatric assent should help culturally heterogeneous societies in the transition of their public health care policies regarding end-of-life choices.</p