An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules.

OBJECTIVES: To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications. STUDY DESIGN AND SETTING: We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada. RESULTS: Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%). CONCLUSION: Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.

Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci.

Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 × 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 × 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 × 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other.

Standard care practices and psychosocial interventions aimed at reducing parental distress following stillbirth: A systematic narrative review

Objective: To summarise and critically evaluate the evidence informing the provision of standard care practices and psychosocial interventions following stillbirth. Background: Stillbirth is increasingly recognised as a significant bereavement experience with the potential to cause substantial psychological distress for parents. Standard care practices and psychosocial interventions to support parents have undergone dramatic changes, with limited basis in evidence. Methods: A systematic narrative review was conducted of quantitative studies examining interventions designed to reduce psychological distress in parents following the loss of a stillborn baby. Results: Twenty-five studies met the inclusion criteria for the review. Substantial methodological weaknesses were identified among reviewed studies, including small and heterogeneous loss samples, weak study designs and lack of clarity in reported methods and outcomes. Inadequate replication of many findings substantially limits the generalisability of the evidence. Conclusion: Tentative evidence was found for the provision of mementoes of the baby and information regarding the cause of the loss, support group attendance, and cognitive behavioural interventions for parents identified with clinical levels of distress. Contradictory findings for the impact of contact with the baby prevent the formation of clear conclusions for this practice. Due to the methodological weaknesses prevalent in the research identified, the current evidence base is not considered sufficiently able to reliably inform care practices and intervention approaches. High-quality research evidence in this field is urgently required.

Paediatric end-of-life care needs in Switzerland: current practices, and perspectives from parents and professionals. A study protocol.

AIM: To present a protocol for a multi-phase study about the current practice of end-of-life care in paediatric settings in Switzerland. BACKGROUND: In Switzerland, paediatric palliative care is usually provided by teams, who may not necessarily have specific training. There is a lack of systematic data about specific aspects of care at the end of a child's life, such as symptom management, involvement of parents in decision-making and family-centred care and experiences and needs of parents, and perspectives of healthcare professionals. DESIGN: This retrospective nationwide multicentre study, Paediatric End-of-LIfe CAre Needs in Switzerland (PELICAN), combines quantitative and qualitative methods of enquiry. METHODS: The PELICAN study consists of three observational parts, PELICAN I describes practices of end-of-life care (defined as the last 4 weeks of life) in the hospital and home care setting of children (0-18 years) who died in the years 2011-2012 due to a cardiac, neurological or oncological disease, or who died in the neonatal period. PELICAN II assesses the experiences and needs of parents during the end-of-life phase of their child. PELICAN III focuses on healthcare professionals and explores their perspectives concerning the provision of end-of-life care. CONCLUSION: This first study across Switzerland will provide comprehensive insight into the current end-of-life care in children with distinct diagnoses and the perspectives of affected parents and health professionals. The results may facilitate the development and implementation of programmes for end-of-life care in children across Switzerland, building on real experiences and needs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01983852.

Structured sparsity through reweighting and application to diffusion MRI

We consider the problem of multiple correlated sparse signals reconstruction and propose a new implementation of structured sparsity through a reweighting scheme. We present a particular application for diffusion Magnetic Resonance Imaging data and show how this procedure can be used for fibre orientation reconstruction in the white matter of the brain. In that framework, our structured sparsity prior can be used to exploit the fundamental coherence between fibre directions in neighbour voxels. Our method approaches the ℓ0 minimisation through a reweighted ℓ1-minimisation scheme. The weights are here defined in such a way to promote correlated sparsity between neighbour signals.

Characterization and application of two RANK-specific antibodies with different biological activities.

Antibodies play an important role in therapy and investigative biomedical research. The TNF-family member Receptor Activator of NF-κB (RANK) is known for its role in bone homeostasis and is increasingly recognized as a central player in immune regulation and epithelial cell activation. However, the study of RANK biology has been hampered by missing or insufficient characterization of high affinity tools that recognize RANK. Here, we present a careful description and comparison of two antibodies, RANK-02 obtained by phage display (Newa, 2014 [1]) and R12-31 generated by immunization (Kamijo, 2006 [2]). We found that both antibodies recognized mouse RANK with high affinity, while RANK-02 and R12-31 recognized human RANK with high and lower affinities, respectively. Using a cell apoptosis assay based on stimulation of a RANK:Fas fusion protein, and a cellular NF-κB signaling assay, we showed that R12-31 was agonist for both species. R12-31 interfered little or not at all with the binding of RANKL to RANK, in contrast to RANK-02 that efficiently prevented this interaction. Depending on the assay and species, RANK-02 was either a weak agonist or a partial antagonist of RANK. Both antibodies recognized human Langerhans cells, previously shown to express RANK, while dermal dendritic cells were poorly labeled. In vivo R12-31 agonist activity was demonstrated by its ability to induce the formation of intestinal villous microfold cells in mice. This characterization of two monoclonal antibodies should now allow better evaluation of their application as therapeutic reagents and investigative tools.