CONVINCE in the context of existing evidence on haemodiafiltration

Haemodiafiltration (HDF) provides a greater removal of larger solutes and protein-bound compounds than conventional high-flux haemodialysis (HD). There are indications that the patients receiving the highest convection volumes of HDF result in improved survival compared with HD. However, the comparative efficacy of HDF versus HD remains unproven. Here we provide a comparative account of the methodology and aims of ‘the comparison of high-dose HDF with high-flux HD’ (CONVINCE) study in the context of the totality of evidence and how this study will contribute to reaching a higher level of certainty regarding the comparative efficacy of HDF versus HD in people with end-stage kidney disease

Acute and rapid degradation of endogenous proteins by Trim-Away.

Protein depletion is a key approach to understanding the functions of a protein in a biological system. We recently developed the Trim-Away approach in order to rapidly degrade endogenous proteins without prior modification. Trim-Away is based on the ubiquitin ligase and Fc receptor TRIM21, which recognizes antibody-bound proteins and targets them for degradation by the proteasome. In a typical Trim-Away experiment, protein degradation is achieved in three steps: first, introduction of an antibody against the target protein; second, recruitment of endogenous or exogenous/overexpressed TRIM21 to the antibody-bound target protein; and third, proteasome-mediated degradation of the target protein, antibody and TRIM21 complex. Protein degradation by Trim-Away is acute and rapid, with half-lives of ~10-20 min. The major advantages of Trim-Away over other protein degradation methods are that it can be applied to any endogenous protein without prior modification; that it uses conventional antibodies that are widely available; and that it can be applied to a wide range of cell types, including nondividing primary human cells, for which other loss-of-function assays are challenging. In this protocol, we describe the detailed procedures for antibody preparation and delivery in mouse oocytes and cultured cells via microinjection and electroporation. In addition, we provide recommendations for antibody selection and validation, and for the generation of TRIM21-overexpressing cell lines for cases in which endogenous TRIM21 is limited. A typical Trim-Away experiment takes just a few hours.The research leading to these results received financial support from the Medical Research Council (MC_U105192711 and MC_U105181010), the Max Planck Society, the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 241548, European Research Council (ERC) Starting Grant no. 337415 and a Wellcome Trust Investigator Award

Implementing core outcomes in kidney disease: report of the Standardized Outcomes in Nephrology (SONG) implementation workshop

There are an estimated 14,000 randomized trials published in chronic kidney disease. The most frequently reported outcomes are biochemical endpoints, rather than clinical and patient-reported outcomes including cardiovascular disease, mortality, and quality of life. While many trials have focused on optimizing kidney health, the heterogeneity and uncertain relevance of outcomes reported across trials may limit their policy and practice impact. The international Standardized Outcomes in Nephrology (SONG) Initiative was formed to identify core outcomes that are critically important to patients and health professionals, to be reported consistently across trials. We convened a SONG Implementation Workshop to discuss the implementation of core outcomes. Eighty-two patients/caregivers and health professionals participated in plenary and breakout discussions. In this report, we summarize the findings of the workshop in two main themes: socializing the concept of core outcomes, and demonstrating feasibility and usability. We outline implementation strategies and pathways to be established through partnership with stakeholders, which may bolster acceptance and reporting of core outcomes in trials, and encourage their use by end-users such as guideline producers and policymakers to help improve patient-important outcomes

Unsupervised Learning of Morphology

Contains fulltext : 94770.pdf (publisher's version ) (Open Access)42 p

Constraining an irregular peptide secondary structure through ring-closing alkyne metathesis

Macrocyclization can be used to constrain peptides in their bioactive conformations, thereby supporting target affinity and bioactivity. In particular, for the targeting of challenging protein–protein interactions, macrocyclic peptides have proven to be very useful. Available approaches focus on the stabilization of α-helices, which limits their general applicability. Here we report for the first time on the use of ring-closing alkyne metathesis for the stabilization of an irregular peptide secondary structure. A small library of alkyne-crosslinked peptides provided a number of derivatives with improved target affinity relative to the linear parent peptide. In addition, we report the crystal structure of the highest-affinity derivative in a complex with its protein target 14-3-3ζ. It can be expected that the alkyne-based macrocyclization of irregular binding epitopes should give rise to new scaffolds suitable for targeting of currently intractable proteins

Treatment-related and health-related quality of life in lipoprotein apheresis patients

FSW - Self-regulation models for health behavior and psychopathology - ou

Benefits and harms of high-dose haemodiafiltration versus high-flux haemodialysis: The comparison of high-dose haemodiafiltration with high-flux haemodialysis (CONVINCE) trial protocol

Introduction End-stage kidney disease (ESKD) is a major public health problem affecting more than 2 million people worldwide. It is one of the most severe chronic non-communicable diseases. Haemodialysis (HD) is the most common therapeutic option but is also associated with a risk of cardiovascular events, hospitalisation and suboptimal quality of life. Over the past decades, haemodiafiltration (HDF) has become available. Although high-dose HDF has shown some promising survival advantage compared to conventional HD, the evidence remains controversial. A Cochrane systematic review found, in low-quality trials, with various convective forms of dialysis, a reduction in cardiovascular, but not all-cause mortality and the effects on non-fatal cardiovascular events and hospitalisation were uncertain. In contrast, an individual patient data analysis suggested that high-dose HDF reduced both all-cause and cardiovascular mortality compared to HD. In view of these discrepant results, a definitive trial is required to determine whether high-dose HDF is preferable to high-flux HD. The comparison of high-dose HDF with high-flux HD (CONVINCE) study will assess the benefits and harms of high-dose HDF versus a conventional high-flux HD in adults with ESKD. Methods and analysis This international, prospective, open label, randomised controlled trial aims to recruit 1800 ESKD adults treated with HD in nine European countries. Patients will be randomised 1:1 to high-dose HDF versus continuation of conventional high-flux HD. The primary outcome will be all-cause mortality at 3 years' follow-up. Secondary outcomes will include cause-specific mortality, cardiovascular events, all-cause and infection-related hospitalisations, patient-reported outcomes (eg, health-related quality of life) and cost-effectiveness. Ethics and dissemination The CONVINCE study will address the question of benefits and harms of high-dose HDF compared to high-flux HD for kidney replacement therapy in patients with ESKD with a focus on survival, patient perspectives and cost-effectiveness. Trial registration number Netherlands National Trial Register (NTR 7138)