Nonclinical Safety, Pharmacokinetics, and Pharmacodynamics of Atacicept

Atacicept, a soluble recombinant fusion protein of the human immunoglobulin (Ig) G1 Fc and the extracellular domain of the human transmembrane activator and calcium modulator and cyclophylin ligand interactor receptor, acts as an antagonist of both B lymphocyte stimulator and a proliferating–inducing ligand. Here we determined the nonclinical safety, pharmacokinetics and pharmacodynamics of atacicept in mice and cynomolgus monkeys. Subcutaneous atacicept treatment (twice weekly in cynomolgus monkeys, three times weekly in mice) was generally safe and well tolerated safe and well tolerated with dosing up to 10 mg/kg every other day for up to 39 weeks or up to 80 mg/kg when dosed for 4 weeks. At a dose of 1 mg/kg subcutaneous (sc) bioavailability of atacicept in mice and monkeys was 76 and 92%, with a mean serum t1/2 of 44 and 179 h, respectively. In accord with its anticipated mechanism of action, repeated administration of atacicept decreased serum IgG concentrations up to 50%, IgM concentrations >99%, and circulating mature B-cell concentrations up to 60%. These effects were dose-related but reversible, as determined in a 25-week follow-up period. Microscopically, B cells numbers were reduced in the follicular marginal zone of the spleen and the mantle surrounding germinal centers of the lymph nodes. These data confirm the preclinical safety and the pharmacological activity of atacicept and support its clinical development

Exploring partnership: Reflections on an international collaboration.

yesThis article explores some of the challenges involved in a collaborative mental health partnership, drawing on the reflections of two project members from the Chainama College of Health Sciences in Zambia and the Leeds Metropolitan University in England. The aim of the project was to support the education and training of the mental health workforce in Zambia as services shift from institutional to community-based care. The discussion is located within Gray’s ‘three-pronged dilemma’ and debates concerning the internationalisation agenda in social work and higher education. The conclusion emphasises the benefits and tensions of partnership working between ‘developed’ and ‘developing’ countries

Cracking the BAFF code.

The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting

Uncertainty-based comparison of the effect of the area shape function on material characterisation in nanoindentation testing

Instrumented Indentation Test (IIT) is largely exploited in industry and academia to achieve multi-scale mechanical characterisation, i.e. ranging from nano- and micro-structure to bulk, of several properties, e.g. Young's modulus, stress-strain curve, creep, and relaxation. IIT is particularly suited to cope with the challenges of the current industrial framework to achieve multi-objective characterisation and requirements of zero-defect manufacturing and zero waste. In fact, IIT requires limited sample preparation and is a non-destructive technique with high throughput. IIT consists of applying a loading-unloading force cycle on the specimen. The capability of continuously measuring the indenter displacement in the material, i.e. being a depth-sensing technique, is the essential feature of IIT. This allows the mechanical characterisation by knowing the shape of the indenter and hence the relationship between the indentation depth and the projected area of the surface in contact between the indenter and the specimen. The relationship is described by the area shape function, whose parameters require calibration according to ISO 14577-2:2015. For a given indenter geometry, several alternative models are available in the literature. These describe both the geometry and the possible presence of errors, e.g. blunt tip and wear effect. However, a comparison of the choice of the different alternatives, when they are equally nominally applicable, is lacking in the literature, although it prescribes some applicability ranges. This work exploits a simulative approach based on bootstrap sampling to estimate the uncertainty of the calibration of area shape function parameters in the nano-range, where the effect is critical. The uncertainty is then propagated to compare performances of different area shape function models on the mechanical characterisation, i.e. indentation hardness and Young's modulus estimate, within a rigorous metrological framework. Results are shown for standard reference materials, i.e. SiO2 and W, to ensure proper composition homogeneity and neglect edge effects, i.e. pile-up and sink-in

Prospective, multicentre observational study of point-of-care ultrasound practice in emergency departments across Australia and New Zealand : the POCUS-ED Registry

Objectives: The present study aimed to describe the characteristics, performance, accuracy and significance of point-of-care ultrasound (POCUS) use in the ED, by utilising an expanded version of the ACEM-mandated special skills placement (SSP) logbook, to develop a novel clinical quality registry. Methods: A prospective, observational study was performed across EDs in Australia and New Zealand over a 12-month period. Trainees undertaking ACEM-approved ultrasound (US) SSPs recorded all US scan interpretations and follow-up imaging reports in an online database. Results: In total, 2647 USs were recorded by 26 special skills trainees across 10 EDs in Australia or New Zealand; of these 2356 scans (89%) were clinically indicated. Overall, 2493 scans (94%) were used for diagnostic assessment, of which 1147 (43%) had abnormal findings. Basic echocardiography, extended Focused Assessment with Sonography in Trauma and right upper quadrant scans were the most commonly used modalities. There were 134 US-guided procedures logged in the registry. Approximately 36% of scans were reported to alter the original provisional diagnosis, whereas in another 37% of cases, POCUS was thought to confirm the original clinical suspicion. The majority of scans (76.5%) entered into the registry were physically reviewed by the SSP supervisor. Conclusions: This multicentred registry provides a detailed description of the current utilisation of POCUS within special skills US placements across EDs in Australia and New Zealand. This data should inform clinical leaders in emergency US to improve both POCUS education and governance around this important tool