ABSTRACT
BACKGROUND: Given the underinvestment in global mental health to-date, it is important to consider how best to maximize the impact of existing investments. Theory of Change (ToC) is increasingly attracting the interest of funders seeking to evaluate their own impact. This is one of four papers investigating Grand Challenges Canada's (GCC's) first global mental health research funding portfolio (2012-2016) using a ToC-driven approach. METHODS: A portfolio-level ToC map was developed through a collaborative process involving GCC grantees and other key stakeholders. Proposed ToC indicators were harmonised with GCC's pre-existing Results-based Management and Accountability Framework to produce a "Core Metrics Framework" of 23 indicators linked to 17 outcomes of the ToC map. For each indicator relevant to their project, the grantee was asked to set a target prior to the start of implementation, then report results at six-month intervals. We used the latest available dataset from all 56 projects in GCC's global mental health funding portfolio to produce a descriptive analysis of projects' characteristics and outcomes related to delivery. RESULTS: 12,999 people were trained to provide services, the majority of whom were lay or other non-specialist health workers. Most projects exceeded their training targets for capacity-building, except for those training lay health workers. Of the 321,933 people screened by GCC-funded projects, 162,915 received treatment. Most projects focused on more than one disorder and exceeded all their targets for screening, diagnosis and treatment. Fewer people than intended were screened for common mental disorders and epilepsy (60% and 54%, respectively), but many more were diagnosed and treated than originally proposed (148% and 174%, respectively). In contrast, the three projects that focused on perinatal depression exceeded screening and diagnosis targets, but only treated 43% of their intended target. CONCLUSIONS: Under- or over-achievement of targets may reflect operational challenges such as high staff turnover, or challenges in setting appropriate targets, for example due to insufficient epidemiological evidence. Differences in delivery outcomes when disaggregated by disorder suggest that these challenges are not universal. We caution implementers, funders and evaluators from taking a one-size-fits all approach and make several recommendations for how to facilitate more in-depth, multi-method evaluation of impact using portfolio-level ToC.
ABSTRACT
Engagement of Fcγ-receptors triggers a range of downstream signalling events resulting in a diverse array of immune functions. As a result, blockade of Fc-mediated function is an important strategy for the control of several autoimmune and inflammatory conditions. We have generated a hexameric-Fc fusion protein (hexameric-Fc) and tested the consequences of multi-valent Fcγ-receptor engagement in in vitro and in vivo systems. In vitro engagement of hexameric-Fc with FcγRs showed complex binding interactions that altered with receptor density and triggered the internalisation and degradation of Fcγ-receptors. This caused a disruption of Fc-binding and phagocytosis. In vivo, in a mouse ITP model we observed a short half-life of hexameric-Fc but were nevertheless able to observe inhibition of platelet phagocytosis several days after hexameric-Fc dosing. In cynomolgus monkeys, we again observed a short half-life, but were able to demonstrate effective FcγR blockade. These findings demonstrate the ability of multi-valent Fc-based therapeutics to interfere with FcγR function and a potential mechanism through which they could have a sustained effect; the internalisation and degradation of FcγRs.
