Untangling fuel, weather and management effects on fire severity: Insights from large-sample LiDAR remote sensing analysis of conditions preceding the 2019-20 Australian wildfires.

Evaluation of fire severity reduction strategies requires the quantification of intervention outcomes and, more broadly, the extent to which fuel characteristics affect fire severity. However, investigations are currently limited by the availability of accurate data on fire severity predictors, particularly relating to fuel. Here, we used airborne LiDAR data collected before the 2019-20 Australian Black Summer fires to investigate the contribution of fuel structure to fire severity under a range of weather conditions. Fire severity was estimated using the Relative Burn Ratio calculated from Sentinel-2 optical remote sensing imagery. We modelled the effects of various fuel structure estimates and other environmental predictors using Random Forest models. In addition to variables estimated at each observation point, we investigated the influence of surrounding landscape characteristics using an innovative method to estimate fireline progression direction. Our models explained 63-76% of fire severity variance using parsimonious predictor sets. Fuel cover in the understorey and canopy, and vertical vegetation heterogeneity, were positively associated with fire severity. Up-fire burnt area and recent planned and unplanned fire reduced fire severity, whereby unplanned fire provided a longer-lasting reduction of fire severity (up to 15 years) than planned fire (up to 10 years). Although fuel structure and land management effects were important predictors, weather and canopy height effects were dominant. By mapping continuous interactions between weather and fuel-related variables, we found strong evidence of diminishing fuel effects below 20-40% relative air humidity. While our findings suggest that land management interventions can provide meaningful fire severity reduction, they also highlight the risk of warmer and drier future climates constraining these advantages.

Living labs for patient engagement and knowledge exchange: an exploratory sequential mixed methods study to develop a living lab in paediatric rehabilitation.

INTRODUCTION: Despite recognition of the importance of patient engagement in research and knowledge translation, systematic approaches to engagement and co-ideation remain limited. Living labs are collaborative knowledge sharing systems that use multimethod, user-centred approaches that hold potential to catalyse these aims. However, their use in healthcare is limited, and no living lab has been developed in paediatric rehabilitation. In response to this gap and to propel innovative knowledge exchange, we propose a mixed methods study to co-develop a living lab prototype (ie, preliminary infrastructure with opportunity for scale up) in paediatric rehabilitation, with relevance to other healthcare contexts. METHODS: An exploratory sequential mixed methods study will be undertaken to determine research and knowledge exchange priorities and to inform the development of the living lab prototype. Stage 1: we will use a multipronged approach to sample 18-21 youth with developmental differences or rehabilitation needs, their youth siblings and parents/guardians from a provincial paediatric rehabilitation centre, to participate in qualitative and arts-based data collection. Data will provide insight into desirable features of the living lab. Stage 2: E-surveys to youth, siblings, parents/guardians and clinicians who receive or provide services at this same centre will expand on priorities and living lab features. Stage 3: integrated analysis will inform the living lab prototype development. ANALYSIS: Inductive thematic analysis using interpretive description, integrated analysis of visual data and descriptive and content analysis of e-survey data will be undertaken. Joint displays will facilitate data integration. Priorities will be identified using a modified rank-order method for each key living lab domain. ETHICS AND DISSEMINATION: Institutional ethics and site approval have been granted. A parent advisory group and rehabilitation engineering partners will confer on data and inform the development of the living lab prototype. User engagement with the prototype will occur during an online or in-person event, and findings shared through non-technical research summaries, journal articles and academic presentations.

Enhancement of the anti-tumor activity of therapeutic monoclonal antibodies by CXCR4 antagonists.

The interaction between CXCR4 on the surface of tumor cells and CXCL12 in the stroma is believed to contribute to tumor cell survival and protection against drug treatment. Inhibition of stromal survival signals by CXCR4 antagonists has been reported to render tumor cells more sensitive to chemotherapy, but little is known about potential synergy with monoclonal antibodies. In this study, administration of the small molecule CXCR4 antagonists plerixafor and GENZ-644494 was found to enhance the anti-tumor activity of the monoclonal antibodies alemtuzumab and rituximab in disseminated lymphoma models. The observed enhancement in therapeutic efficacy by CXCR4 antagonists appeared to involve several factors, including interference with the tumor-promoting signals delivered by CXCL12, disruption of the tumor/stroma interaction and mobilization of effector neutrophils capable of mediating antibody-dependent cell-mediated cytotoxicity. The involvement of neutrophils was further supported by the observed reversal in therapeutic benefit upon neutrophil depletion.

Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model.

Alemtuzumab is a humanized monoclonal antibody against CD52, an antigen found on the surface of normal and malignant lymphocytes. It is approved for the treatment of B-cell chronic lymphocytic leukaemia and is undergoing Phase III clinical trials for the treatment of multiple sclerosis. The exact mechanism by which alemtuzumab mediates its biological effects in vivo is not clearly defined and mechanism of action studies have been hampered by the lack of cross-reactivity between human and mouse CD52. To address this issue, a transgenic mouse expressing human CD52 (hCD52) was created. Transgenic mice did not display any phenotypic abnormalities and were able to mount normal immune responses. The tissue distribution of hCD52 and the level of expression by various immune cell populations were comparable to those seen in humans. Treatment with alemtuzumab replicated the transient increase in serum cytokines and depletion of peripheral blood lymphocytes observed in humans. Lymphocyte depletion was not as profound in lymphoid organs, providing a possible explanation for the relatively low incidence of infection in alemtuzumab-treated patients. Interestingly, both lymphocyte depletion and cytokine induction by alemtuzumab were largely independent of complement and appeared to be mediated by neutrophils and natural killer cells because removal of these populations with antibodies to Gr-1 or asialo-GM-1, respectively, strongly inhibited the activity of alemtuzumab whereas removal of complement by treatment with cobra venom factor had no impact. The hCD52 transgenic mouse appears to be a useful model and has provided evidence for the previously uncharacterized involvement of neutrophils in the activity of alemtuzumab.