Final Report: Trialling an assessment and monitoring program for the human dimensions of the Reef 2050 Integrated Monitoring and Reporting Program

The Great Barrier Reef (GBR) is recognised as one of Australia’s and the worlds’ great natural treasures. It also provides many social, cultural, institutional and economic benefits that contribute to human wellbeing. In turn, each person’s relationship with the GBR is also influenced by a range of social, cultural, institutional and economic factors. Understanding these interactions is critical if we are to manage the GBR in a way that not only protects its natural values, but preserves and enhances its social values and the communities that have a relationship with it. These interactions (of the GBR and of people on the GBR) should inform the design of GBR-related governance and management systems at different scales. At the whole of GBR scale, managers need to understand wider societal interests in the GBR and socio-economic trends that influence whole of GBR outcomes. As a more local level example, managers are interested in how many people directly use or visit particular sites within the GBR; who these people are, where they go, what they do and why. The GBR’s human dimensions also have regional, GBR-wide, national and international aspects. National Environmental Science Program (NESP) Tropical Water Quality (TWQ) Hub Project 3.2.2 provides a methodology for assessing and monitoring the GBR’s human dimensions as a key mechanism to support governance and management of the GBR. It uses a conceptual framework to identify appropriate sets of indicators for characterising the desired state of the GBR’s human dimensions at the whole-of-GBR and regional scales. Some 25 indicator attributes that describe people’s relationship with the GBR can be grouped into five key attribute clusters. These include: (i) human aspirations, capacities and stewardship associated with the GBR; (ii) community vitality related to GBR outcomes; (iii) economic values related to GBR outcomes; (iv) culture and heritage related to the GBR; and (v) the health of governance systems affecting GBR outcomes. The framework is presented in full in Table 1 which also highlights major data gaps needed to inform this approach. Ongoing collection (regular and funded) of data related to these gaps is needed to fulfil the Reef 2050 Plan reporting of the GBR’s human dimensions. By populating the framework with available evidence (mostly secondary data sets) and regional discussions, we were able to demonstrate that all of the six natural resource management (NRM) regions within the GBR catchment scored moderately to well against all human dimension clusters, with conditions tending to decline with distance away from Brisbane for all clusters. Through the application of this framework, the project has already highlighted several significant and emerging implications for the Reef 2050 Plan review including: 1) The Australian and Queensland governments need to continue building partnerships with agricultural, tourism, fishing and recreational user communities and progress effective stewardship approaches. 2) Government agencies/researchers need to implement a stronger free, prior and informed consent-based approach in working with GBR Traditional Owners. 3) Government agencies and research institutions need to increase efforts to understand human use patterns across the GBR – how many people visit the GBR, where do people they go, how do they get there, why do they go. 4) Government agencies, in partnership with stakeholders, should progress system-wide approaches for continuous improvement within the wider system of governance affecting GBR outcomes. Efforts are needed to align policy and programs across a range of major policy areas that affect GBR outcomes, and significantly enhancing long term delivery systems. Improved connectivity is needed between environment, economic/regional development policy and social resilience programs of the Australian and Queensland governments and local governments. Effort needs to be better aligned across portfolios and levels of decision-making to address social and economic wellbeing and ecological health in the GBR. 5) A significant social license to operate needs to be built across the international and Australian community levels if government policies are to seek more urgent approaches to GBR protection and restoration in the face of climate change. 6) Government agencies and research institutions significantly need to increase efforts to protect historical maritime heritage in the GBR. 7) T o assist implementing the Reef 2050 Plan, the Australian and Queensland governments could more actively explore policies that increase the economic diversity and adaptive capacity of GBR-dependent regions - particularly north of Gladstone. This NESP-funded work was undertaken with collaboration and input from a GBR-wide (RIMReP) Human Dimensions Expert Group and six Regional Discussion Panels in the GBR catchment. As a result of this work, alignment of the human dimensions framework with Reef 2050 Plan targets, objectives and outcomes has revealed several gaps in the structure and implementation of the Reef 2050 Plan. It has also identified some human dimension attributes that are under-represented or overlooked in the Reef 2050 Plan. The consultation and expert- advisory processes used, and an associated literature review, also helped to shape the human dimensions framework

Activity of a Carbohydrate-Binding Module Therapy, Neumifil, against SARS-CoV-2 Disease in a Hamster Model of Infection.

The rapid global spread of severe acute respiratory coronavirus 2 (SARS-CoV-2) has resulted in an urgent effort to find efficacious therapeutics. Broad-spectrum therapies which could be used for other respiratory pathogens confer advantages, as do those based on targeting host cells that are not prone to the development of resistance by the pathogen. We tested an intranasally delivered carbohydrate-binding module (CBM) therapy, termed Neumifil, which is based on a CBM that has previously been shown to offer protection against the influenza virus through the binding of sialic acid receptors. Using the recognised hamster model of SARS-CoV-2 infection, we demonstrate that Neumifil significantly reduces clinical disease severity and pathological changes in the nasal cavity. Furthermore, we demonstrate Neumifil binding to the human angiotensin-converting enzyme 2 (ACE2) receptor and spike protein of SARS-CoV-2. This is the first report describing the testing of this type of broad-spectrum antiviral therapy in vivo and provides evidence for the advancement of Neumifil in further preclinical and clinical studies

Influenza A virus challenge models in cynomolgus macaques using the authentic inhaled aerosol and intra-nasal routes of infection

Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections

Development of a Hamster Natural Transmission Model of SARS-CoV-2 Infection.

The global pandemic of coronavirus disease (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to an international thrust to study pathogenesis and evaluate interventions. Experimental infection of hamsters and the resulting respiratory disease is one of the preferred animal models since clinical signs of disease and virus shedding are similar to more severe cases of human COVID-19. The main route of challenge has been direct inoculation of the virus via the intranasal route. To resemble the natural infection, we designed a bespoke natural transmission cage system to assess whether recipient animals housed in physically separate adjacent cages could become infected from a challenged donor animal in a central cage, with equal airflow across the two side cages. To optimise viral shedding in the donor animals, a low and moderate challenge dose were compared after direct intranasal challenge, but similar viral shedding responses were observed and no discernible difference in kinetics. The results from our natural transmission set-up demonstrate that most recipient hamsters are infected within the system developed, with variation in the kinetics and levels of disease between individual animals. Common clinical outputs used for the assessment in directly-challenged hamsters, such as weight loss, are less obvious in hamsters who become infected from naturally acquiring the infection. The results demonstrate the utility of a natural transmission model for further work on assessing the differences between virus strains and evaluating interventions using a challenge system which more closely resembles human infection

Genetic Population Structure in the Antarctic Benthos: Insights from the Widespread Amphipod, Orchomenella franklini

Currently there is very limited understanding of genetic population structure in the Antarctic benthos. We conducted one of the first studies of microsatellite variation in an Antarctic benthic invertebrate, using the ubiquitous amphipod Orchomenella franklini (Walker, 1903). Seven microsatellite loci were used to assess genetic structure on three spatial scales: sites (100 s of metres), locations (1–10 kilometres) and regions (1000 s of kilometres) sampled in East Antarctica at Casey and Davis stations. Considerable genetic diversity was revealed, which varied between the two regions and also between polluted and unpolluted sites. Genetic differentiation among all populations was highly significant (FST = 0.086, RST = 0.139, p<0.001) consistent with the brooding mode of development in O. franklini. Hierarchical AMOVA revealed that the majority of the genetic subdivision occurred across the largest geographical scale, with Nem≈1 suggesting insufficient gene flow to prevent independent evolution of the two regions, i.e., Casey and Davis are effectively isolated. Isolation by distance was detected at smaller scales and indicates that gene flow in O. franklini occurs primarily through stepping-stone dispersal. Three of the microsatellite loci showed signs of selection, providing evidence that localised adaptation may occur within the Antarctic benthos. These results provide insights into processes of speciation in Antarctic brooders, and will help inform the design of spatial management initiatives recently endorsed for the Antarctic benthos

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

A study of immune responses to BCG-immunisation and Mycobacterium tuberculosis infection in non-human primates

Introduction: In 2010, 1.4 million people died from tuberculosis. Bacille Calmette Guerin (BCG) is the only vaccine against tuberculosis that is available, but it has variable efficacy around the world. There is not only an urgent need for a new vaccine, but also identification of a correlate of protection and/or biomarker of disease to enable rapid progression of efficacious and safe vaccine candidates into the clinic. Methods: In order to identify correlates of protection or biomarkers of disease, mycobacteria-specific lymphoproliferation was measured by thymidine incorporation, T cell kinetics were evaluated using a no-wash whole blood flow cytometric approach and cytokine secretion was measured by intracellular cytokine staining. These approaches were used to measure immune responses in rhesus macaques (RM) vaccinated with BCG or BCG/MVA85A and subsequently challenged with M. tuberculosis, and responses in RM and cynomolgus macaques of Mauritian (MCM) and Chinese origin (CCM) after infection with M. tuberculosis. Results: Proliferative and cytokine responses were detected after vaccination, but these responses did not correlate with protection following challenge. Animals that were unable to control disease progression had C!. decline in the number of lymphocytes and T cells and an increase in granulocytes in the periphery. A decline in lymphocyte proliferative capacity and a higher proportion of IFNy-producing T cells after infection was also observed in animals that developed severe disease symptoms. Higher proliferative and IFNy-secreting T cells were observed in RM compared to MCM or CCM and there were also intrinsic differences in white blood cell and T cell numbers between the groups of macaques of different origin and those differences remained after challenge with M. tuberculosis. Conclusion: Studies performed during this research degree confirm that measurement of IFNy-producing T cells, lymphocyte proliferation and polyfunctional T cells does not provide a correlate of protection. However, a decline in lymphocyte and T cell numbers, an increase in granulocytes, a decline in lymphocyte proliferation and increase in IFNy-producing T cells early after infection are biomarkers of disease progression.EThOS - Electronic Theses Online ServiceGBUnited Kingdo