Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Abstract. The Cicerone Project was a collaborative effort by livestock producers, researchers and extension specialists, which aimed to explore the profitability and sustainability of grazing enterprises on the Northern Tablelands of New South Wales, Australia. A major part of the Project was the creation of a moderate scale, unreplicated farmlet experiment. The process of selecting the farmlet treatments and the design of the experiment involved considerable negotiation over an extended period in order to achieve 'ownership' by all those involved.The farmlets were designed to compare a typical farmlet (B) as the control with a second farmlet (A), which received higher levels of pasture renovation and soil fertility, and a third (C), which employed intensive rotational grazing management with short graze and long rest periods. Management guidelines were developed for all soil, pasture, livestock and grazing management decisions on the three farmlets.Whole-farmlet data are presented for the pastures sown, fertiliser applied, supplement fed, the stocking rates attained and the pattern of graze and rest periods over the experimental period from July 2000 to December 2006. Over the first 4 years of the trial, pastures were renovated on 71% of farmlet A while 8% of each of farmlets B and C were renovated. The rates of fertiliser applied to the three farmlets varied according to soil test values and the different target values for soil phosphorus and sulfur. In the first year of the trial (2000-01), the annual average stocking rates on farmlets A, B and C were 9.5, 7.9 and 9.1 dry sheep eqivalents/ha, respectively, whereas by the fifth year (2005), the stocking rates were 11.2, 7.8 and 7.4 dry sheep equivalents/ha, respectively. This paper provides details of the general methods used in the farmlet trial, of relevance to a series of related papers which explore all aspects of the farmlet experiment and its findings. It also reports on the selection and definition of the farmlet treatments and describes how the guidelines evolved over the duration of the trial in response to the practical realities of conducting this complex, agroecosystem experiment.

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Abstract. The Cicerone Project was a partnership between livestock producers, researchers and extension specialists on the Northern Tablelands of New South Wales, Australia that investigated several complex grazing enterprise issues between 1998 and 2006. It was conducted as a Participatory Action Research project, which first surveyed livestock producers to learn of their problems and then carried out investigations according to the Project's chosen motto of 'compare -measure -learn -adopt'. The Project included research into footrot diagnosis and an investigation of whole-farmlet livestock and pasture management systems complemented by a multi-faceted extension and education component, which delivered findings to a wide array of stakeholders across the Northern Tablelands and adjacent regions. This paper describes the extension and education methods and outcomes and reflects on how successful the engagement of livestock producers was through a partnership, which focussed on co-learning by all participants. Several different communication approaches were used including the production of 40 newsletters and the delivery of 61 field days. Collaborators also held two symposia, which presented comprehensive overviews of the research results. In the final year of the Project, a roadshow was held to communicate results to a wider audience in neighbouring districts.The results of the two footrot trials, which were conducted as Participatory Action Research projects, led to rapid and substantial changes in the testing regime for virulent footrot, resulting in large savings for livestock producers through more accurate detection of the disease. Other valued extension and industry outcomes were the ability to compare the biophysical and economic performance of different whole farmlets, an appreciation of the value of the whole-farm system approach, the trustworthiness of the results and the stimulation of livestock producers to think more deeply about their management systems, stocking rate and risk.The Project benefited from the research efforts of four postgraduate students and was of benefit to~300 high school and technical college students and also some 500 university undergraduate students who undertook learning projects in conjunction with Project members and collaborators. This Special Issue of 24 journal papers represents a substantial delivery of the findings from this complex agroecosystem Project, which broke new ground in terms of securing much closer working relationships between livestock producers, scientists and extension specialists. Ultimately, this volume will allow extension of the results of the Cicerone Project to reach a wider audience than has typically been achieved through other Participatory Action Research projects.

Abstract. The Cicerone Project conducted a grazed farmlet experiment on the Northern Tablelands of New South Wales, Australia, from July 2000 to December 2006, to address questions raised by local graziers concerning how they might improve the profitability and sustainability of their grazing enterprises. This unreplicated experiment examined three management systems at a whole-farmlet scale. The control farmlet (farmlet B) represented typical management for the region, with flexible rotational grazing and moderate inputs. A second farmlet (farmlet A) also used flexible rotational grazing but had a higher level of pasture renovation and soil fertility, while the third farmlet (farmlet C) had the same moderate inputs as farmlet B but employed intensive rotational grazing. The present paper provides an integrated overview of the results collated from component papers and discusses the inferences that can be drawn from what was a complex, agroecosystem experiment. The measurements recorded both early and late in the experiment were tabulated for each of the farmlets and compared with each other as relative proportions, allowing visual presentation on a common, indexed scale. Because of equivalent starting conditions, there was little difference between farmlets early in the experimental period (2000-01) across a wide array of measured parameters, including herbage mass, potential pasture growth rate, liveweight, wool production per head, stocking rate, gross margin and equity. Although the experiment experienced drier-than-average conditions, marked differences emerged among farmlets over time, due to the effects of treatments. During the latter half of the experimental period (2003-06), farmlet A showed numerous positive and a few negative consequences of the higher rate of pasture renovation and increased soil fertility compared with the other two farmlets. While intensive rotational grazing resulted in superior control of gastrointestinal nematodes and slightly finer wool, this system had few effects on pastures and no positive effects on sheep liveweights, wool production or stocking rate. Whereas farmlet A showed higher gross margins, it had a negative and lower short-term cash position than did farmlets B and C, due largely to the artificially high rate of pasture renovation undertaken on this farmlet during the experiment. Although farmlet B had the highest cash position at the end of the experiment, this came at a cost of the declining quality of its pastures. Modelling of the farmlet systems allowed the results to be considered over the longer timeframes needed to assess sustainability. Thus, returns on investment were compared over realistic amortisation periods and produced outcomes based on long-term climatic expectations which were compared with those that arose under the drier-than-average conditions experienced during the experimental period. The main factors responsible for lifting the productivity of farmlet A were the sowing of temperate species and increased soil fertility, which enhanced the amo...