Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

The biostratigraphic and palaeoenvironmental significance of the late middle jurassic-early late cretaceous palynology of the Great Australian Bight Region

The late Middle Jurassic to early Late Cretaceous non-marine and marine sediments in the Great Australian Bight region were deposited during initial rifting between Australia and Antarctica. These sediments have been drilled and logged in Echidna-1 and Platypus-1 in the Duntroon Embayment. Potoroo-1 on the northernmost margin of the Great Australian Bight Basin, and Jerboa-1 in the Eyre Sub-basin. In these logged wells is recorded a conformable sequence through the Murospora florida, Retitriletes watherooensis, Cicatricosisporites australiensis, Foraminisporis wonthaggiensis and Cyclosporites hughesii spore-pollen Zones. The Coptospora paradoxa spore-pollen Zone is present in Platypus-1 and Potoroo-1, and three wells(Jerboa-1, Platypus-1, Potoroo-1) include the Phimopollenites pannosus and Appendicisporites distocarinatus spore-pollen Zones. In these three zones, dinoflagellates represent the Canninginopsis denticulata, Pseudoceratium ludbrookiae and Diconodinium multispinum Zones. The palynological zonation of the wells in this study assumes that the first appearance of certain spore-pollen species in the Great Australian Bight region were reliable, in the sense that they corresponded with those elsewhere in the continent as summarised in Helby et al. (1987). The ages of these first appearance datums have been critically re-evaluated to allow correlation of the wells with the standard geological time scale. The age control established by using palynological information suggests that depositional history of the Great Australian Bight region commenced in the Callovian, and this sequence of non-marine sedimentation continued without interference through until the early Aptian. Albian marine sedimentation (recorded in Jerboa-1 and Potoroo-1) most probably relates to a major marine transgression in the Eucla Basin. In Platypus-1 age equivalent sediments are non-marine. Cenomanian marine sediments indicate a marine transgression that probably encroached from the west of the continent following the separation of Australia and Antarctica. The establishment of reliable spore-pollen first appearance datums showed that the ranges of other species are at variance with those elsewhere on the continent. For some species, a west-east variation in the ranges suggested a migration path across the Great Australian Bight region in the Callovian to early Aptian, which corresponded to a movement of flora from high to low latitudes. This migration path from the west to the east appears to have been maintained until the Cenomanian, even though it no longer involved a latitudinal gradient. This seems to imply that the unique, unstable rift environment was the chief vehicle of floral channeling, perhaps reinforced by the encroaching marine environment from the west into the region during the younger interval. During the Callovian to Berriasian vegetation in the Great Australian Bight region was dominated by the gymnosperm family Araucariaceae. A possible increase in precipitation during the late Berriasian saw a decrease in the Araucariaceae, with podocarps taking over the dominant role. Albian and Cenomanian vegetation in the Great Australian Bight region was also dominated by podocarpaceous gymnosperms, with the fern family Gleicheniaceae being the major component of the local vegetation. The dinoflagellate assemblages at this time are typified by taxa of the Heterosphaeridium Superzone of Helby et al. (1987)

Early Cretaceous polar biotas of Victoria, southeastern Australia—an overview of research to date

Although Cretaceous fossils (coal excluded) from Victoria, Australia, were first reported in the 1850s, it was not until the 1950s that detailed studies of these fossils were undertaken. Numerous fossil localities have been identified in Victoria since the 1960s, including the Koonwarra Fossil Bed (Strzelecki Group) near Leongatha, the Dinosaur Cove and Eric the Red West sites (Otway Group) at Cape Otway, and the Flat Rocks site (Strzelecki Group) near Cape Paterson. Systematic exploration over the past five decades has resulted in the collection of thousands of fossils representing various plants, invertebrates and vertebrates. Some of the best-preserved and most diverse Hauterivian–Barremian floral assemblages in Australia derive from outcrops of the lower Strzelecki Group in the Gippsland Basin. The slightly younger Koonwarra Fossil Bed (Aptian) is a Konservat-Lagerstätte that also preserves abundant plants, including one of the oldest known flowers. In addition, insects, crustaceans (including the only syncaridans known from Australia between the Triassic and the present), arachnids (including Australia’s only known opilione), the stratigraphically youngest xiphosurans from Australia, bryozoans, unionoid molluscs and a rich assemblage of actinopterygian fish are known from the Koonwarra Fossil Bed. The oldest known—and only Mesozoic—fossil feathers from the Australian continent constitute the only evidence for tetrapods at Koonwarra. By contrast, the Barremian–Aptian-aged deposits at the Flat Rocks site, and the Aptian–Albian-aged strata at the Dinosaur Cove and Eric the Red West sites, are all dominated by tetrapod fossils, with actinopterygians and dipnoans relatively rare. Small ornithopod (=basal neornithischian) dinosaurs are numerically common, known from four partial skeletons and a multitude of isolated bones. Aquatic meiolaniform turtles constitute another prominent faunal element, represented by numerous isolated bones and articulated carapaces and plastrons. More than 50 specimens—mostly lower jaws—evince a high diversity of mammals, including monotremes, a multituberculate and several enigmatic ausktribosphenids. Relatively minor components of these fossil assemblages are diverse theropods (including birds), rare ankylosaurs and ceratopsians, pterosaurs, non-marine plesiosaurs and a lepidosaur. In the older strata of the upper Strzelecki Group, temnospondyl amphibians—the youngest known worldwide—are a conspicuous component of the fauna, whereas crocodylomorphs appear to be present only in up-sequence deposits of the Otway Group. Invertebrates are uncommon, although decapod crustaceans and unionoid bivalves have been described. Collectively, the Early Cretaceous biota of Victoria provides insights into a unique Mesozoic high-latitude palaeoenvironment and elucidates both palaeoclimatic and palaeobiogeographic changes throughout more than 25 million years of geological time.We are grateful to the National Geographic Society and private donors for funding

The mandible and dentition of the Early Cretaceous monotreme Teinolophos trusleri

The monotreme Teinolophos trusleri Rich, Vickers-Rich, Constantine, Flannery, Kool & van Klaveren, 1999 from the Early Cretaceous of Australia is redescribed and reinterpreted here in light of additional specimens of that species and compared with the exquisitely preserved Early Cretaceous mammals from Liaoning Province, China. Together, this material indicates that although T. trusleri lacked a rod of postdentary bones contacting the dentary, as occurs in non-mammalian cynodonts and basal mammaliaforms, it did not share the condition present in all living mammals, including monotremes, of having the three auditory ossicles, which directly connect the tympanic membrane to the fenestra ovalis, being freely suspended within the middle ear cavity. Rather, T. trusleri appears to have had an intermediate condition, present in some Early Cretaceous mammals from Liaoning, in which the postdentary bones cum ear ossicles retained a connection to a persisting Meckel’s cartilage although not to the dentary. Teinolophos thus indicates that the condition of freely suspended auditory ossicles was acquired independently in monotremes and therian mammals. Much of the anterior region of the lower jaw of Teinolophos is now known, along with an isolated upper ultimate premolar. The previously unknown anterior region of the jaw is elongated and delicate as in extant monotremes, but differs in having at least seven antemolar teeth, which are separated by distinct diastemata. The dental formula of the lower jaw of Teinolophos trusleri as now known is i2 c1 p4 m5. Both the deep lower jaw and the long-rooted upper premolar indicate that Teinolophos, unlike undoubted ornithorhynchids (including the extinct Obdurodon), lacked a bill.The Committee for Research and Exploration of the National Geographic Society and the Australian Research Council provided much of the funding needed for the fieldwork carried out at the Flat Rocks locality. We acknowledge travel funding provided by the International Synchrotron Access Program managed by the Australian Synchrotron and funded by the Australian Government

Cheirolepidiacean foliage and pollen from Cretaceous high-latitudes of southeastern Australia

Cheirolepidiaceae leaves and pollen are recorded from Valanginian–Albian strata of southeastern Australia that were deposited at high-latitudes under cool, moist climates in contrast to the semi-arid or coastal habitats preferred by many northern Gondwanan and Laurasian representatives of this group. Leaves of this family are characterized by thick cuticles and cyclocytic stomata with randomly oriented apertures, arranged in scattered or longitudinal rows or bands. Stomata are deeply sunken and surrounded by four to six subsidiary cells that bear one or two ranks of prominent overarching papillae, which may constrict the mouth of the pit. Three new taxa (Otwayia denticulata Tosolini, Cheirolepidiaceae cuticle sp. A and sp. B) are distinguished based on cuticular features, adding to several previously documented cheirolepid conifers in the Early Cretaceous of eastern Australia. Cheirolepidiaceae foliage is preserved predominantly in fluvial floodbasin settings and is interpreted to be derived from small trees occupying disturbed or low-nutrient sites. The foliage is associated with Classopollis/Corollina pollen and roots characterized by prominent mycorrhizal nodules. A Cenomanian Classopollis type recognised from Bathurst Island, Northern Australia, is recorded for the first time from the Early Cretaceous Eumeralla Formation, Otway Basin. Classopollis locally is rare in Valanginian–Barremian strata of Boola Boola, Gippsland, but constitutes up to 14% of the palynomorph assemblage in Albian strata. This indicates that the family was locally abundant in cool southern high-latitude climates of the Mesozoic, contrary to previous reports of its rarity in this region.Reconstructing the lost forests of Antarctica: the palaeoecology, anatomy and phylogeny of the iconic Glossopteris floraExceptional permineralized biotas - windows into the evolution and functional diversity of terrestrial ecosystems through tim

AIRWAYS-ICPs (European Innovation Partnership on Active and Healthy Ageing) from concept to implementation

Chronic respiratory diseases (CRDs) are major non-communicable diseases (NCDs) that induce a significant burden. Asthma often occurs along the life cycle from early childhood, affecting 30 million children and adults under 45 years of age in Europe. Chronic obstructive pulmonary disease (COPD) has an estimated annual death rate of over 3 million people globally. The annual direct and indirect costs in the 28 European Union (EU) countries due to COPD or asthma are estimated at 48 billion euros and 34 billion euros respectively. Rhinitis occurs in over 100 million people in Europe, and indirect costs are enormous. Asthma is a common risk factor for COPD. CRDs impact ageing and should be prevented, recognised and managed across the life cycle to promote active and healthy ageing (AHA). There is an urgent need to act globally. European Innovation Partnerships (EIPs) aim to enhance EU competitiveness and tackle societal challenges through research and innovation. To tackle the potential of ageing in the EU, the European Commission, within its Innovation Union policy, launched the EIP on AHA (between the Directorate General for Health and Food Safety (DG Santé) and Directorate General for Communications Networks, Content and Technology (DG CONNECT)). The B3 Action Plan promotes integrated care models for chronic diseases, including the use of remote monitoring. The initiative AIRWAYS-ICPs (integrated care pathways for airway diseases) has been approved by the EIP on AHA as the model of chronic diseases of the B3 Action Plan. It is a Research Demonstration Project of the World Health Organization's Global Alliance against Chronic Respiratory Diseases (GARD). AIRWAYS-ICPs was initiated in 2013 by the WHO Collaborating Centre of Montpellier and the EIP on AHA Reference Site MACVIA-LR (Contre les MAladies Chroniques Pour un VIeillissement Actif en Languedoc-Roussillon, France) led by the Région Languedoc-Roussillon (France)