Remarkable preservation of brain tissues in an Early Cretaceous iguanodontian dinosaur

It has become accepted in recent years that the fossil record can preserve labile tissues. We report here the highly detailed mineralization of soft tissues associated with a naturally occurring brain endocast of an iguanodontian dinosaur found in c. 133 Ma fluvial sediments of the Wealden at Bexhill, Sussex, UK. Moulding of the braincase wall and the mineral replacement of the adjacent brain tissues by phosphates and carbonates allowed the direct examination of petrified brain tissues. Scanning electron microscopy (SEM) imaging and computed tomography (CT) scanning revealed preservation of the tough membranes (meninges) that enveloped and supported the brain proper. Collagen strands of the meningeal layers were preserved in collophane. The blood vessels, also preserved in collophane, were either lined by, or infilled with, microcrystalline siderite. The meninges were preserved in the hindbrain region and exhibit structural similarities with those of living archosaurs. Greater definition of the forebrain (cerebrum) than the hindbrain (cerebellar and medullary regions) is consistent with the anatomical and implied behavioural complexity previously described in iguanodontian-grade ornithopods. However, we caution that the observed proximity of probable cortical layers to the braincase walls probably resulted from the settling of brain tissues against the roof of the braincase after inversion of the skull during decay and burial

Understanding ancient life: how Martin Brasier changed the way we think about the fossil record

Crucial to our understanding of life on Earth is the ability to judge the validity of claims of very ancient ‘fossils’. Martin Brasier's most important contribution to this debate was to establish a framework within which to discuss claims of the ‘oldest’ life. In particular, he made it clear that the burden of proof must fall on those making the claim of ancient life, not those refuting it. This led to his formulation of the concept of the continuum of morphologies produced by life and non-life and the considerable challenges of differentiating biogenesis from abiogenesis. Martin Brasier developed a set of criteria for distinguishing life from non-life and extended the use of many new high-resolution analytical techniques to palaeontological research. He was also renowned for his work on the Cambrian explosion and the origin of animals. Although he had spent much of his early career working on the geological context of these events, it was not until he returned to studying the Ediacaran and Cambrian periods in his later years that he began to apply this null hypothesis way of thinking to these other major transitions in the history of life. This led to him becoming involved in the development of a series of nested null hypotheses, his ‘cone of contention’, to analyse enigmatic fossils more generally. In short, Martin Brasier taught us how to formulate biological hypotheses in deep time, established the rules for how those hypotheses should be tested and championed a host of novel analytical techniques to gather the data required. As a consequence, future discussions of enigmatic specimens and very old fossils will be greatly enriched by his contributions

Application of therapeutic drug monitoring to the treatment of bacterial central nervous system infection: a scoping review

BackgroundBacterial central nervous system (CNS) infection is challenging to treat and carries high risk of recurrence, morbidity, and mortality. Low CNS penetration of antibiotics may contribute to poor clinical outcomes from bacterial CNS infections. The current application of therapeutic drug monitoring (TDM) to management of bacterial CNS infection was reviewed.MethodsStudies were included if they described adults treated for a suspected/confirmed bacterial CNS infection and had antibiotic drug concentration(s) determined that affected individual treatment.ResultsOne-hundred-and-thirty-six citations were retrieved. Seventeen manuscripts were included describing management of 68 patients. TDM for vancomycin (58/68) and the beta-lactams (29/68) was most common. Timing of clinical sampling varied widely between studies and across different antibiotics. Methods for setting individual PK-PD targets, determining parameters and making treatment changes varied widely and were sometimes unclear.DiscussionDespite increasing observational data showing low CNS penetration of various antibiotics, there are few clinical studies describing practical implementation of TDM in management of CNS infection. Lack of consensus around clinically relevant CSF PK-PD targets and protocols for dose-adjustment may contribute. Standardised investigation of TDM as a tool to improve treatment is required, especially as innovative drug concentration-sensing and PK-PD modelling technologies are emerging. Data generated at different centres offering TDM should be open access and aggregated to enrich understanding and optimize application

Assessing the safety of physical rehabilitation in critically ill patients: a Delphi study

Background Physical rehabilitation of critically ill patients is implemented to improve physical outcomes from an intensive care stay. However, before rehabilitation is implemented, a risk assessment is essential, based on robust safety data. To develop this information, a uniform definition of relevant adverse events is required. The assessment of cardiovascular stability is particularly relevant before physical activity as there is uncertainty over when it is safe to start rehabilitation with patients receiving vasoactive drugs. Methods A three-stage Delphi study was carried out to (a) define adverse events for a general ICU cohort, and (b) to define which risks should be assessed before physical rehabilitation of patients receiving vasoactive drugs. An international group of intensive care clinicians and clinician researchers took part. Former ICU patients and their family members/carers were involved in generating consensus for the definition of adverse events. Round one was an open round where participants gave their suggestions of what to include. In round two, participants rated their agreements with these suggestions using a five-point Likert scale; a 70% consensus agreement threshold was used. Round three was used to re-rate suggestions that had not reached consensus, whilst viewing anonymous feedback of participant ratings from round two. Results Twenty-four multi-professional ICU clinicians and clinician researchers from 10 countries across five continents were recruited. Average duration of ICU experience was 18 years (standard deviation 8) and 61% had publications related to ICU rehabilitation. For the adverse event definition, five former ICU patients and one patient relative were recruited. The Delphi process had a 97% response rate. Firstly, 54 adverse events reached consensus; an adverse event tool was created and informed by these events. Secondly, 50 risk factors requiring assessment before physical rehabilitation of patients receiving vasoactive drugs reached consensus. A second tool was created, informed by these suggestions. Conclusions The adverse event tool can be used in studies of physical rehabilitation to ensure uniform measurement of safety. The risk assessment tool can be used to inform clinical practise when risk assessing when to start rehabilitation with patients receiving vasoactive drugs. Trial registration This study protocol was retrospectively registered on https://www.researchregistry.com/ (researchregistry2991)

Transcriptomic Signatures in Sepsis and a Differential Response to Steroids. From the VANISH Randomized Trial.

Non-commercial use onlyRATIONALE: There remains uncertainty about the role of corticosteroids in sepsis with clear beneficial effects on shock duration, but conflicting survival effects. Two transcriptomic sepsis response signatures (SRSs) have been identified. SRS1 is relatively immunosuppressed, whereas SRS2 is relatively immunocompetent. OBJECTIVES: We aimed to categorize patients based on SRS endotypes to determine if these profiles influenced response to either norepinephrine or vasopressin, or to corticosteroids in septic shock. METHODS: A post hoc analysis was performed of a double-blind, randomized clinical trial in septic shock (VANISH [Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock]). Patients were included within 6 hours of onset of shock and were randomized to receive norepinephrine or vasopressin followed by hydrocortisone or placebo. Genome-wide gene expression profiling was performed and SRS endotype was determined by a previously established model using seven discriminant genes. MEASUREMENTS AND MAIN RESULTS: Samples were available from 176 patients: 83 SRS1 and 93 SRS2. There was no significant interaction between SRS group and vasopressor assignment (P = 0.50). However, there was an interaction between assignment to hydrocortisone or placebo, and SRS endotype (P = 0.02). Hydrocortisone use was associated with increased mortality in those with an SRS2 phenotype (odds ratio = 7.9; 95% confidence interval = 1.6-39.9). CONCLUSIONS: Transcriptomic profile at onset of septic shock was associated with response to corticosteroids. Those with the immunocompetent SRS2 endotype had significantly higher mortality when given corticosteroids compared with placebo. Clinical trial registered with www.clinicaltrials.gov (ISRCTN 20769191).Supported by the UK National Institute for Health Research (NIHR) under Research for Patient Benefit program grant PB-PG-0610-22350, NIHR Clinician Scientist Award NIHR/CS/009/007, and NIHR Research Professor award RP-2015-06-018 (A.C.G.); also supported by the NIHR Imperial Biomedical Research Centre, the UK Intensive Care Foundation, Wellcome Trust grant 090532/Z/09/Z to core facilities at the Wellcome Centre for Human Genetics, Wellcome Trust Investigator Award 204969/Z/16/Z (J.C.K.), and by the NIHR Oxford Biomedical Research Centre

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

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Management of Bacterial and Fungal Infections in the ICU: Diagnosis, Treatment, and Prevention Recommendations.

Bacterial and fungal infections are common issues for patients in the intensive care unit (ICU). Large, multinational point prevalence surveys have identified that up to 50% of ICU patients have a diagnosis of bacterial or fungal infection at any one time. Infection in the ICU is associated with its own challenges. Causative organisms often harbour intrinsic and acquired mechanisms of drug-resistance, making empiric and targeted antimicrobial selection challenging. Infection in the ICU is associated with worse clinical outcomes for patients. We review the epidemiology of bacterial and fungal infection in the ICU. We discuss risk factors for acquisition, approaches to diagnosis and management, and common strategies for the prevention of infection