Metabolic signatures of pneumonia in critical care: a paradigm shift in diagnosis and therapeutic monitoring

Pneumonia and ventilator associated pneumonia (VAP) are a frequent cause for admission to Intensive Care and complication of ventilation respectively. VAP occurs in 10-40% of patients requiring mechanical ventilation and is associated with increased mortality, morbidity and healthcare costs. Diagnosis can be difficult due to poor predictive value of clinical features and low specificity of radiological changes. Bronchoscopic techniques are often invasive, may not be suitable for all patients and are not without complications. New tests are required to improve the diagnosis of these conditions allowing early, appropriate antibiotic treatment. In this study several techniques were used to explore the value of profiling of a range of biofluids obtained from ventilated patients as an aid to diagnosis of pneumonia. Patients were recruited from Intensive Care with either a diagnosis of pneumonia or brain injury. Those with brain injuries were tracked to identify patients who developed VAP. Serum, urine and exhaled breath condensate (EBC) were collected from all patients. Metabonomics, an approach that identifies changes in metabolic profiles associated with disease, was applied using proton nuclear magnetic resonance spectroscopy to both blood and urine and with mass spectrometry (MS) to exhaled breath condensate. Following from the metabonomic work a panel of inflammatory mediators, including cytokines and eicosanoids were measured in serum using MS and flow cytometry to explore the inflammatory changes in these patients. Overall metabolic and inflammatory profiling of serum showed potential as an adjunct to clinical diagnosis especially when combined with clinical data. Analysis of urine and EBC proved more challenging due the number of drug metabolites and low concentration of metabolites they respectively contained. In summary this study has added to the field by demonstrating the potential for profiling techniques of serum from critically ill patients to assist in the diagnosis of both pneumonia and VAP.Open Acces

Novel Techniques for Gas Demand Modeling and Forecasting

The ability to provide accurate forecasts of future gas demand has a major impact on several business processes for Gas Regions in the UK and elsewhere in the world. Long term forecasts provide the guidance for major structural needs, while short term forecasts guide the operations management on requirements of supply purchase, supply storage and delivery. Accurate forecasts guarantee optimum and safe gas supply at the lowest cost. Currently there is no single technique that produces the perfect forecast, this research will attempt to improve on current methods by applying Non-Linear techniques. The technique to be tested is defined as ”Non-Linear Autoregressive Moving Average with eXogeneous Inputs, polynomials, and a Forward Regression with Orthogonal Least Squares estimation procedure”. The goal of the research is is to produce a Mean Average Percentage Error of between 4-6% or better, which was proposed by DNV GL (supplier of software for the Gas Industry), as a valid level of error to make any new methodology of value

Changing the picture of Earth's earliest fossils (3.5-1.9 Ga) with new approaches and new discoveries

New analytical approaches and discoveries are demanding fresh thinking about the early fossil record. The 1.88-Ga Gunflint chert provides an important benchmark for the analysis of early fossil preservation. High-resolution analysis of Gunflintia shows that microtaphonomy can help to resolve long-standing paleobiological questions. Novel 3D nanoscale reconstructions of the most ancient complex fossil Eosphaera reveal features hitherto unmatched in any crown-group microbe. While Eosphaera may preserve a symbiotic consortium, a stronger conclusion is that multicellular morphospace was differently occupied in the Paleoproterozoic. The 3.46-Ga Apex chert provides a test bed for claims of biogenicity of cell-like structures. Mapping plus focused ion beam milling combined with transmission electron microscopy data demonstrate that microfossil-like taxa, including species of Archaeoscillatoriopsis and Primaevifilum, are pseudofossils formed from vermiform phyllosilicate grains during hydrothermal alteration events. The 3.43-Ga Strelley Pool Formation shows that plausible early fossil candidates are turning up in unexpected environmental settings. Our data reveal how cellular clusters of unexpectedly large coccoids and tubular sheath-like envelopes were trapped between sand grains and entombed within coatings of dripstone beach-rock silica cement. These fossils come from Earth’s earliest known intertidal to supratidal shoreline deposit, accumulated under aerated but oxygen poor conditions

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. Here we report highly detailed mineralisation of soft tissues associated with a naturally occurring brain endocast of an iguanodontian dinosaur, found in ~133 Ma fluvial sediments of the Wealden at Bexhill, Sussex, U.K. Moulding of the braincase wall, and mineral replacement of adjacent brain tissues by phosphates and carbonates, permits direct examination of petrified brain tissues. SEM imaging and CT-scanning reveal preservation of the tough membranes (meninges) that enveloped and supported the brain proper. Collagen strands of the meningeal layers are preserved in collophane. Blood vessels, also preserved in collophane, are either lined by, or infilled with, microcrystalline siderite. Meninges are preserved in the hindbrain region, and exhibit structural similarities with those of living archosaurs. Greater definition of the forebrain (cerebrum) compared to 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 likely results from settling of brain tissues against the roof of the braincase following inversion of the skull during decay and burial

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

Machine learning and synthetic outcome estimation for individualised antimicrobial cessation.

The decision on when it is appropriate to stop antimicrobial treatment in an individual patient is complex and under-researched. Ceasing too early can drive treatment failure, while excessive treatment risks adverse events. Under- and over-treatment can promote the development of antimicrobial resistance (AMR). We extracted routinely collected electronic health record data from the MIMIC-IV database for 18,988 patients (22,845 unique stays) who received intravenous antibiotic treatment during an intensive care unit (ICU) admission. A model was developed that utilises a recurrent neural network autoencoder and a synthetic control-based approach to estimate patients' ICU length of stay (LOS) and mortality outcomes for any given day, under the alternative scenarios of if they were to stop vs. continue antibiotic treatment. Control days where our model should reproduce labels demonstrated minimal difference for both stopping and continuing scenarios indicating estimations are reliable (LOS results of 0.24 and 0.42 days mean delta, 1.93 and 3.76 root mean squared error, respectively). Meanwhile, impact days where we assess the potential effect of the unobserved scenario showed that stopping antibiotic therapy earlier had a statistically significant shorter LOS (mean reduction 2.71 days, p -value <0.01). No impact on mortality was observed. In summary, we have developed a model to reliably estimate patient outcomes under the contrasting scenarios of stopping or continuing antibiotic treatment. Retrospective results are in line with previous clinical studies that demonstrate shorter antibiotic treatment durations are often non-inferior. With additional development into a clinical decision support system, this could be used to support individualised antimicrobial cessation decision-making, reduce the excessive use of antibiotics, and address the problem of AMR

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