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Experimental exposure of healthy volunteers to the T-cell dependent neoantigen keyhole limpet hemocyanin (KLH) permits the evaluation of immunomodulatory investigational medicinal product (IMP) pharmacology prior to the recruitment of patient populations. Despite widespread use, no standardized approach to the design and conduct of such studies has been agreed. The objective of this systematic review was to survey the published literature where KLH was used as a challenge agent, describing methodology, therapeutic targets addressed, and pharmacodynamic outcome measures. We searched MEDLINE, EMBASE, clinicaltrials.gov, and Cochrane CENTRAL for studies using KLH challenge in humans between January 1, 1994, and April 1, 2022. We described key study features, including KLH formulation, dose, use of adjuvants, route of administration, co-administered IMPs, and end points. Of 2421 titles and abstracts screened, 46 met the inclusion criteria, including 14 (31%) early phase trials of IMP, of which 10 (71%) targeted T-cell co-stimulation. IMPs with diverse mechanisms demonstrated modulation of the humoral response to KLH, suggesting limited specificity of this end point. Two early phase IMP studies (14%) described the response to intradermal re-challenge (delayed type hypersensitivity). Challenge regimens for IMP assessment were often incompletely described, and exhibited marked heterogeneity, including primary KLH dose (25-fold variation: 100–2500 mcg), KLH formulation, and co-administration with adjuvants. Methodological heterogeneity and failure to exploit the access to tissue-level mechanism-relevant end points afforded by KLH challenge has impaired the translational utility of this paradigm to date. Future standardization, characterization, and methodological development is required to permit tailored, appropriately powered, mechanism-dependent study design to optimize drug development decisions.

The sorting of specific cell populations is an established tool in biological research, with new applications demanding greater cell throughput, sterility and elimination of cross-contamination. Here we report 'vortex-actuated cell sorting' (VACS), a new technique that deflects cells individually, via the generation of a transient microfluidic vortex by a thermal vapour bubble: a novel mechanism, which is able to sort cells based on fluorescently-labelled molecular markers. Using in silico simulation and experiments on beads, an immortal cell line and human peripheral blood mononuclear cells (PBMCs), we demonstrate high-purity and high-recovery sorting with input rates up to 104 cells per s and switching speeds comparable to existing techniques (>40 kHz). A tiny footprint (1 × 0.25 mm) affords miniaturization and the potential to achieve multiplexing: a crucial step in increasing processing rate. Simple construction using biocompatible materials potentially minimizes cost of fabrication and permits single-use sterile cartridges. We believe VACS potentially enables parallel sorting at throughputs relevant to cell therapy, liquid biopsy and phenotypic screening.

AIMS: Very little data exist regarding the effect of cardiopulmonary bypass (CPB) on cefuroxime (CXM) pharmacokinetics in children less than one year of age. METHODS: 50 mg kg(−1) CXM i.v. after induction were followed by 75 mg kg(−1) into the CPB circuit. In 42 patients undergoing cardiac surgery, 15–20 samples were obtained between 5 and 360 min after the first dose. Total CXM concentrations were measured by high‐performance liquid chromatography and a pharmacokinetic/pharmacodynamic (PK/PD) modelling was performed. RESULTS: Using a fixed protein binding of 15.6% for CXM, peak plasma concentrations of unbound CXM were 229 ± 52 μg ml(−1) after the first bolus and 341 ± 86 μg ml(−1) on CPB. Nadir concentrations before CPB were 69 ± 20 μg ml(−1) and six hours later decreased to 41 ± 19 μg ml(−1) with and 24 ± 14 μg ml(−1) without CPB. A two‐compartment model was fitted with the main covariates body weight, CPB and postmenstrual age (PMA). PK parameters were as follows: systemic clearance, 5.15 [95% CI 4.5–5.8] l h(−1); central volume of distribution, 11.25 [9.41–13.09] l; intercompartmental clearance, 18.19 [14.79–21.58] l h(−1); and peripheral volume, 17.07 [15.7–18.5] L. ƒT > MIC of 32 μg ml(−1) for an 8‐h time period was between 70 and 100% (2.5–10 kg BW). According to our simulation, 25 mg ml(−1) CXM as a primary bolus and into the prime plus a 5 mg kg(−1) h(−1) infusion maintain CXM concentrations continuously above 32 μg ml(−1). CONCLUSIONS: The routine dosing regimen provided was sufficient for prophylaxis, but continuous dosing can provide a higher percentage of ƒT > MIC.

Dysregulated inflammation is a central pathological process in diverse disease states. Traditionally, therapeutic approaches have sought to modulate the pro- or anti-inflammatory limbs of inflammation, with mixed success. However, insight into the pathways by which inflammation is resolved has highlighted novel opportunities to pharmacologically manipulate these processes - a strategy that might represent a complementary (and perhaps even superior) therapeutic approach. This Review discusses the state of the art in the biology of resolution of inflammation, highlighting the opportunities and challenges for translational research in this field.

Background: Delirium is a common post-operative complication, particularly in older adults undergoing major or emergency procedures. It is associated with increased length of intensive care and hospital stay, post-operative mortality and subsequent dementia risk. Current methods of predicting delirium incidence, duration and severity have limitations. Investigation of blood and cerebrospinal fluid (CSF) biomarkers linked to delirium may improve understanding of the underlying pathophysiology, particularly with regard to the extent this is shared or distinct with underlying dementia. Together, these have the potential for development of better risk stratification tools and perioperative interventions. Methods: 200 patients over the age of 70 scheduled for surgery with routine spinal anaesthetic will be recruited from UK hospitals. Their cognitive and functional baseline status will be assessed pre-operatively by telephone. Time-matched CSF and blood samples will be taken at the time of surgery and analysed for known biomarkers of neurodegeneration and neuroinflammation. Patients will be assessed daily for delirium until hospital discharge and will have regular cognitive follow-up for two years. Primary outcomes will be change in modified Telephone Interview for Cognitive Status (TICS-m) score at 12 months and rate of change of TICS-m score. Delirium severity, duration and biomarker levels will be treated as exposures in a random effects linear regression models. PRIMED Risk has received regulatory approvals from Health Research Authority and London – South East Research Ethics Committee. Discussion: The main anticipated output from this study will be the quantification of biomarkers of acute and chronic contributors to cognitive impairment after surgery. In addition, we aim to develop better risk prediction models for adverse cognitive outcomes.

To estimate the impact of adopting the proposed new diagnostic criteria for sepsis, based on Sequential Organ Failure Assessment (SOFA) criteria, on the diagnosis and apparent mortality of sepsis in Australian and New Zealand intensive care units.A two-stage, post hoc analysis of prospectively collected ICU research data from 3780 adult patients in 77 Australian and New Zealand ICUs on 7 study days, between 2009 and 2014.The proportion of patients who were diagnosed with sepsis using the criteria for systemic inflammatory response syndrome (SIRS) and who met the SOFA criteria for sepsis, and the proportion of patients who were admitted to the ICU with a diagnosis consistent with infection, who met either, both or neither sets of criteria for sepsis; comparison of the demographic differences and in-hospital mortality between these groups.Of 926 patients diagnosed with sepsis on a study day using SIRS criteria, 796/923 (86.2% [95% CI, 84.0%-88.5%]) satisfied the SOFA criteria. Inhospital mortality was similar in these groups, with death recorded for 216/872 patients (24.8% [95% CI, 21.9%-27.8%]) who met the SIRS criteria for sepsis, and for 200/747 patients (26.8% [95% CI, 23.6%-30.1%]) who met both the SIRS and SOFA criteria for sepsis. Of 122 patients meeting the SIRS criteria but not the SOFA criteria, 16 (13.1% [95% CI, 7.7%-19.1%]) died. Of 241 patients admitted with an infective condition and complete data, 142 (58.9% [95% CI, 52.4%-65.2%]) satisfied the SIRS criteria for sepsis and 210 (87.1% [95% CI, 82.2%-91.1%]) satisfied the SOFA criteria. Of the 241 patients, 99 (41.1%) were not classified as having sepsis on the study day by SIRS criteria and, of these, 80 (80.8%) met the SOFA criteria.Adopting the SOFA criteria will increase the apparent incidence of sepsis in patients admitted to the ICU with infective conditions without affecting the mortality rate. Prospective evaluation of the effect of adopting the new definition of sepsis is required.

Patients with critical illness, and in particular sepsis, are now recognized to undergo unifying, pathogenic disturbances of immune function. Whilst scientific and therapeutic focus has traditionally been on understanding and modulating the initial pro-inflammatory limb, recent years have witnessed a refocusing on the development and importance of immunosuppressive 'anti-inflammatory' pathways. Several mechanisms are known to drive this phenomenon; however, no overriding conceptual framework justifies them. In this article we review the contribution of pro-resolution pathways to this phenotype, describing the observed immune alterations in terms of either a failure of resolution of inflammation or the persistence of pro-resolution processes causing inappropriate 'injurious resolution'-a novel hypothesis. The dysregulation of key processes in critical illness, including apoptosis of infiltrating neutrophils and their efferocytosis by macrophages, are discussed, along with the emerging role of specialized cell subtypes Gr1(+) CD11b(+) myeloid-derived suppressor cells and CD4(+) CD25(+) FoxP3(+) T-regulatory cells.

Activation of inflammatory pathways represents a central mechanism in multiple disease states both acute and chronic. Triggered via either pathogen or tissue damage-associated molecular motifs, common biochemical pathways lead to conserved yet variable physiological and immunological alterations. Dissection and delineation of the determinants and mechanisms underlying phenotypic variance in response is expected to yield novel therapeutic advances. Intravenous (IV) administration of endotoxin (gram-negative bacterial lipopolysaccharide), a specific Toll-like receptor 4 agonist, represents an in vivo model of systemic inflammation in man. National Institutes for Health Clinical Center Reference Endotoxin (CCRE, Escherichia coli O:113:H10:K negative) is employed to reliably and reproducibly generate vascular, hematological, endocrine, immunological and organ-specific functional effects that parallel, to varying degrees, those seen in the early stages of pathological states. Alteration of dose (0.06 - 4 ng/kg) and time-scale of exposure (bolus vs. infusion) allows replication of either acute or chronic inflammation and a range of severity to be elicited, with higher doses (2 - 4 ng/kg) frequently being used to create a 'sepsis-like' state. Established and novel medicinal compounds may additionally be administered prior to or post endotoxin exposure to appreciate their effect on the inflammatory cascade. Despite limitations in scope and generalizability, human IV endotoxin challenge offers a unique platform to gain mechanistic insights into inducible physiological responses and inflammatory pathways. Rationally employed it may aid translation of this knowledge into therapeutic innovations.

Objective: Reduced ex vivo lipopolysaccharide (LPS) stimulated whole blood pro-inflammatory cytokine release is a hallmark of immunosuppression in the critically ill and predicts adverse clinical outcomes. No standard technique for performing the assay currently exists. The impact of methodological heterogeneity was determined. Design, Setting, Subjects, and Interventions: Clinical experimental study set in a research laboratory. Venous blood from 5 to 10 healthy volunteers/experiment (total participant group: 18 subjects, 72% men, mean age 32) was stimulated ex vivo to evaluate the effect of variables identified via literature review on tumor necrosis factor-α (TNFα) release. These included sample handling, stimulation technique, and incubation conditions. Reporting convention was additionally assessed. Main Results: Measured TNFα release was significantly altered by source of LPS, concentration of LPS employed, duration and temperature of incubation prior to supernatant aspiration, and predilution of blood (repeated measures ANOVA, all P

Oxygen therapy is primarily administered to alleviate arterial hypoxaemia and tissue hypoxia, and to facilitate aerobic cellular respiration. Hypoxaemia (PaO2 < 8 kPa [60 mmHg], SaO2 PO2. Increasing the fraction of inspired oxygen should form part of an overall strategy to maximize tissue oxygen delivery. Permissive hypoxaemia represents a valid treatment strategy in a selected patient cohort. Oxygen is a drug and oxygen therapy is not benign, and oxygen administration at high, sustained doses (FiO2 >0.5, >12 hours) may cause oxygen toxicity. Observational studies in both mechanically-ventilated patients and survivors of non-traumatic cardiac arrest indicate an independent association between increasing hyperoxaemia and mortality. Oxygen therapy may additionally precipitate hypercapnic ventilatory failure in those at risk and oxygen should be administered to achieve a prescribed target SaO2 or PaO2 range, via adjustment of dose and delivery device. If no monitoring is available, hypoxaemia should be avoided by giving high-flow oxygen to achieve a FiO2 of near 1.0 with subsequent titration once oxygenation status is established.

Whilst numerous studies investigating the aetiology of inflammatory diseases have been performed in rodents, the applicability of these data to human pathophysiology is frequently debated. Regardless of the strengths and weaknesses of rodent models in biomedical research, there is a need to develop models of experimental inflammation in humans. Here, we describe a self‐resolving acute inflammatory response triggered by the intradermal injection of UV‐killed Escherichia coli into the forearm of healthy volunteers. Cells and exudates were harvested from onset to resolution by applying negative pressure over the inflamed site. Onset was characterized by high blood flow, neutrophilia and peak levels of pro‐inflammatory cytokines, whilst resolution showed a decline in blood blow, reduction in neutrophils, increase in monocytes/macrophages and waning of classic pro‐inflammatory cytokine levels. An anti‐inflammatory effect, defined as suppression of onset phase events, was demonstrated by administering naproxen, a conventional non‐steroidal anti‐inflammatory drug. In summary, this model of resolving acute inflammation is minimally invasive, highly tractable and allows simultaneous investigation of the vascular response, cellular trafficking and chemical mediator profile of onset and resolution phases of acute inflammation in humans. It can serve as a translational platform to provide mechanistic insights and to test the clinical efficacy of novel anti‐inflammatory and pro‐resolving drugs, and also as a tool in patients to explore inherent defects in resolution pathways.

The physiological and biochemical abnormalities that constitute multiple organ failure represent cellular perturbations that, importantly, need to be reconciled with a lack of significant cell death together with availability but impaired utilization of oxygen. In conjunction with the relatively rapid ability of the organ to recover in surviving patients, a paradigm of metabolic shutdown triggered by a decrease in mitochondrial energy production appears increasingly valid. This review discusses data demonstrating temporal changes in oxygen utilization through the septic process, evidence for mitochondrial derangements, and recovery of mitochondrial function preceding clinical recovery.

Introduction The use of rapid sequence induction and tracheal intubation (RSI) in the pre-hospital environment is controversial. Currently, it is felt that competence to perform RSI should be defined by skills in anaesthesia not by the primary speciality of a practitioner. This aim of the study was to evaluate the tracheal intubation success rate of doctors drawn from different clinical specialities performing RSI in the pre-hospital environment. Method Retrospective review of all RSI performed by doctors operating on the Warwickshire and Northamptonshire Air Ambulance over a 5-year period. Tracheal intubation failure rates were calculated and analysed for proportional differences between groups by χ 2 and, where appropriate, Fisher9s exact test. Results 4362 active missions were flown. RSI was performed in 200 cases (4.6%, 3.1/month). Successful intubation occurred in 194 cases, giving a failure rate of 3% (6 cases, 95% CI 0.6 to 5.3%). While no difference in failure rate was observed between emergency department (ED) staff and anaesthetists (2.73% (3/110, 95% CI 0 to 5.7%) vs 0% (0/55, 95% CI 0 to 0%); p=0.55), a significant difference was found when non-ED, non-anaesthetic staff (GP and surgical) were compared to anaesthetists (10.34% (3/29, 95% CI 0 to 21.4%) vs 0%; p=0.04). There was no significant difference associated with seniority of practitioner (p=0.65). Conclusions Non-anaesthetic practitioners have a higher tracheal intubation failure rate during pre-hospital RSI. This likely reflects a lack of training opportunities and infrequency of clinical experience. Strategies to improve pre-hospital airway management are required.

Background: The role of e-learning in contemporary healthcare education is quickly developing. The aim of this study was to examine the relationship between the use of an e-learning simulation programme (Microsim (TM), Laerdal, UK) prior to attending an Advanced Life Support (ALS) course and the subsequent relationship to candidate performance.\ud \ud Methods: An open label, multi-centre randomised controlled study was conducted. The control group received a course manual and pre-course MCQ four weeks prior to the face to face course. The intervention group in addition received the Microsim programme on a CD. The primary outcome was performance during a simulated cardiac arrest at the end of the course. Secondary outcomes were performance during multiple choice exams, resuscitation skills assessments and feedback to Microsim programme.\ud \ud Results: 572 participants were randomised (287 Microsim, 285 control). There were no significant differences in the primary outcome (performance during a standard cardiac arrest simulation) or secondary outcomes. User evaluations were favorable. 79% would recommend it to colleagues. 9% stated Microsim could replace the entire ALS course, 25% parts. Over 70% of participants' perceived that Microsim improved their understanding of the key learning domains of the ALS course.\ud \ud Conclusion: Distributing Microsim to healthcare providers prior to attending an ALS courses did not improve either cognitive or psychomotor skills performance during cardiac arrest simulation testing. The challenge that lies ahead is to identify the optimal way to use e-learning as part of a blended approach to learning for this type of training programme.

Aims Paramedic tracheal intubation has been reported to carry a high failure rate and morbidity. A comparison between doctor and paramedic-led intubation at out-of-hospital cardiac arrests (OHCA) was conducted to assess whether this finding was observed in our clinical practice. Methods Retrospective review of all medical OHCA attended by the Warwickshire and Northamptonshire Air Ambulance (WNAA) over a 64-month period. Cases were identified and divided into doctor-led or paramedic-led groups. Self-reported intubation failure rate, morbidity and clinical outcome were observed and compared. Paramedic exposure to tracheal intubation was assessed. Results 286 cases of medical OHCA were identified, 199 (69.6%) were doctor-led and 87 (30.4%) paramedic-led. Paramedic and doctor-led crews intubated an equivalent proportion of cases (Para-led 60.7% [37] vs. Dr-led 62.8% [98]; p =0.89) and no significant difference in failure rate was observed (Para-led 2.7% [1 case, 95% CI 0.0–7.9%] vs. Dr-led 3.1% [3 cases, 95% CI 0.0–6.5%]; p =1). No morbidity from failure-to-intubate was recorded, and equal rates of return of spontaneous circulation (ROSC) were observed (Para-led 20.7% [18] vs. Dr-led 20.6% [41]; p =0.89). Paramedics operating with the WNAA were found to have a higher exposure to tracheal intubation (WNAA 0.03 TT/shift vs. unselected paramedics 0.004 TT/shift). Conclusions Experienced paramedics regularly operating with physicians have a low tracheal intubation failure rate at OHCA, whether practicing independently or as part of a doctor-led team. This is likely due to increased and regular clinical exposure.

Solid organ transplantation is a vital therapy for end stage diseases. Decades of research has established that the components of the adaptive immune system are critical for transplant rejection, but the role of the innate immune system in organ transplantation is just emerging. Accumulating evidence indicates that the innate immune system is activated at the time of organ implantation by the release of endogenous inflammatory triggers. This review discusses the nature of these triggers in organ transplantation and also potential mediators that may enhance inflammation resolution after organ implantation.

Key points Critical (or intensive) care involves the management of acutely ill patients who have or are at risk of organ failure.[1][1] It is a specialty of acuity, not of organ or apparatus, dealing with heterogeneous patients and complex pathology.[2][2] Critical care services are now an

AIM Physiological track and trigger scores have an established role in enhancing the detection of critical illness in hospitalized patients. Their potential to identify individuals at risk of clinical deterioration in the pre-hospital environment is unknown. This study compared the predictive accuracy of the Modified Early Warning Score (MEWS) with current clinical practice. METHODS A retrospective observational cohort study of consecutive adult (≥16 yrs) emergency department attendances to a single centre over a two-month period. The outcome of interest was the occurrence or not of an adverse event within 24h of admission. Hospital pre-alerting was used as a measure of current critical illness detection and its accuracy compared with MEWS scores calculated from pre-hospital observations. RESULTS 3504 patients were included in the study. 76 (2.5%) suffered an adverse event within 24 h of admission. Paramedics pre-alerted the hospital in 224 cases (7.3%). Clinical judgement demonstrated a sensitivity of 61.8% (95% CI 51.0-72.8%) with a specificity of 94.1% (95% CI 93.2-94.9%). MEWS was a good predictor of adverse outcomes and hence critical illness detection (AUC 0.799, 95% CI 0.738-0.856). Combination systems of MEWS and clinical judgement may be effective MEWS ≥4+clinical judgement: sensitivity 72.4% (95% CI 62.5-82.7%), specificity 84.8% (95% CI 83.52-86.1%). CONCLUSIONS Clinical judgement alone has a low sensitivity for critical illness in the pre-hospital environment. The addition of MEWS improves detection at the expense of reduced specificity. The optimal scoring system to be employed in this setting is yet to be elucidated.

Background and Aims: Patients with cirrhosis are at a greatly increased risk of severe bacterial infection with survival directly related to extra-hepatic organ dysfunction. A defective innate immune response is considered to underlie this risk. There is however no medical strategy to restore immune competence in these patients. Elevated circulating Prostaglandin E2 (PGE2) levels contribute to immune suppression in acutely decompensated (AD) cirrhosis. PGE2 is more bioavailable because of decreased serum albumin levels in AD patients as albumin binds PGE2. The binding capacity of endogenous albumin is also known to be defective in cirrhosis. Human Albumin Solution (HAS), a safe and common intervention, could thus be repurposed as an immune restorative drug in AD patients. The primary aim of ATTIRE is to determine if raising serum albumin to >30 g/L in patients with decompensated cirrhosis will decrease rates of infection, extra hepatic organ dysfunction and death.

O154 PROSTAGLANDIN E2 MEDIATES IMMUNOSUPPRESSION IN ACUTELY DECOMPENSATED CIRRHOSIS A. O’Brien, J. Fullerton, G. Auld, S. James, J. Newson, E. Karra, K. Massey, W. Alazawi, A. Winstanley, C. Juan, R. Garcia-Marquez, A. Nicolaou, D. Gilroy. Hepatology, Medicine, University College London (UCL), London, University of Manchester, Manchester, Barts and The London Medical School, London, United Kingdom; Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Madrid, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain E-mail: rmhaajo@ucl.ac.uk Background and Aims: Liver cirrhosis is one of the top 10 causes of death globally. Patients with advanced cirrhosis experience frequent infections leading to sepsis, which carries high mortality. Innate immune dysfunction is thought to underlie this vulnerability, however no unifying cause has been identified. Methods: Lipidomic analysis was performed on plasma from patients with acutely decompensated (AD) cirrhosis, stable cirrhosis, end-stage liver disease (ESLD) and healthy volunteers. Human monocyte-derived macrophages were incubated in media containing plasma from cirrhosis patients in the presence/absence of prostaglandin E2 (PGE2) modulators. Cytokine levels/bacterial killing were used as markers of immune competence. In-vivo bacterial challenge/survival experiments were performed on bile duct ligation and carbon tetrachloride liver-injury mouse models. Results: PGE2 was elevated in acutely decompensated patients at immunosuppressive levels. Plasma from AD and ESLD patients suppressed macrophage cytokine secretion and bacteria killing in a PGE2 receptor-dependent manner. This immunosuppressive effect persisted up to 24 weeks after initial sampling, but was absent in stable cirrhosis. Both mouse models demonstrated elevated PGE2, which when inhibited restored immune competence and survival following infection. Albumin binds PGE2 and we found the immunosuppressive effects of AD plasma were enhanced in patients with low albumin levels. Administering 20% Human Albumin Solution to AD patients reversed the immunosuppressive properties of their plasma. Conclusions: We demonstrate for the first time that elevated PGE2 combined with hypoalbuminemia mediates immunosuppression in AD and ESLD patients. We propose the use of albumin to raise levels above 30mg/dl to inhibit PGE2 and restore immune competence in these patients.

I was delighted to see the BMJ Therapeutics series covering non-steroidal anti-inflammatory agents—a class of drugs that has perhaps been unfairly maligned and shunned recently.1 Although the article focused on the use of these drugs as analgesics, they can be used as immunomodulatory agents. Clinicians commonly associate prostaglandins, the predominant downstream product of cyclo-oxygenase action on …

Background Current international guidelines for predicting cardiovascular disease (CVD) risk include non-invasive assessment of arterial stiffness. We aimed to evaluate how estimates of pulse wave velocity (PWV), calculated using a new, rapid, validated non-invasive device, compare with traditional risk scores in discriminating patients at increased risk of CVD. Subjects and Methods: We used a non-invasive oscillometric device (Arteriograph, Unimedic Ltd) to estimate PWV in patients with and without established CVD (n=80, 79% male; mean age 67±1(SEM)years). Risk factors included hypertension (70%), hypercholesterolaemia (65%), type 2 diabetes mellitus (35%) and current smoking (18%). 59% had clinical ischaemic heart disease. Individuals were categorised as ‘high’ or ‘low’ CVD risk according to published thresholds using 3 established methods (Framingham (JBS2) risk charts, European Society of Cardiology (ESC) HeartScore® and the Pocock risk score). Data were analysed using SPSS (version 14.0). The study was approved by the local research ethics committee. Results PWV was positively correlated (Spearman) with increasing risk estimated by all three scoring systems (Framingham r s = 0.420, p = 0.001; HeartScore r s = 0.394, p = 0.000; Pocock r s = 0.305, p = 0.006). For all three scoring systems, in at least 25% of subjects assessed as low risk, PWV indicated CVD high risk (Framingham: 27%; HeartScore: 25%; Pocock: 44%). In contrast, around half of our subjects identified as ‘high’ risk by conventional risk scores, were identified as in the low CVD risk category when assessed by PWV (Framingham: 49%; HeartScore: 47%; Pocock: 50%). Conclusion We observed important disagreement in the stratification of CVD risk in a high risk population by an index of arterial stiffness compared with commonly used risk scores. One interpretation of our data is that combination of non-invasive measurements of arterial stiffness with classical CVD risk scoring systems may improve stratification in high risk populations. However, further prospective work is needed to determine clinical outcomes for patients misclassified by assessment of arterial stiffness compared with classical risk scoring. This will help to test the clinical utility of combined risk scoring and arterial stiffness, in producing finer CVD risk stratification.

Liver disease is one of the leading causes of death worldwide. Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system; however, the causative mechanism has remained elusive. We present evidence that the cyclooxygenase (COX)-derived eicosanoid prostaglandin E2 (PGE2) drives cirrhosis-associated immunosuppression. We observed elevated circulating concentrations (more than seven times as high as in healthy volunteers) of PGE2 in patients with acute decompensation of cirrhosis. Plasma from these and patients with end-stage liver disease (ESLD) suppressed macrophage proinflammatory cytokine secretion and bacterial killing in vitro in a PGE2-dependent manner via the prostanoid type E receptor-2 (EP2), effects not seen with plasma from patients with stable cirrhosis (Child-Pugh score grade A). Albumin, which reduces PGE2 bioavailability, was decreased in the serum of patients with acute decompensation or ESLD (