Szakmany, Tamas; Fitzgerald, Eleanor; Garlant, Harriet; Abdullatif, Muhammad; Whitehouse, Tony; Molnar, Tamas; Shah, Sanjoy; Tong, Dong; Hall, Judith; Ball, Graham; Kempsell, Karen Author Information

IntroductionEarly diagnosis of sepsis and discrimination from SIRS is crucial for clinicians to provide appropriate care, management and treatment to critically ill patients. We describe identification of mRNA biomarkers from peripheral blood leukocytes, able to identify severe, systemic inflammation (irrespective of origin) and differentiate Sepsis from SIRS, in adult patients within a multi-center clinical study.MethodsParticipants were recruited in Intensive Care Units (ICUs) from multiple UK hospitals, including fifty-nine patients with abdominal sepsis, eighty-four patients with pulmonary sepsis, forty-two SIRS patients with Out-of-Hospital Cardiac Arrest (OOHCA), sampled at four time points, in addition to thirty healthy control donors. Multiple clinical parameters were measured, including SOFA score, with many differences observed between SIRS and sepsis groups. Differential gene expression analyses were performed using microarray hybridization and data analyzed using a combination of parametric and non-parametric statistical tools.ResultsNineteen high-performance, differentially expressed mRNA biomarkers were identified between control and combined SIRS/Sepsis groups (FC>20.0, p<0.05), termed ‘indicators of inflammation’ (I°I), including CD177, FAM20A and OLAH. Best-performing minimal signatures e.g. FAM20A/OLAH showed good accuracy for determination of severe, systemic inflammation (AUC>0.99). Twenty entities, termed ‘SIRS or Sepsis’ (S°S) biomarkers, were differentially expressed between sepsis and SIRS (FC>2·0, p-value<0.05). DiscussionThe best performing signature for discriminating sepsis from SIRS was CMTM5/CETP/PLA2G7/MIA/MPP3 (AUC=0.9758). The I°I and S°S signatures performed variably in other independent gene expression datasets, this may be due to technical variation in the study/assay platform.

In Africa, refusal of COVID-19 and other vaccines is widespread for different reasons, including disbelief in the existence of the virus itself and faith in traditional remedies. In sub-Saharan countries, refusal is often made worse by opposition to vaccines by the religious establishments. This is a pressing problem, as Africa has the highest vaccine-avoidable mortality rate for children under the age of five in the world. Dialogue between those wishing to promote vaccines and those who resist them is essential if the situation is to be improved. This article argues that Western and other aid agencies seeking to promote vaccination programs need to develop a dialogue with resisters, and in this process to embrace and commend the ancient African philosophical tradition of Ubuntu, incorporating it into these programs as a way to overcome such entrenched resistance. The paper concludes with concrete recommendations for how to accomplish this goal.

Hypoxic hypoxia (inspiratory hypoxia) stimulates an increase in cerebral blood fl ow (CBF) maintaining oxygen delivery to the brain. However, this response, particularly at the tissue level, is not well characterised. This study quanti fi es the CBF response to acute hypoxic hypoxia in healthy subjects. A 20-min hypoxic (mean P ET O 2 =52 mmHg) challenge was induced and controlled by dynamic end-tidal forcing whilst CBF was measured using pulsed arterial spin labelling perfusion MRI. The rate constant, temporal delay and magnitude of the CBF response were characterised using an exponential model for whole-brain and regional grey matter. Grey matter CBF increased from 76.1 mL/100 g/min (95% con fi dence interval (CI) of fi tting: 75.5 mL/100 g/min, 76.7 mL/100 g/min) to 87.8 mL/100 g/min (95% CI: 86.7 mL/100 g/min, 89.6 mL/100 g/min) during hypoxia, and the temporal delay and rate constant for the response to hypoxia were 185 s (95% CI: 132 s, 230 s) and 0.0035 s – 1 (95% CI: 0.0019 s – 1 , 0.0046 s – 1 ), respectively. Recovery from hypoxia was faster with a delay of 20 s (95% CI: – 38 s, 38 s) and a rate constant of 0.0069 s – 1 (95% CI: 0.0020 s – 1 , 0.0103 s – 1 ). R 2 *, an index of blood oxygenation obtained simultaneously with the CBF measurement, increased from 30.33 s – 1 (CI: 30.31 s – 1 , 30.34 s – 1 ) to 31.48 s – 1 (CI: 31.47 s – 1 , 31.49 s – 1 ) with hypoxia. The delay and rate constant for changes in R 2 * were 24 s (95% CI: 21 s, 26 s) and 0.0392 s – 1 (95% CI: 0.0333 s – 1 , 0.045 s – 1 ), respectively, for the hypoxic response, and 12 s (95% CI: 10 s, 13 s) and 0.0921 s – 1 (95% CI: 0.0744 s – 1 , 0.1098 s – 1 /) during the return to normoxia, con fi rming rapid changes in blood oxygenation with the end-tidal forcing system. CBF and R 2 * reactivity to hypoxia differed between subjects, but only R 2 * reactivity to hypoxia differed signi fi cantly between brain regions. © 2013 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd. Supporting information may be found in the online version of this paper.

This paper presents lessons learnt and recommendations for future studies attempting to apply a parachute design approach to design for Namibia. The focus of this project is the development of a low cost, fit for purpose trauma pack for use in Namibia. The project was undertaken by an interdisciplinary team of medics, designers and engineers in an effort to reduce high mortality rates that occur as a result of road traffic collisions in Namibia. The pack was developed through applying a human centred design (HCD) approach that calls upon Design Thinking and end-user engagement. The key focus of the paper is a design development process that responded to key findings from user testing and design for manufacture requirements. The design was guided by the World Health Organisation's (2010) Four A's: accessibility, availability, affordability and appropriateness.

Immunoglobulin IgM is important for controlling viral and bacterial infections, and low immunoglobulin levels have been found in sepsis. There is a clear need to stratify sepsis patients according to the presence of an invading organism, compared to no organism identified, and SIRS patients, where organ dysfunction is a result of a non-infective process. The aim of this pilot study in a small cohort of patients with sepsis was to evaluate the association between IgM plasma levels and survival in 47 patients with sepsis and 11 patients diagnosed with organ failure without the identification of a pathogen (SIRS). Patients were admitted to the intensive care unit (ICU) at The Royal Glamorgan Hospital, Llantrisant, UK between 2010 and 2014. We found that low IgM levels were associated with sepsis, but not SIRS. IgM levels did not differ significantly for culture-positive (CP) compared with culture-negative (CN, no organism found) sepsis samples. Kaplan–Meier analysis was used to compare survival curves according to IgM levels, with no significant difference. We observed significantly higher survival in the CP samples when comparing with CN. Cut-off value for IgM (266 μg/mL) for diagnosis of sepsis patients was determined using receiver operator characteristic (ROC) curves with 70% sensitivity, 69% specificity and 92% negative predictive values (NPV), respectively. The corresponding area under the curve (AUC) for the discrimination of sepsis patients was AUC = 0.73, and in a subgroup analysis of CP was AUC = 0.77 and for CN was AUC = 0.79. We confirm IgM as a good diagnostic marker of sepsis. These findings indicate a difference in the pathology between culture-positive versus negative sepsis, SIRS and survival. This indicates that IgM is likely relevant to pathology, because of its role in the early immune response against pathogens, the potentially protective role of natural IgM antibodies, and supports its application in immunoglobulin therapy.

Studying changes in cortical oscillations can help elucidate the mechanistic link between receptor physiology and the clinical effects of anaesthetic drugs. Propofol, a GABA-ergic drug produces divergent effects on visual cortical activity: increasing induced gamma-band responses (GBR) while decreasing evoked responses. Dexmedetomidine, an α2- adrenergic agonist, differs from GABA-ergic sedatives both mechanistically and clinically as it allows easy arousability from deep sedation with less cognitive side-effects. Here we use magnetoencephalography (MEG) to characterize and compare the effects of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation, on visual and motor cortical oscillations. Sixteen male participants received target-controlled infusions of propofol and dexmedetomidine, producing mild-sedation, in a placebo-controlled, cross-over study. MEG data was collected during a combined visuomotor task. The key findings were that propofol significantly enhanced visual stimulus induced GBR (44% increase in amplitude) while dexmedetomidine decreased it (40%). Propofol also decreased the amplitudes of the Mv100 (visual M100) (27%) and Mv150 (52%) visual evoked fields (VEF), whilst dexmedetomidine had no effect on these. During the motor task, neither drug had any significant effect on movement related gamma synchrony (MRGS), movement related beta de-synchronisation (MRBD) or Mm100 (movement-related M100) movement-related evoked fields (MEF), although dexmedetomidine slowed the Mm300. Dexmedetomidine increased (92%) post-movement beta synchronisation/rebound (PMBR) power while propofol reduced it (70%, statistically non- significant). Overall, dexmedetomidine and propofol, at equi-sedative doses, produce contrasting effects on visual induced GBR, VEF, PMBR and MEF. These findings provide a mechanistic link between the known receptor physiology of these sedative drugs with their known clinical effects and may be used to explore mechanisms of other anaesthetic drugs on human consciousness.

Mechanisms of anesthetic drug-induced sedation and unconsciousness are still incompletely understood. Functional neuroimaging modalities provide a window to study brain function changes during anesthesia allowing us to explore the sequence of neuro-physiological changes associated with anesthesia. Cerebral perfusion change under an assumption of intact neurovascular coupling is an indicator of change in large-scale neural activity. In this experiment, we have investigated resting state cerebral blood flow (CBF) changes in the human brain during mild sedation, with propofol. Arterial spin labeling (ASL) provides a non-invasive, reliable, and robust means of measuring cerebral blood flow (CBF) and can therefore be used to investigate central drug effects. Mild propofol sedation-related CBF changes were studied at rest (n = 15), in a 3 T MR scanner using a PICORE-QUIPSS II ASL technique. CBF was reduced in bilateral paracingulate cortex, premotor cortex, Broca’s areas, right superior frontal gyrus and also the thalamus. This cerebral perfusion study demonstrates that propofol induces suppression of key cortical (frontal lobe) and subcortical (thalamus) regions during mild sedation.

Recent description of the microbiology of sepsis on the wards or information on the real-life antibiotic choices used in sepsis is lacking. There is growing concern of the indiscriminate use of antibiotics and omission of microbiological investigations in the management of septic patients. We performed a secondary analysis of three annual 24-h point-prevalence studies on the general wards across all Welsh acute hospitals in years 2016-2018. Data were collected on patient demographics, as well as radiological, laboratory and microbiological data within 48-h of the study. We screened 19,453 patients over the three 24 h study periods and recruited 1252 patients who fulfilled the entry criteria. 775 (64.9%) patients were treated with intravenous antibiotics. Only in 33.65% (421/1252) of all recruited patients did healthcare providers obtain blood cultures; in 25.64% (321/1252) urine cultures; in 8.63% (108/1252) sputum cultures; in 6.79% (85/1252) wound cultures; in 15.25% (191/1252) other cultures. Out of the recruited patients, 59.1% (740/1252) fulfilled SEPSIS-3 criteria. Patients with SEPSIS-3 criteria were significantly more likely to receive antibiotics than the non-septic cohort (p < 0.0001). In a multivariable regression analysis increase in SOFA score, increased number of SIRS criteria and the use of the official sepsis screening tool were associated with antibiotic administration, however obtaining microbiology cultures was not. Our study shows that antibiotics prescription practice is not accompanied by microbiological investigations. A significant proportion of sepsis patients are still at risk of not receiving appropriate antibiotics treatment and microbiological investigations; this may be improved by a more thorough implementation of sepsis screening tools.

Background: The Anaesthetic department of the University Hospital Wales in Cardiff, South Wales, houses the Mushin Museum-an extensive collection of historical anaesthetic equipment started by William Mushin in 1947. We have recently reached a key point of museum development and offered a fantastic opportunity for students to be involved. The funded students had the opportunity to establish a new museum exhibition space and invaluable research experience was gained as the candidates explored the history of objects earmarked for inclusion in the new exhibition.

BACKGROUND:Postpartum haemorrhage (PPH) can be exacerbated by haemostatic failure. We hypothesized that early fibrinogen replacement, guided by viscoelastometric testing, reduces blood product usage and bleed size. METHODS:Women with PPH 1000-1500 ml were enrolled. If Fibtem A5 was ≤15 mm and bleeding continued, subjects were randomized to fibrinogen concentrate or placebo. The primary outcome compared the number of units of red blood cells, plasma, cryoprecipitate and platelets transfused. RESULTS:Of 663 women enrolled 55 were randomized. The adjusted incidence rate ratio (IRR) (95% CI) for the number of allogeneic units transfused in the fibrinogen group compared with placebo was 0.72 (0.3-1.7), P =0.45. In pre-specified subgroup analyses, subjects who had a Fibtem A5 ≤12 mm at the time of randomization and who received fibrinogen concentrate received a median (25th-75th centile) of 1 (0-4.5) unit of allogeneic blood products and had an additional 300 (100-350) ml blood loss whereas those who received placebo also received 3 (0-6) units of allogeneic blood products and had 700 (200-1550) ml additional blood loss; these differences were not statistically significantly different. There was one thrombotic event in each group. CONCLUSIONS:Infusion of fibrinogen concentrate triggered by Fibtem A5 ≤15 mm did not improve outcomes in PPH. Pre-specified subgroup analyses suggest that fibrinogen replacement is not required if the Fibtem A5 is > 12 mm or Clauss fibrinogen >2 g litre -1 , but an effect below these levels cannot be excluded. The raised fibrinogen at term appears to be a physiological buffer rather than required for haemostasis. TRIAL REGISTRATION:ISRCTN46295339 ( http://www.isrctn.com/ISRCTN46295339 , last accessed 5 July 2017), EudraCT 2012-005511-11 ( https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-005511-11 , last accessed 5 July 2017).

Soluble TLR2 levels are elevated in infective and inflammatory conditions, but its diagnostic value with sepsis-induced multi-organ failure has not been evaluated. 37 patients with a diagnosis of severe sepsis/septic shock (sepsis) and 27 patients with organ failure without infection (SIRS) were studied. Median (IQR) plasma sTLR2 levels were 2.7 ng/ml (1.4-6.1) in sepsis and 0.6 ng/ml (0.4-0.9) in SIRS p < 0.001. sTLR2 showed good diagnostic value for sepsis at cut-off of 1.0 ng/ml, AUC: 0.959. We report the ability of sTLR2 levels to discriminate between sepsis and SIRS within 12 h of ICU admission in patients with multi-organ failure.

Carotid endarterectomy (CEA) is a surgical procedure to remove stenotic atherosclerotic plaque from the origin of the carotid artery to reduce the risk of major stroke. Its impact on postoperative cognitive function (POCF) remains controversial; complicated, in part, by a traditional failure to account for practice effects incurred during consecutive psychometric testing. To address this for the first time, we performed psychometric testing (learning and memory, working memory, attention and information processing, and visuomotor coordination) in 15 male patients aged 68 +/- 8years with symptomatic carotid stenosis the day before and 24h following elective CEA (two consecutive tests, 48h apart). Multiple baselining was also performed in a separate cohort of 13 educationally, anthropometrically and age-matched controls (63 +/- 9years) not undergoing revascularization at identical time points with additional measures performed over a further 96h (four consecutive tests, each 48h apart). A single consecutive test in the control group resulted in progressive improvements in learning and memory, working memory, and attention and information (P<0.05 vs. Test 1), with three tests required before cognitive performance stabilized. Following correction for practice effects in the patient group, CEA was associated with a deterioration rather than an improvement in learning and memory as originally observed (P<0.05). These findings highlight the potential for the clinical misinterpretation of POCF unless practice effects are taken into account and provide practical recommendations for implementation within the clinical setting.

This paper presents case study material relating to the application of a process of Human-Centred Design that draws upon Design Thinking for the development of medical products for rural Zambia. The underpinning method was developed in response to calls for the development of culturally and contextually appropriate medical product solutions as opposed to the current solution; directly imported products and methods from industrialised nations. The authors note the benefits and limitations of the approach taken, reflect on the resulting insights and provide recommendations for future studies.

This study aims to map the acute effects of caffeine ingestion on grey matter oxygen metabolism and haemodynamics with a novel MRI method. Sixteen healthy caffeine consumers (8 males, age=24.7 +/- 5.1) were recruited to this randomised, double-blind, placebo-controlled study. Each participant was scanned on two days before and after the delivery of an oral caffeine (250 mg) or placebo capsule.Our measurements were obtained with a newly proposed estimation approach applied to data from a dual calibration fMRI experiment that uses hypercapnia and hyperoxia to modulate brain blood flow and oxygenation. Estimates were based on a forward model that describes analytically the contributions of cerebral blood flow (CBF) and of the measured end-tidal partial pressures of CO2 and O-2 to the acquired dual-echo GRE signal. The method allows the estimation of grey matter maps of: oxygen extraction fraction (OEF), CBF, CBF-related cerebrovascular reactivity (CVR) and cerebral metabolic rate of oxygen consumption (CMRO2). Other estimates from a multi inversion time ASL acquisition (mTI-ASL), salivary samples of the caffeine concentration and behavioural measurements are also reported.We observed significant differences between caffeine and placebo on average across grey matter, with OEF showing an increase of 15.6% (SEM +/- 4.9%, p < 0.05) with caffeine, while CBF and CMRO2 showed differences of -30.4% (SEM +/- 1.6%, p < 0.01) and -18.6% (SEM +/- 2.9%, p < 0.01) respectively with caffeine administration. The reduction in oxygen metabolism found is somehow unexpected, but consistent with a hypothesis of decreased energetic demand, supported by previous electrophysiological studies reporting reductions in spectral power with EEG.Moreover the maps of the physiological parameters estimated illustrate the spatial distribution of changes across grey matter enabling us to localise the effects of caffeine with voxel-wise resolution. CBF changes were widespread as reported by previous findings, while changes in OEF were found to be more restricted, leading to unprecedented mapping of significant CMRO2 reductions mainly in frontal gyrus, parietal and occipital lobes.In conclusion, we propose the estimation framework based on our novel forward model with a dual calibrated fMRI experiment as a viable MRI method to map the effects of drugs on brain oxygen metabolism and haemodynamics with voxel-wise resolution.

Simulation education is an important part of health care education and training. There is growing evidence to support the usefulness of simulation, especially in training for infrequently occurring situations, such as medical emergencies seen by dental practitioners. There are, however, few data on the longer term effects of simulation, including usefulness, relevance, emotional effect and ability to affect changes to daily practice.

Collins, Peter, Cannings-John, Rebecca, Bruynseels, Daniel, Mallaiah, S, Dick, J, Elton, C, Weeks, A. D., Sanders, Julia, Aawar, N, Townson, Julia, Hood, Kerenza, Hall, Judith, Harding, K, Gauntlett, R and Collis, R.E. 2017. Viscoelastometry guided fresh frozen plasma infusion for postpartum haemorrhage: an observational study. British Journal of Anaesthesia 119 (3) , pp. 422434. 10.1093/bja/aex245 file

Summary Our aim was to prospectively determine the predictive capabilities of SEPSIS ‐1 and SEPSIS ‐3 definitions in the emergency departments and general wards. Patients with National Early Warning Score (NEWS) of 3 or above and suspected or proven infection were enrolled over a 24‐h period in 13 Welsh hospitals. The primary outcome measure was mortality within 30 days. Out of the 5422 patients screened, 431 fulfilled inclusion criteria and 380 (88%) were recruited. Using the SEPSIS ‐1 definition, 212 patients had sepsis. When using the SEPSIS ‐3 definitions with Sequential Organ Failure Assessment (SOFA) score ≥ 2, there were 272 septic patients, whereas with quick SOFA score ≥ 2, 50 patients were identified. For the prediction of primary outcome, SEPSIS ‐1 criteria had a sensitivity (95%CI) of 65% (54–75%) and specificity of 47% (41–53%); SEPSIS ‐3 criteria had a sensitivity of 86% (76–92%) and specificity of 32% (27–38%). SEPSIS ‐3 and SEPSIS ‐1 definitions were associated with a hazard ratio (95%CI) 2.7 (1.5–5.6) and 1.6 (1.3–2.5), respectively. Scoring system discrimination evaluated by receiver operating characteristic curves was highest for Sequential Organ Failure Assessment score (0.69 (95%CI 0.63–0.76)), followed by NEWS (0.58 (0.51–0.66)) (p < 0.001). Systemic inflammatory response syndrome criteria (0.55 (0.49–0.61)) and quick SOFA score (0.56 (0.49–0.64)) could not predict outcome. The SEPSIS ‐3 definition identified patients with the highest risk. Sequential Organ Failure Assessment score and NEWS were better predictors of poor outcome. The Sequential Organ Failure Assessment score appeared to be the best tool for identifying patients with high risk of death and sepsis‐induced organ dysfunction.