Pooled prevalence of lymphopenia in all-cause hospitalisations and association with infection: a systematic review and meta-analysis.

BACKGROUND: Lymphopenia is defined as a decrease below normal value (often 1.0 x 109 cells/L) of blood circulating lymphocyte count. In the general population, lymphopenia is associated with an increased risk of hospitalisation secondary to infection, independent of traditional clinical risk factors. In hospital, lymphopenia is associated with increased risk of healthcare-associated infection and mortality. By summarising lymphopenia's prevalence and impact on clinical outcomes, we can identify an at-risk population and inform future studies of immune dysfunction following severe illness. METHODS: Peer-reviewed search strategy was performed on three databases. Primary objective was to summarise the pooled prevalence of lymphopenia. Primary outcome was infection including pre-existing lymphopenia as a risk factor for admission with infection and as an in-hospital risk factor for healthcare-associated infection. Secondary outcomes were length of stay and mortality. Mortality data extracted included in-hospital, 28/30-day ('early'), and 90-day/1-year ('late') mortality. Meta-analysis was carried out using random-effects models for each outcome measure. Heterogeneity was assessed using I2 statistic. Joanna Briggs Institute checklist for cohort studies was used to assess risk of bias. The protocol was published on PROSPERO. RESULTS: Fifteen observational studies were included. The pooled prevalence of lymphopenia in all-cause hospitalisations was 38% (CI 0.34-0.42, I2= 97%, p< 0.01). Lymphopenia was not associated with an infection diagnosis at hospital admission and healthcare associated infection (RR 1.03; 95% CI 0.26-3.99, p=0.97, I2 = 55% and RR 1.31; 95% CI 0.78-2.20, p=0.31, I2=97%, respectively), but was associated with septic shock (RR 2.72; 95% CI 1.02-7.21, p=0.04, I2 =98%). Lymphopenia was associated with higher in-hospital mortality and higher 'early' mortality rates (RR 2.44; 95% CI 1.71-3.47, p < 0.00001, I2 = 89% and RR 2.05; 95% CI 1.64-2.56, p < 0.00001, I2 = 29%, respectively). Lymphopenia was associated with higher 'late' mortality (RR 1.59; 1.33-1.90, p < 0.00001, I2 = 0%). CONCLUSIONS: This meta-analysis demonstrates the high prevalence of lymphopenia across all-cause hospitalisations and associated increased risk of septic shock, early and late mortality. Lymphopenia is a readily available marker that may identify immune dysfunctional patients. Greater understanding of immune trajectories following survival may provide insights into longer-term poor clinical outcomes.

Environmental metabolomics uncovers oxidative stress, amino acid dysregulation, and energy impairment in Daphnia magna with exposure to industrial effluents.

Anthropogenic activities are regarded as point sources of pollution entering freshwater bodies worldwide. With over 350,000 chemicals used in manufacturing, wastewater treatment and industrial effluents are comprised of complex mixtures of organic and inorganic pollutants of known and unknown origins. Consequently, their combined toxicity and mode of action are not well understood in aquatic organisms such as Daphnia magna. In this study, effluent samples from wastewater treatment and industrial sectors were used to examine molecular-level perturbations to the polar metabolic profile of D. magna. To determine if the industrial sector and/or the effluent chemistries played a role in the observed biochemical responses, Daphnia were acutely (48 h) exposed to undiluted (100%) and diluted (10, 25, and 50%) effluent samples. Endogenous metabolites were extracted from single daphnids and analyzed using targeted mass spectrometry-based metabolomics. The metabolic profile of Daphnia exposed to effluent samples resulted in significant separation compared to the unexposed controls. Linear regression analysis determined that no single pollutant detected in the effluents was significantly correlated with the responses of metabolites. Significant perturbations were uncovered across many classes of metabolites (amino acids, nucleosides, nucleotides, polyamines, and their derivatives) which serve as intermediates in keystone biochemical processes. The combined metabolic responses are consistent with oxidative stress, disruptions to energy metabolism, and protein dysregulation which were identified through biochemical pathway analysis. These results provide insight into the molecular processes driving stress responses in D. magna. Overall, we determined that the metabolic profile of Daphnia could not be predicted by the chemical composition of environmentally relevant mixtures. The findings of this study demonstrate the advantage of metabolomics in conjunction with chemical analyses to assess the interactions of industrial effluents. This work further demonstrates the ability of environmental metabolomics to characterize molecular-level perturbations in aquatic organisms exposed to complex chemical mixtures directly.

Diagnosing ventilator-associated pneumonia (VAP) in UK NHS ICUs: the perceived value and role of a novel optical technology.

BACKGROUND: Diagnosing ventilator-associated pneumonia (VAP) in an intensive care unit (ICU) is a complex process. Our aim was to collect, evaluate and represent the information relating to current clinical practice for the diagnosis of VAP in UK NHS ICUs, and to explore the potential value and role of a novel diagnostic for VAP, which uses optical molecular alveoscopy to visualise the alveolar space. METHODS: Qualitative study performing semi-structured interviews with clinical experts. Interviews were recorded, transcribed, and thematically analysed. A flow diagram of the VAP patient pathway was elicited and validated with the expert interviewees. Fourteen clinicians were interviewed from a range of UK NHS hospitals: 12 ICU consultants, 1 professor of respiratory medicine and 1 professor of critical care. RESULTS: Five themes were identified, relating to [1] current practice for the diagnosis of VAP, [2] current clinical need in VAP diagnostics, [3] the potential value and role of the technology, [4] the barriers to adoption and [5] the evidence requirements for the technology, to help facilitate a successful adoption. These themes indicated that diagnosis of VAP is extremely difficult, as is the decision to stop antibiotic treatment. The analysis revealed that there is a clinical need for a diagnostic that provides an accurate and timely diagnosis of the causative pathogen, without the long delays associated with return of culture results, and which is not dangerous to the patient. It was determined that the technology would satisfy important aspects of this clinical need for diagnosing VAP (and pneumonia, more generally), but would require further evidence on safety and efficacy in the patient population to facilitate adoption. CONCLUSIONS: Care pathway analysis performed in this study was deemed accurate and representative of current practice for diagnosing VAP in a UK ICU as determined by relevant clinical experts, and explored the value and role of a novel diagnostic, which uses optical technology, and could streamline the diagnostic pathway for VAP and other pneumonias.

Undifferentiated febrile illnesses in South Sudan: a case series from Operation TRENTON from June to August 2017.

Undifferentiated febrile illnesses present diagnostic and treatment challenges in the Firm Base, let alone in the deployed austere environment. We report a series of 14 cases from Operation TRENTON in South Sudan in 2017 that coincided with the rainy season, increased insect numbers and a Relief in Place. The majority of patients had headaches, myalgia, arthralgia and back pain, as well as leucopenia and thrombocytopenia. No diagnoses could be made in theatre, despite a sophisticated deployed laboratory being available, and further testing in the UK, including next-generation sequencing, was unable to establish an aetiology. Such illnesses are very likely to present in tropical environments, where increasing numbers of military personnel are being deployed, and clinicians must be aware of the non-specific presentation and treatment, as well as the availability of Military Infection Reachback services to assist in the management of these cases.

Donor monocyte-derived macrophages promote human acute graft-versus-host disease.

Myelopoiesis is invariably present and contributes to pathology in animal models of graft-versus-host disease (GVHD). In humans, a rich inflammatory infiltrate bearing macrophage markers has also been described in histological studies. In order to determine the origin, functional properties, and role in pathogenesis of these cells, we isolated single-cell suspensions from acute cutaneous GVHD and subjected them to genotype, transcriptome, and in vitro functional analysis. A donor-derived population of CD11c+CD14+ cells was the dominant population of all leukocytes in GVHD. Surface phenotype and NanoString gene expression profiling indicated the closest steady-state counterpart of these cells to be monocyte-derived macrophages. In GVHD, however, there was upregulation of monocyte antigens SIRPα and S100A8/9 transcripts associated with leukocyte trafficking, pattern recognition, antigen presentation, and costimulation. Isolated GVHD macrophages stimulated greater proliferation and activation of allogeneic T cells and secreted higher levels of inflammatory cytokines than their steady-state counterparts. In HLA-matched mixed leukocyte reactions, we also observed differentiation of activated macrophages with a similar phenotype. These exhibited cytopathicity to a keratinocyte cell line and mediated pathological damage to skin explants independently of T cells. Together, these results define the origin, functional properties, and potential pathogenic roles of human GVHD macrophages.

Electrodiagnostic applications of somatosensory evoked high-frequency EEG oscillations: Technical considerations.

INTRODUCTION: High frequency oscillations (HFOs) embedded within the somatosensory evoked potential (SEP) are not routinely recorded/measured as part of standard clinical SEPs. However, HFOs could provide important additional diagnostic/prognostic information in various patient groups in whom SEPs are tested routinely. One area is the management of patients with hypoxic ischaemic encephalopathy (HIE) in the intensive care unit (ICU). However, the sensitivity of standard clinical SEP recording techniques for detecting HFOs is unknown. METHODS: SEPs were recorded using routine clinical methods in 17 healthy subjects (median nerve stimulation; 0.5 ms pulse width; 5 Hz; maximum 4000 stimuli) in an unshielded laboratory. Bipolar EEG recordings were acquired (gain 50 k; bandpass 3Hz-2 kHz; sampling rate 5 kHz; non-inverting electrode 2 cm anterior to C3/C4; inverting electrode 2 cm posterior to C3/C4). Data analysis was performed in MATLAB. RESULTS: SEP-HFOs were detected in 65% of controls using standard clinical recording techniques. In 3 controls without significant HFOs, experiments were repeated using a linear electrode array with higher spatial sampling frequency. SEP-HFOs were observed in all 3 subjects. CONCLUSIONS: Currently standard clinical methods of recording SEPs are not sufficiently sensitive to permit the inclusion of SEP-HFOs in routine clinical diagnostic/prognostic assessments. Whilst an increase in the number/density of EEG electrodes should improve the sensitivity for detecting SEP-HFOs, this requires confirmation. By improving and standardising clinical SEP recording protocols to permit the acquisition/analysis of SEP-HFOs, it should be possible to gain important insights into the pathophysiology of neurological disorders and refine the management of conditions such as HIE.

Cost implications for the NHS of using the Alere™ i Influenza A & B near patient test with nasal swabs.

BACKGROUND: Influenza is an acute viral infection of the respiratory tract. A rapid confirmatory diagnosis of influenza is important, since it is highly transmissible and outbreaks of influenza within the hospital setting increase morbidity and mortality. The objective of this study was to evaluate the cost implications, from the perspective of the UK NHS, of using on-label nasal swabs with the Alere™ i Influenza A & B test in a near patient setting. METHODS: A cost consequence model was developed. The time horizon of the model was from hospital admission on suspicion of influenza until the end of treatment (following a diagnosis of influenza or discharge from hospital). Data on the prevalence of influenza and the sensitivity and specificity of the Alere™ i Influenza A & B test came from two prospective observational diagnostic accuracy studies. Costs were obtained from published resources. Uncertainties in the model data were investigated using deterministic, one-way sensitivity analyses. RESULTS: Using the Alere™ i Influenza A & B point of care test with nasal swabs (on label) in NHS medical assessment units and emergency departments could save approximately £242,730 per 1000 adults presenting with influenza-like symptoms. The main cause for this was reduced times to availability of the result compared with the laboratory RT-PCR test. Other key drivers of savings were the cost of isolation, the prevalence of influenza, the specificity of the test, and the availability of isolation resources. CONCLUSIONS: The Alere™ i Influenza A & B point of care test would have greatest impact in hospitals that have extensive delays in the time to receive a result. Sensitivity analyses identified the model parameters which would have greatest effect on the result and confirmed that assumptions were conservative, i.e. did not change key results.

Enhanced case management can be delivered for patients with EVD in Africa: Experience from a UK military Ebola treatment centre in Sierra Leone.

BACKGROUND: Limited data exist describing supportive care management, laboratory abnormalities and outcomes in patients with Ebola virus disease (EVD) in West Africa. We report data which constitute the first description of the provision of enhanced EVD case management protocols in a West African setting. METHODS: Demographic, clinical and laboratory data were collected by retrospective review of clinical and laboratory records of patients with confirmed EVD admitted between 5 November 2014 and 30 June 2015. RESULTS: A total of 44 EVD patients were admitted (median age 37 years (range 17-63), 32/44 healthcare workers), and excluding those evacuated, the case fatality rate was 49% (95% CI 33%-65%). No pregnant women were admitted. At admission 9/44 had stage 1 disease (fever and constitutional symptoms only), 12/44 had stage 2 disease (presence of diarrhoea and/or vomiting) and 23/44 had stage 3 disease (presence of diarrhoea and/or vomiting with organ failure), with case fatality rates of 11% (95% CI 1%-58%), 27% (95% CI 6%-61%), and 70% (95% CI 47%-87%) respectively (p = 0.009). Haemorrhage occurred in 17/41 (41%) patients. The majority (21/40) of patients had hypokalaemia with hyperkalaemia occurring in 12/40 patients. Acute kidney injury (AKI) occurred in 20/40 patients, with 14/20 (70%, 95% CI 46%-88%) dying, compared to 5/20 (25%, 95% CI 9%-49%) dying who did not have AKI (p = 0.01). Ebola virus (EBOV) PCR cycle threshold value at baseline was mean 20.3 (SD 4.3) in fatal cases and 24.8 (SD 5.5) in survivors (p = 0.007). Mean national early warning score (NEWS) at admission was 5.5 (SD 4.4) in fatal cases and 3.0 (SD 1.9) in survivors (p = 0.02). Central venous catheters were placed in 37/41 patients and intravenous fluid administered to 40/41 patients (median duration of 5 days). Faecal management systems were inserted in 21/41 patients, urinary catheters placed in 27/41 and blood component therapy administered to 20/41 patients. CONCLUSIONS: EVD is commonly associated life-threatening electrolyte imbalance and organ dysfunction. We believe that the enhanced levels of protocolized care, scale and range of medical interventions we report, offer a blueprint for the future management of EVD in resource-limited settings.

Towards single egg toxicity screening using microcoil NMR.

Planar microcoils with diameter ranging from 20 to 1000 µm I.D. (130-1130 µm O.D.) are evaluated for their applications in NMR spectroscopy. The coils are first overfilled with a standard sucrose solution and compared against each other. Coils with smaller I.D. (≤100 µm) perform extremely well. One hypothesis is that as the coils get smaller the volume occupied by the copper turns increases relative to the open I.D.; as such a large proportion of the sample is brought in close proximity to the coil turns and likely gives rise to strong sample-coil magnetic coupling, which increases the signal. The applications of the planar microcoils are demonstrated on Cypselurus poecilopterus (fish) and Daphnia magna (water flea) eggs. A single D. magna egg on a 50 µm coil yielded at least 3000 times the mass sensitivity (∼9,000,000 time saving) when compared to a 5 mm probe. This value could be at least 4 times higher if the B1 homogeneity of the coils could be improved. With the current design, 80% of the signal is lost in multiple pulse experiments that rely on phase inversion and signal cancellation between scans. The data were extrapolated to predict that biological samples as small as ∼4 µm may become accessible via planar microcoil designs. To fulfill their potential for in situ metabolic screening, specialized magnetic susceptibility matched sample holders that restrict the sample to the homogeneous B1 field region (i.e. within the 90% RF field) of the coil and advanced experiments that narrow spectral lines, suppress lipids and disperse signals into multiple dimensions will be required.

Early clinical experiences with nintedanib in three UK tertiary interstitial lung disease centres.

BACKGROUND: Nintedanib has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). It was approved by the National Institute for Health and Care Excellence (NICE) in January 2016 for IPF patients with a forced vital capacity (FVC) of 50-80% in the United Kingdom (UK). AIM: To report real world data about our early clinical experience using nintedanib in 187 patients with a multi-disciplinary (MDT) diagnosis of IPF in a manufacturer funded patient in need scheme (three UK centres) prior to NICE approval. METHODS: All patients with a MDT diagnosis of IPF from December 2014 to January 2016 commenced on nintedanib were included. Demographic details, adverse events (AEs) and where available lung function results were retrospectively collected from clinical letters. RESULTS: 187 patients (76% males) with a median age of 72 years (49-89) were treated with nintedanib. The average pre-treatment FVC was 81.1 ± 19.8% and diffusion capacity of the lungs for carbon monoxide was 43.9 ± 15% (n = 82). Fifty percent of patients started nintedanib because they were ineligible for pirfenidone due to an FVC > 80%. The median treatment course was 8 ± 4 months. The majority of patients experienced 1-3 AEs with nintedanib (52%, n = 97). The most frequent AEs were diarrhoea (50%), nausea (36%), reduced appetite (24%), tiredness (20%) and gastro-oesophageal reflux (18%). The majority of AEs resulted in no change in treatment (64%, n = 461). 21% (n = 150) of AEs resulted in a dose reduction and 13% (n = 94) necessitated discontinuation of treatment. 1 in 5 patients discontinued treatment either temporarily or on a permanent basis during the monitoring period. In a select cohort of patients, a statistically significant greater proportion of patients remained stable or improved and a lower proportion declined, as depicted by FVC changes of > 5% after nintedanib commencement (P < 0.05 using Chi squared test). CONCLUSIONS: Nintedanib is well tolerated and has an acceptable safety profile. Only 8% of those reporting diarrhoea discontinued treatment either on a temporary or permanent basis. There were no signals with respect to increased cardiovascular morbidity or major bleeding risk. This is in keeping with the INPULSIS clinical trial findings but in a real world cohort.

Diagnostic accuracy and cost analysis of the Alere™ i Influenza A&B near-patient test using throat swabs.

BACKGROUND: Clinical diagnostic sensitivity alone is inadequate in the diagnosis of influenza. Polymerase chain reaction (PCR) testing is sensitive but the inherent delays in result availability potentially prolong time to isolation and treatment. Until recently no near-patient test (NPT) has demonstrated adequate sensitivity for routine clinical use. AIM: To evaluate diagnostic accuracy, time to result availability, clinical impact, and cost consequences of Alere™ i Influenza A&B NPT (Alere Inc., Waltham, MA, USA) using off-label throat swabs. METHODS: Prospective, multi-centre [four UK National Health Service (NHS) hospitals], diagnostic accuracy cohort study with cost modelling. Throat swab samples from suspected influenza patients were tested for influenza using the reference standard of PCR; a second throat swab was tested using NPT. FINDINGS: A total of 827 participants were recruited; 589 were suitable for analysis: sensitivity was 75.8% [95% confidence interval (CI): 67.0-84.6]; specificity was 96.8% (95% CI: 95.2-98.3). Sensitivity varied between Sheffield (Northern General Hospital: 82.1%; Royal Hallamshire Hospital: 83.3%) and other sites (Doncaster Royal Infirmary: 71.4%; Newcastle's Royal Victoria Infirmary: 50.0%) whereas specificity was high (92-100%). Positive predictive value (PPV) was 81.2% (95% CI: 72.9-89.5) with negative predictive value 95.6% (95% CI: 93.9-97.4) with observed prevalence of 15.4%. Median time to result for PCR was 1.1 days (on-site laboratories) and 5.2 days (remote laboratories). Isolation findings: 75% influenza positive not isolated; 69% of isolated participants did not have influenza. For a cohort of 1000 participants, annual estimated non-diagnostic cost savings with NPT are £215,040. CONCLUSION: This first prospective study of the Alere i NPT using throat swabs demonstrates high specificity, high PPV during seasonal epidemics, and rapid result availability which could lead to substantial cost savings.

Exercise-induced dehydration alters pulmonary function but does not modify airway responsiveness to dry air in athletes with mild asthma.

Local airway water loss is the main physiological trigger for exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effects of whole body water loss on airway responsiveness and pulmonary function in athletes with mild asthma and/or EIB. Ten recreational athletes with a medical diagnosis of mild asthma and/or EIB completed a randomized, crossover study. Pulmonary function tests, including spirometry, whole body plethysmography, and diffusing capacity of the lung for carbon monoxide (DlCO), were conducted before and after three conditions: 1) 2 h of exercise in the heat with no fluid intake (dehydration), 2) 2 h of exercise with ad libitum fluid intake (control), and 3) a time-matched rest period (rest). Airway responsiveness was assessed 2 h postexercise/rest via eucapnic voluntary hyperpnea (EVH) to dry air. Exercise in the heat with no fluid intake induced a state of mild dehydration, with a body mass loss of 2.3 ± 0.8% (SD). After EVH, airway narrowing was not different between conditions: median (interquartile range) maximum fall in forced expiratory volume in 1 s was 13 (7-15)%, 11 (9-24)%, and 12 (7-20)% in dehydration, control, and rest conditions, respectively. Dehydration caused a significant reduction in forced vital capacity (300 ± 190 ml, P = 0.001) and concomitant increases in residual volume (260 ± 180 ml, P = 0.001) and functional residual capacity (260 ± 250 ml, P = 0.011), with no change in DlCO Mild exercise-induced dehydration does not exaggerate airway responsiveness to dry air in athletes with mild asthma/EIB but may affect small airway function.NEW & NOTEWORTHY This study is the first to investigate the effect of whole body dehydration on airway responsiveness. Our data suggest that the airway response to dry air hyperpnea in athletes with mild asthma and/or exercise-induced bronchoconstriction is not exacerbated in a state of mild dehydration. On the basis of alterations in lung volumes, however, exercise-induced dehydration appears to compromise small airway function.

The PEARL score predicts 90-day readmission or death after hospitalisation for acute exacerbation of COPD.

BACKGROUND: One in three patients hospitalised due to acute exacerbation of COPD (AECOPD) is readmitted within 90 days. No tool has been developed specifically in this population to predict readmission or death. Clinicians are unable to identify patients at particular risk, yet resources to prevent readmission are allocated based on clinical judgement. METHODS: In participating hospitals, consecutive admissions of patients with AECOPD were identified by screening wards and reviewing coding records. A tool to predict 90-day readmission or death without readmission was developed in two hospitals (the derivation cohort) and validated in: (a) the same hospitals at a later timeframe (internal validation cohort) and (b) four further UK hospitals (external validation cohort). Performance was compared with ADO, BODEX, CODEX, DOSE and LACE scores. RESULTS: Of 2417 patients, 936 were readmitted or died within 90 days of discharge. The five independent variables in the final model were: Previous admissions, eMRCD score, Age, Right-sided heart failure and Left-sided heart failure (PEARL). The PEARL score was consistently discriminative and accurate with a c-statistic of 0.73, 0.68 and 0.70 in the derivation, internal validation and external validation cohorts. Higher PEARL scores were associated with a shorter time to readmission. CONCLUSIONS: The PEARL score is a simple tool that can effectively stratify patients' risk of 90-day readmission or death, which could help guide readmission avoidance strategies within the clinical and research setting. It is superior to other scores that have been used in this population. TRIAL REGISTRATION NUMBER: UKCRN ID 14214.

Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS.

RATIONALE: Platelets play an active role in the pathogenesis of acute respiratory distress syndrome (ARDS). Animal and observational studies have shown aspirin's antiplatelet and immunomodulatory effects may be beneficial in ARDS. OBJECTIVE: To test the hypothesis that aspirin reduces inflammation in clinically relevant human models that recapitulate pathophysiological mechanisms implicated in the development of ARDS. METHODS: Healthy volunteers were randomised to receive placebo or aspirin 75  or 1200 mg (1:1:1) for seven days prior to lipopolysaccharide (LPS) inhalation, in a double-blind, placebo-controlled, allocation-concealed study. Bronchoalveolar lavage (BAL) was performed 6 hours after inhaling 50 µg of LPS. The primary outcome measure was BAL IL-8. Secondary outcome measures included markers of alveolar inflammation (BAL neutrophils, cytokines, neutrophil proteases), alveolar epithelial cell injury, systemic inflammation (neutrophils and plasma C-reactive protein (CRP)) and platelet activation (thromboxane B2, TXB2). Human lungs, perfused and ventilated ex vivo (EVLP) were randomised to placebo or 24 mg aspirin and injured with LPS. BAL was carried out 4 hours later. Inflammation was assessed by BAL differential cell counts and histological changes. RESULTS: In the healthy volunteer (n=33) model, data for the aspirin groups were combined. Aspirin did not reduce BAL IL-8. However, aspirin reduced pulmonary neutrophilia and tissue damaging neutrophil proteases (Matrix Metalloproteinase (MMP)-8/-9), reduced BAL concentrations of tumour necrosis factor α and reduced systemic and pulmonary TXB2. There was no difference between high-dose and low-dose aspirin. In the EVLP model, aspirin reduced BAL neutrophilia and alveolar injury as measured by histological damage. CONCLUSIONS: These are the first prospective human data indicating that aspirin inhibits pulmonary neutrophilic inflammation, at both low and high doses. Further clinical studies are indicated to assess the role of aspirin in the prevention and treatment of ARDS. TRIAL REGISTRATION NUMBER: NCT01659307 Results.

Low-pathogenicity Mycoplasma spp. alter human monocyte and macrophage function and are highly prevalent among patients with ventilator-acquired pneumonia.

BACKGROUND: Ventilator-acquired pneumonia (VAP) remains a significant problem within intensive care units (ICUs). There is a growing recognition of the impact of critical-illness-induced immunoparesis on the pathogenesis of VAP, but the mechanisms remain incompletely understood. We hypothesised that, because of limitations in their routine detection, Mycoplasmataceae are more prevalent among patients with VAP than previously recognised, and that these organisms potentially impair immune cell function. METHODS AND SETTING: 159 patients were recruited from 12 UK ICUs. All patients had suspected VAP and underwent bronchoscopy and bronchoalveolar lavage (BAL). VAP was defined as growth of organisms at >10(4) colony forming units per ml of BAL fluid on conventional culture. Samples were tested for Mycoplasmataceae (Mycoplasma and Ureaplasma spp.) by PCR, and positive samples underwent sequencing for speciation. 36 healthy donors underwent BAL for comparison. Additionally, healthy donor monocytes and macrophages were exposed to Mycoplasma salivarium and their ability to respond to lipopolysaccharide and undertake phagocytosis was assessed. RESULTS: Mycoplasmataceae were found in 49% (95% CI 33% to 65%) of patients with VAP, compared with 14% (95% CI 9% to 25%) of patients without VAP. Patients with sterile BAL fluid had a similar prevalence to healthy donor BAL fluid (10% (95% CI 4% to 20%) vs 8% (95% CI 2% to 22%)). The most common organism identified was M. salivarium. Blood monocytes from healthy volunteers incubated with M. salivarium displayed an impaired TNF-α response to lipopolysaccharide (p=0.0003), as did monocyte-derived macrophages (MDMs) (p=0.024). MDM exposed to M. salivarium demonstrated impaired phagocytosis (p=0.005). DISCUSSION AND CONCLUSIONS: This study demonstrates a high prevalence of Mycoplasmataceae among patients with VAP, with a markedly lower prevalence among patients with suspected VAP in whom subsequent cultures refuted the diagnosis. The most common organism found, M. salivarium, is able to alter the functions of key immune cells. Mycoplasmataceae may contribute to VAP pathogenesis.

A standard, single dose of inhaled terbutaline attenuates hyperpnea-induced bronchoconstriction and mast cell activation in athletes.

Release of bronchoactive mediators from mast cells during exercise hyperpnea is a key factor in the pathophysiology of exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effect of a standard, single dose of an inhaled ß2-adrenoceptor agonist on mast cell activation in response to dry air hyperpnea in athletes with EIB. Twenty-seven athletes with EIB completed a randomized, double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was inhaled 15 min prior to 8 min of eucapnic voluntary hyperpnea (EVH) with dry air. Pre- and postbronchial challenge, urine samples were analyzed by enzyme immunoassay for 11ß-prostaglandin F2α (11ß-PGF2α). The maximum fall in forced expiratory volume in 1 s of 14 (12-20)% (median and interquartile range) following placebo was attenuated to 7 (5-9)% with the administration of terbutaline (P < 0.001). EVH caused a significant increase in 11ß-PGF2α from 41 (27-57) ng/mmol creatinine at baseline to 58 (43-72) ng/mmol creatinine at its peak post-EVH following placebo (P = 0.002). The rise in 11ß-PGF2α was inhibited with administration of terbutaline: 39 (28-44) ng/mmol creatinine at baseline vs. 40 (33-58) ng/mmol creatinine at its peak post-EVH (P = 0.118). These data provide novel in vivo evidence of mast cell stabilization following inhalation of a standard dose of terbutaline prior to bronchial provocation with EVH in athletes with EIB.

Validation of the DECAF score to predict hospital mortality in acute exacerbations of COPD.

BACKGROUND: Hospitalisation due to acute exacerbations of COPD (AECOPD) is common, and subsequent mortality high. The DECAF score was derived for accurate prediction of mortality and risk stratification to inform patient care. We aimed to validate the DECAF score, internally and externally, and to compare its performance to other predictive tools. METHODS: The study took place in the two hospitals within the derivation study (internal validation) and in four additional hospitals (external validation) between January 2012 and May 2014. Consecutive admissions were identified by screening admissions and searching coding records. Admission clinical data, including DECAF indices, and mortality were recorded. The prognostic value of DECAF and other scores were assessed by the area under the receiver operator characteristic (AUROC) curve. RESULTS: In the internal and external validation cohorts, 880 and 845 patients were recruited. Mean age was 73.1 (SD 10.3) years, 54.3% were female, and mean (SD) FEV1 45.5 (18.3) per cent predicted. Overall mortality was 7.7%. The DECAF AUROC curve for inhospital mortality was 0.83 (95% CI 0.78 to 0.87) in the internal cohort and 0.82 (95% CI 0.77 to 0.87) in the external cohort, and was superior to other prognostic scores for inhospital or 30-day mortality. CONCLUSIONS: DECAF is a robust predictor of mortality, using indices routinely available on admission. Its generalisability is supported by consistent strong performance; it can identify low-risk patients (DECAF 0-1) potentially suitable for Hospital at Home or early supported discharge services, and high-risk patients (DECAF 3-6) for escalation planning or appropriate early palliation. TRIAL REGISTRATION NUMBER: UKCRN ID 14214.

Sleep-disordered breathing and idiopathic pulmonary fibrosis--is there an association?

BACKGROUND: Very little data exists on the prevalence and impact of sleep-disordered breathing (SDB) in patients with idiopathic pulmonary fibrosis (IPF). The aim of this study was to examine the impact of SDB on newly diagnosed IPF patients and explore associations with lung function parameters. METHODS: From 2005 to 2009, a cohort of 27 newly diagnosed patients with IPF underwent unattended polygraphy. All patients were diagnosed according to ATS 2000 diagnostic criteria and were not on supplemental oxygen or other treatment. Standard statistical analysis was undertaken using SPSS v. 19 (IBM). RESULTS: Of the 27 patients, 19 were men. There was no correlation at baseline of apnoea + hypopnoea per time in bed (AH), oxygen desaturation index, or 4% desaturations with any lung function variables, age, or body mass index. Six patients had significant SDB (AH >20). Two patients were started on CPAP following polygraphy. No variables from the original sleep studies at baseline predicted eventual long-term oxygen therapy (LTOT) use. At 5-year follow-up, 18 of 27 patients had died (67%). Cox regression analysis showed no association of time spent at SpO2 <90% on baseline polygraphy with survival (p = 0.39). There was no association with survival for AH >20 (p = 0.4) or LTOT use (p = 0.19). CONCLUSION: Our results do not support the contention that nocturnal upper airway obstruction in steroid-free patients with IPF is a common problem or correlated with lung function. In this cohort of patients, there was no evidence that significant SDB at baseline was a predictor of survival.

Evaluation of a point-of-care blood test for identification of Ebola virus disease at Ebola holding units, Western Area, Sierra Leone, January to February 2015.

Current Ebola virus disease (EVD) diagnosis relies on reverse transcription-PCR (RT-PCR) technology, requiring skilled laboratory personnel and technical infrastructure. Lack of laboratory diagnostic capacity has led to diagnostic delays in the current West African EVD outbreak of 2014 and 2015, compromising outbreak control. We evaluated the diagnostic accuracy of the EVD bedside rapid diagnostic antigen test (RDT) developed by the United Kingdom's Defence Science and Technology Laboratory, compared with Ebola virus RT-PCR, in an operational setting for EVD diagnosis of suspected cases admitted to Ebola holding units in the Western Area of Sierra Leone. From 22 January to 16 February 2015, 138 participants were enrolled. EVD prevalence was 11.5%. All EVD cases were identified by a positive RDT with a test line score of 6 or more, giving a sensitivity of 100% (95% confidence interval (CI): 78.2-100). The corresponding specificity was high (96.6%, 95% CI: 91.3-99.1). The positive and negative predictive values for the population prevalence were 79.0% (95% CI: 54.4-93.8) and 100% (95% CI: 96.7-100), respectively. These results, if confirmed in a larger study, suggest that this RDT could be used as a 'rule-out' screening test for EVD to improve rapid case identification and resource allocation.

Refractory dissolved organic nitrogen accumulation in high-elevation lakes.

The role of dissolved organic matter (DOM) as either a sink for inorganic nutrients or an additional nutrient source is an often-neglected component of nutrient budgets in aquatic environments. Here, we examined the role of DOM in reactive nitrogen (N) storage in Sierra Nevada (California, USA) lakes where atmospheric deposition of N has shifted the lakes toward seasonal phosphorus (P)-limitation. Nuclear magnetic resonance (NMR) spectroscopy and isotope analyses performed on DOM isolated from Lake Tahoe reveal the accumulation of refractory proteinaceous material with a 100-200-year residence time. In contrast, smaller lakes in the same watershed contain DOM with typical terrestrial characteristics, indicating that proteins in Lake Tahoe are autochthonously produced. These data support the role of DOM as a possible sink for reactive N in these lake ecosystems and identify a potential role for DOM in affecting the inorganic nutrient stoichiometry of these environments.