Effect of portable noninvasive ventilation on thoracoabdominal volumes in recovery from intermittent exercise in patients with COPD.

We previously showed that use of portable noninvasive ventilation (pNIV) during recovery periods within intermittent exercise improved breathlessness and exercise tolerance in patients with COPD compared with pursed-lip breathing (PLB). However, in a minority of patients recovery from dynamic hyperinflation (DH) was better with PLB, based on inspiratory capacity. We further explored this using Optoelectronic Plethysmography to assess total and compartmental thoracoabdominal volumes. Fourteen patients with COPD (means ± SD) (FEV1: 55% ± 22% predicted) underwent, in a balanced order sequence, two intermittent exercise protocols on the cycle ergometer consisting of five repeated 2-min exercise bouts at 80% peak capacity, separated by 2-min recovery periods, with application of pNIV or PLB in the 5 min of recovery. Our findings identified seven patients showing recovery in DH with pNIV (DH responders) whereas seven showed similar or better recovery in DH with PLB. When pNIV was applied, DH responders compared with DH nonresponders exhibited greater tidal volume (by 0.8 ± 0.3 L, P = 0.015), inspiratory flow rate (by 0.6 ± 0.5 L/s, P = 0.049), prolonged expiratory time (by 0.6 ± 0.5 s, P = 0.006), and duty cycle (by 0.7 ± 0.6 s, P = 0.007). DH responders showed a reduction in end-expiratory thoracoabdominal DH (by 265 ± 633 mL) predominantly driven by reduction in the abdominal compartment (by 210 ± 494 mL); this effectively offset end-inspiratory rib-cage DH. Compared with DH nonresponders, DH responders had significantly greater body mass index (BMI) by 8.4 ± 3.2 kg/m2, P = 0.022 and tended toward less severe resting hyperinflation by 0.3 ± 0.3 L. Patients with COPD who mitigate end-expiratory rib-cage DH by expiratory abdominal muscle recruitment benefit from pNIV application.NEW & NOTEWORTHY Compared with the pursed-lip breathing technique, acute application of portable noninvasive ventilation during recovery from intermittent exercise improved end-expiratory thoracoabdominal dynamic hyperinflation (DH) in 50% of patients with COPD (DH responders). DH responders, compared with DH nonresponders, exhibited a reduction in end-expiratory thoracoabdominal DH predominantly driven by the abdominal compartment that effectively offset end-expiratory rib cage DH. The essential difference between DH responders and DH nonresponders was, therefore, in the behavior of the abdomen.

Cost-Effectiveness of Dementia Prevention Interventions.

BACKGROUND: Assessment of cost-effectiveness of interventions to address modifiable risk factors associated with dementia requires estimates of long-term impacts of these interventions which are rarely directly available and must be estimated using a range of assumptions. OBJECTIVES: To test the cost-effectiveness of dementia prevention measures using a methodology which transparently addresses the many assumptions required to use data from short-term studies, and which readily incorporates sensitivity analyses. DESIGN: We explore an approach to estimating cost-effective prices which uses aggregate data including estimated lifetime costs of dementia, both financial and quality of life, and incorporates a range of assumptions regarding sustainability of short- term gains and other parameters. SETTING: The approach is addressed in the context of the theoretical reduction in a range of risk factors, and in the context of a specific small-scale trial of an internet-based intervention augmented with diet and physical activity consultations. MEASUREMENTS: The principal outcomes were prices per unit of interventions at which interventions were cost-effective or cost-saving. RESULTS: Taking a societal perspective, a notional intervention reducing a range of dementia risk-factors by 5% was cost-effective at $A460 per person with higher risk groups at $2,148 per person. The on-line program costing $825 per person was cost-effective at $1,850 per person even if program effect diminished by 75% over time. CONCLUSIONS: Interventions to address risk factors for dementia are likely to be cost-effective if appropriately designed, but confirmation of this conclusion requires longer term follow-up of trials to measure the impact and sustainability of short-term gains.

Coding of COPD Exacerbations and the Implications on Clinical Practice, Audit and Research.

International Classification of Disease 10 (ICD-10) codes record hospital admissions. We aimed to measure the accuracy of COPD exacerbation (ECOPD) codes and examine coding practices for COPD exacerbation.Prospective screening and ICD-10 codes were used to identify potential ECOPD within the DECAF internal validation cohort. Two coding searches were performed. The first search identified patients with an ECOPD discharge code, and a second, broad search was developed to identify all clinically confirmed ECOPD.717 of 1,122 (64%) patients with an ECOPD code had confirmed ECOPD. Common reasons for misclassification in the 405 patients who did not have an ECOPD included: lack of obstructive spirometry to diagnose COPD; and hospital admission due to progressive malignancy, asthma or cardiovascular disease. The broad search identified an additional 297 patients with ECOPD missed by the ECOPD codes. The vast majority of this group had pneumonia complicating ECOPD.ECOPD codes are insufficiently reliable to identify patients with clinically confirmed ECOPD for the purposes of audit or research. Search strategies should include pneumonia codes, specialist review of medical notes and spirometry confirmation of COPD.

Author Correction: Superluminal motion of a relativistic jet in the neutron-star merger GW170817.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

An evaluation of methods for the isolation of nontuberculous mycobacteria from patients with cystic fibrosis, bronchiectasis and patients assessed for lung transplantation.

BACKGROUND: RGM medium is an agar-based, selective culture medium designed for the isolation of nontuberculous mycobacteria (NTM) from the sputum of patients with cystic fibrosis (CF). We evaluated RGM medium for the detection of NTM in patients with CF (405 samples), bronchiectasis (323 samples) and other lung diseases necessitating lung transplantation (274 samples). METHODS: In total, 1002 respiratory samples from 676 patients were included in the study. Direct culture on RGM medium, with incubation at two temperatures (30 °C and 37 °C), was compared with conventional culture of decontaminated samples for acid-fast bacilli (AFB) using both a solid medium (Löwenstein-Jensen medium) and a liquid medium (the Mycobacterial Growth Indicator Tube; MGIT). RESULTS: For all three patient groups, significantly more isolates of NTM were recovered using RGM medium incubated at 30 °C than by any other method (sensitivity: 94.6% vs. 22.4% for conventional AFB culture; P < 0.0001). Significantly more isolates of Mycobacterium abscessus complex were isolated on RGM at 30 °C than by AFB culture (sensitivity: 96.1% vs. 58.8%; P < 0.0001). The recovery of Mycobacterium avium complex was also greater using RGM medium at 30 °C compared to AFB culture (sensitivity: 83% vs. 70.2%), although this difference was not statistically significant and a combination of methods was necessary for optimal recovery (P = 0.21). CONCLUSIONS: In the largest study of RGM medium to date, we reaffirm its utility for isolation of NTM from patients with CF. Furthermore; we show that it also provides an effective tool for culture of respiratory samples from patients with bronchiectasis and other lung diseases.

Superluminal motion of a relativistic jet in the neutron-star merger GW170817.

The binary neutron-star merger GW1708171 was accompanied by radiation across the electromagnetic spectrum2 and localized2 to the galaxy NGC 4993 at a distance3 of about 41 megaparsecs from Earth. The radio and X-ray afterglows of GW170817 exhibited delayed onset4-7, a gradual increase8 in the emission with time (proportional to t0.8) to a peak about 150 days after the merger event9, followed by a relatively rapid decline9,10. So far, various models have been proposed to explain the afterglow emission, including a choked-jet cocoon4,8,11-13 and a successful-jet cocoon4,8,11-18 (also called a structured jet). However, the observational data have remained inconclusive10,15,19,20 as to whether GW170817 launched a successful relativistic jet. Here we report radio observations using very long-baseline interferometry. We find that the compact radio source associated with GW170817 exhibits superluminal apparent motion between 75 days and 230 days after the merger event. This measurement breaks the degeneracy between the choked- and successful-jet cocoon models and indicates that, although the early-time radio emission was powered by a wide-angle outflow8 (a cocoon), the late-time emission was most probably dominated by an energetic and narrowly collimated jet (with an opening angle of less than five degrees) and observed from a viewing angle of about 20 degrees. The imaging of a collimated relativistic outflow emerging from GW170817 adds substantial weight to the evidence linking binary neutron-star mergers and short γ-ray bursts.

Magnetic conjugated polymer nanoparticles doped with a europium complex for biomedical imaging.

Self-assembling conjugated polymer nanoparticles containing PVK and PLGA-PEG as a matrix polymer were doped with both a luminescent rare-earth complex and magnetic nanoparticles (SPIONs), giving rise to materials that are both luminescent and magnetic. Nanoparticle sizes ranged from 80-110 nm without SPIONs and showed an increase in size (200-1000 nm) with additional SPION content (11-54%). Quantum yields (QYs) of 24% and 18% were measured for systems without and with 11% SPIONs, respectively. Optical properties were stable and suitable for biological imaging applications.

A mildly relativistic wide-angle outflow in the neutron-star merger event GW170817.

GW170817 was the first gravitational-wave detection of a binary neutron-star merger. It was accompanied by radiation across the electromagnetic spectrum and localized to the galaxy NGC 4993 at a distance of 40 megaparsecs. It has been proposed that the observed γ-ray, X-ray and radio emission is due to an ultra-relativistic jet being launched during the merger (and successfully breaking out of the surrounding material), directed away from our line of sight (off-axis). The presence of such a jet is predicted from models that posit neutron-star mergers as the drivers of short hard-γ-ray bursts. Here we report that the radio light curve of GW170817 has no direct signature of the afterglow of an off-axis jet. Although we cannot completely rule out the existence of a jet directed away from the line of sight, the observed γ-ray emission could not have originated from such a jet. Instead, the radio data require the existence of a mildly relativistic wide-angle outflow moving towards us. This outflow could be the high-velocity tail of the neutron-rich material that was ejected dynamically during the merger, or a cocoon of material that breaks out when a jet launched during the merger transfers its energy to the dynamical ejecta. Because the cocoon model explains the radio light curve of GW170817, as well as the γ-ray and X-ray emission (and possibly also the ultraviolet and optical emission), it is the model that is most consistent with the observational data. Cocoons may be a ubiquitous phenomenon produced in neutron-star mergers, giving rise to a hitherto unidentified population of radio, ultraviolet, X-ray and γ-ray transients in the local Universe.

Nontuberculous mycobacteria in gastrostomy fed patients with cystic fibrosis.

Multi-drug resistant Mycobacterium abscessus complex (MABSC) is a form of Nontuberculous mycobacteria (NTM) of special, international concern in Cystic Fibrosis (CF). We hypothesised that gastric juice and percutaneous endoscopic gastrostomy (PEG) feeding devices might yield MABSC isolates. Gastric juice and sputa from sixteen adult PEG fed CF patients and five replaced PEG tubes were studied. Bacterial and fungal isolates were cultured. Mycobacterium were identified by rpoB, sodA and hsp65 gene sequencing and strain typed using variable number tandem repeat. Bacteria and/or fungi grew from all gastric juice, sputa and PEG samples. MABSC were detected in 7 patients. Five had MABSC in their sputum. Two had an identical MABSC strain in their sputum and gastric juice and one had the same strain isolated from their PEG tube and sputum. Two patients who were sputum sample negative had MABSC isolated in their gastric juice or PEG tube. MABSC were therefore identified for the first time from a gastric sample in a minority of patients. We conclude that gastric juice and PEG-tubes may be a potential source of MABSC isolates in CF patients, and these findings warrant further study.

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.

Red-emitting protein-coated conjugated polymer nanoparticles.

Red emitting materials are desirable in biology due to the transparency of certain biological tissues at these wavelengths. Here, we report the synthesis of aqueous dispersions of amphiphilic protein (hydrophobin) capped red-emitting cyano-substituted poly(p-phenylenevinylene) conjugated polymer nanoparticles (CPNs) and their use in labeling live mammalian (HeLa) cells.

Microbiological profiles of sputum and gastric juice aspirates in Cystic Fibrosis patients.

Gastro-Oesophageal Reflux (GOR) is a key problem in Cystic Fibrosis (CF), but the relationship between lung and gastric microbiomes is not well understood. We hypothesised that CF gastric and lung microbiomes are related. Gastric and sputum cultures were obtained from fifteen CF patients receiving percutaneous endoscopic gastrostomy feeding. Non-CF gastric juice data was obtained through endoscopy from 14 patients without lung disease. Bacterial and fungal isolates were identified by culture. Molecular bacterial profiling used next generation sequencing (NGS) of the 16S rRNA gene. Cultures grew bacteria and/or fungi in all CF gastric juice and sputa and in 9/14 non-CF gastric juices. Pseudomonas aeruginosa(Pa) was present in CF sputum in 11 patients, 4 had identical Pa strains in the stomach. NGS data from non-CF gastric juice samples were significantly more diverse compared to CF samples. NGS showed CF gastric juice had markedly lower abundance of normal gut bacteria; Bacteroides and Faecalibacterium, but increased Pseudomonas compared with non-CF. Multivariate partial least squares discriminant analysis demonstrated similar bacterial profiles of CF sputum and gastric juice samples, which were distinct from non-CF gastric juice. We provide novel evidence suggesting the existence of an aerodigestive microbiome in CF, which may have clinical relevance.

A review of a pleural service.

This paper reviews the organisation and outcomes of a pleural service, specifically geared towards the management of malignant pleural effusions, in a district general hospital in the north east of England. We summarise the evidence behind local anaesthetic thoracoscopy and indwelling pleural catheters. We then summarise the review of our service, including a discussion around complications.

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.

Evidence against solar influence on nuclear decay constants.

The hypothesis that proximity to the Sun causes variation of decay constants at permille level has been tested and disproved. Repeated activity measurements of mono-radionuclide sources were performed over periods from 200 days up to four decades at 14 laboratories across the globe. Residuals from the exponential nuclear decay curves were inspected for annual oscillations. Systematic deviations from a purely exponential decay curve differ from one data set to another and are attributable to instabilities in the instrumentation and measurement conditions. The most stable activity measurements of alpha, beta-minus, electron capture, and beta-plus decaying sources set an upper limit of 0.0006% to 0.008% to the amplitude of annual oscillations in the decay rate. Oscillations in phase with Earth's orbital distance to the Sun could not be observed within a 10-6 to 10-5 range of precision. There are also no apparent modulations over periods of weeks or months. Consequently, there is no indication of a natural impediment against sub-permille accuracy in half-life determinations, renormalisation of activity to a distant reference date, application of nuclear dating for archaeology, geo- and cosmochronology, nor in establishing the SI unit becquerel and seeking international equivalence of activity standards.

Magnetospherically driven optical and radio aurorae at the end of the stellar main sequence.

Aurorae are detected from all the magnetized planets in our Solar System, including Earth. They are powered by magnetospheric current systems that lead to the precipitation of energetic electrons into the high-latitude regions of the upper atmosphere. In the case of the gas-giant planets, these aurorae include highly polarized radio emission at kilohertz and megahertz frequencies produced by the precipitating electrons, as well as continuum and line emission in the infrared, optical, ultraviolet and X-ray parts of the spectrum, associated with the collisional excitation and heating of the hydrogen-dominated atmosphere. Here we report simultaneous radio and optical spectroscopic observations of an object at the end of the stellar main sequence, located right at the boundary between stars and brown dwarfs, from which we have detected radio and optical auroral emissions both powered by magnetospheric currents. Whereas the magnetic activity of stars like our Sun is powered by processes that occur in their lower atmospheres, these aurorae are powered by processes originating much further out in the magnetosphere of the dwarf star that couple energy into the lower atmosphere. The dissipated power is at least four orders of magnitude larger than what is produced in the Jovian magnetosphere, revealing aurorae to be a potentially ubiquitous signature of large-scale magnetospheres that can scale to luminosities far greater than those observed in our Solar System. These magnetospheric current systems may also play a part in powering some of the weather phenomena reported on brown dwarfs.

Lack of association between KIR and HLA-C type and susceptibility to idiopathic bronchiectasis.

INTRODUCTION: Idiopathic bronchiectasis is a poorly defined disease characterised by persistent inflammation, infection and progressive lung damage. Natural killer (NK) cells provide a major defense against infection, through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin-like receptors (KIR), and human leukocyte antigens (HLA) class I molecules. Homozygosity for HLA-C has been shown in a single study to confer increased genetic susceptibility to idiopathic bronchiectasis. We aimed to assess whether the KIR and HLA repertoire, alone or in combination, may influence the risk of developing idiopathic bronchiectasis, in an independent replication study. METHODS: In this prospective, observational, case-control association study, 79 idiopathic bronchiectasis patients diagnosed following extensive aetiological investigation were compared with 98 anonymous, healthy, age, sex and ethnically-matched controls attending blood donor sessions in the same geographical location. DNA extraction was performed according to standardised techniques. Determination of presence or absence of KIR genes was performed by a sequence specific oligonucleotide probe method. Allele frequencies for the proposed KIR, HLA-B and HLA-C risk alleles both individually and in combinations were compared. RESULTS: We found no significant differences in allele frequency between the idiopathic bronchiectasis and control samples, whether considering HLA-C group homozygosity alone or in combination with the KIR type. DISCUSSION: Our results do not show an association between HLA-C and KIR and therefore do not confirm previous positive findings. This may be explained by the lower frequency of HLA-C1 group homozygosity in the control population of the previous study (27.2%), compared to 42.3% in our study, which is consistent with the genetic profiling of control groups across the UK. The previous positive association study may therefore have been driven by an anomalous control group. Further larger prospective multicentre replication studies are needed to determine if an association exists.

Employment in adults with cystic fibrosis.

BACKGROUND: Chronic ill-health may significantly impact on an individual's ability to work. This not only relates to disease severity but also to psychosocial factors such as illness perception and coping strategies. AIMS: To explore the factors associated with employment status in adults with cystic fibrosis (CF). METHODS: Subjects recruited from adult CF clinics in Aberdeen, Birmingham and Newcastle completed questionnaires assessing health-related quality of life (HRQoL), workplace productivity (presenteeism) and employment. Clinical data indicative of disease severity were also recorded. RESULTS: A total of 254 subjects were recruited, 41 from Aberdeen, 63 from Birmingham and 150 from Newcastle. Sixty-five per cent of subjects were in employment or education. If employed/self-employed, median hours worked was 37.3h/week. Forty per cent reported stopping a job due to CF; 47% felt CF had affected career choice and 24% changed duties because of CF. Ten per cent had taken a pay cut and 23% reported workplace discrimination due to CF. Multivariate modelling demonstrated that employment status was independently associated with educational attainment, centre and the HRQoL domains of role and health perception and is independent of clinical parameters of disease severity. CONCLUSIONS: Adults with CF reported that CF impacted on their ability to work. Employment appeared to be most strongly associated with educational attainment, locality and HRQoL domains and not clinical parameters of severity. Specific guidance is needed for both adults with CF and potential employers, with appropriate targeted interventions aimed at improving health perceptions and coping strategies.

Phenotyping adults with non-cystic fibrosis bronchiectasis: a prospective observational cohort study.

BACKGROUND: Bronchiectasis is the outcome of a number of different airway insults. Very few studies have characterised the aetiology and utility of a dedicated screening proforma in adult patients attending a general bronchiectasis clinic. METHODS: A prospective observational study of 189 bronchiectasis patients attending two centres in the North East of England over a two-year period was performed. RESULTS: The aetiology of bronchiectasis was identified in 107/189(57%) patients. Idiopathic bronchiectasis (IB) represented the largest subgroup (43%). Post-infection bronchiectasis (PIB) constituted the largest proportion (24%) of known causes. Mean age (SD) at diagnosis was 54(20) years with a mean age at symptom onset of 37(24) years, accounting for a diagnostic delay of 17 years. Age of symptom onset was significantly younger in patients with PIB compared to IB (p < 0.0001) and in Pseudomonas sputum positive patients (p = 0.007). Screening for APBA and total immunoglobulin deficiency identified 9 (5%) patients who then had tailored treatment. Routine screening for other aetiologies was deemed unnecessary. CONCLUSION: IB and PIB accounted for two thirds of cases of bronchiectasis in a general population. We recommend routine screening for ABPA and total immunoglobulin deficiency but not for other rarer aetiologies.