Fulfilling the Promise of Breathomics: Considerations for the Discovery and Validation of Exhaled Volatile Biomarkers.

The exhaled breath represents an ideal matrix for non-invasive biomarker discovery, and exhaled metabolomics have the potential to be clinically useful in the era of precision medicine. In this concise translational review we will specifically address volatile organic compounds in the breath, with a view towards fulfilling the promise of these as actionable biomarkers, in particular for lung diseases. We review the literature paying attention to seminal work linked to key milestones in breath research; discuss potential applications for breath biomarkers across disease areas and healthcare systems, including the perspectives of industry; and outline critical aspects of study design that will need to be considered for any pivotal research going forward, if breath analysis is to provide robust validated biomarkers that meet the requirements for future clinical implementation.

Supermarket Transaction Records In Dietary Evaluation: the STRIDE study: validation against self-reported dietary intake.

OBJECTIVE: Scalable methods are required for population dietary monitoring. The Supermarket Transaction Records In Dietary Evaluation (STRIDE) study compares dietary estimates from supermarket transactions with an online FFQ. DESIGN: Participants were recruited in four waves, accounting for seasonal dietary variation. Purchases were collected for 1 year during and 1 year prior to the study. Bland-Altman agreement and limits of agreement (LoA) were calculated for energy, sugar, fat, saturated fat, protein and sodium (absolute and relative). SETTING: This study was partnered with a large UK retailer. PARTICIPANTS: Totally, 1788 participants from four UK regions were recruited from the retailer's loyalty card customer database, according to breadth and frequency of purchases. Six hundred and eighty-six participants were included for analysis. RESULTS: The analysis sample were mostly female (72 %), with a mean age of 56 years (sd 13). The ratio of purchases to intakes varied depending on amounts purchased and consumed; purchases under-estimated intakes for smaller amounts on average, but over-estimated for larger amounts. For absolute measures, the LoA across households were wide, for example, for energy intake of 2000 kcal, purchases could under- or over-estimate intake by a factor of 5; values could be between 400 kcal and 10000 kcal. LoA for relative (energy-adjusted) estimates were smaller, for example, for 14 % of total energy from saturated fat, purchase estimates may be between 7 % and 27 %. CONCLUSIONS: Agreement between purchases and intake was highly variable, strongest for smaller loyal households and for relative values. For some customers, relative nutrient purchases are a reasonable proxy for dietary composition indicating utility in population-level dietary research.

Cropland displacement contributed 60% of the increase in carbon emissions of grain transport in China over 1990-2015.

Rapid urbanization and population growth have increased the need for grain transportation in China, as more grain is being consumed and croplands have been moved away from cities. Increased grain transportation has, in turn, led to higher energy consumption and carbon emissions. Here we undertook a model-based approach to estimate the carbon emissions associated with grain transportation in the country between 1990 and 2015. We found that emissions more than tripled, from 5.68 million tons of CO2 emission equivalent in 1990 to 17.69 million tons in 2015. Grain production displacement contributed more than 60% of the increase in carbon emissions associated with grain transport over the study period, whereas changes in grain consumption and population growth contributed 31.7% and 16.6%, respectively. Infrastructure development, such as newly built highways and railways in western China, helped offset 0.54 million tons of CO2 emission equivalent from grain transport. These findings shed light on the life cycle environmental impact within food supply chains.

Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA).

BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies. METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria. RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately). CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.

Objectively measuring the association between the built environment and physical activity: a systematic review and reporting framework.

BACKGROUND: Objective measures of built environment and physical activity provide the opportunity to directly compare their relationship across different populations and spatial contexts. This systematic review synthesises the current body of knowledge and knowledge gaps around the impact of objectively measured built environment metrics on physical activity levels in adults (≥ 18 years). Additionally, this review aims to address the need for improved quality of methodological reporting to evaluate studies and improve inter-study comparability though the creation of a reporting framework. METHODS: A systematic search of the literature was conducted following the PRISMA guidelines. After abstract and full-text screening, 94 studies were included in the final review. Results were synthesised using an association matrix to show overall association between built environment and physical activity variables. Finally, the new PERFORM ('Physical and Environmental Reporting Framework for Objectively Recorded Measures') checklist was created and applied to the included studies rating them on their reporting quality across four key areas: study design and characteristics, built environment exposures, physical activity metrics, and the association between built environment and physical activity. RESULTS: Studies came from 21 countries and ranged from two days to six years in duration. Accelerometers and using geographic information system (GIS) to define the spatial extent of exposure around a pre-defined geocoded location were the most popular tools to capture physical activity and built environment respectively. Ethnicity and socio-economic status of participants were generally poorly reported. Moderate-to-vigorous physical activity (MVPA) was the most common metric of physical activity used followed by walking. Commonly investigated elements of the built environment included walkability, access to parks and green space. Areas where there was a strong body of evidence for a positive or negative association between the built environment and physical activity were identified. The new PERFORM checklist was devised and poorly reported areas identified, included poor reporting of built environment data sources and poor justification of method choice. CONCLUSIONS: This systematic review highlights key gaps in studies objectively measuring the built environment and physical activity both in terms of the breadth and quality of reporting. Broadening the variety measures of the built environment and physical activity across different demographic groups and spatial areas will grow the body and quality of evidence around built environment effect on activity behaviour. Whilst following the PERFORM reporting guidance will ensure the high quality, reproducibility, and comparability of future research.

A systematic review of supermarket automated electronic sales data for population dietary surveillance.

CONTEXT: Most dietary assessment methods are limited by self-report biases, how long they take for participants to complete, and cost of time for dietitians to extract content. Electronically recorded, supermarket-obtained transactions are an objective measure of food purchases, with reduced bias and improved timeliness and scale. OBJECTIVE: The use, breadth, context, and utility of electronic purchase records for dietary research is assessed and discussed in this systematic review. DATA SOURCES: Four electronic databases (MEDLINE, EMBASE, PsycINFO, Global Health) were searched. Included studies used electronically recorded supermarket transactions to investigate the diet of healthy, free-living adults. DATA EXTRACTION: Searches identified 3422 articles, of which 145 full texts were retrieved and 72 met inclusion criteria. Study quality was assessed using the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. DATA ANALYSIS: Purchase records were used in observational studies, policy evaluations, and experimental designs. Nutrition outcomes included dietary patterns, nutrients, and food category sales. Transactions were linked to nutrient data from retailers, commercial data sources, and national food composition databases. CONCLUSION: Electronic sales data have the potential to transform dietary assessment and worldwide understanding of dietary behavior. Validation studies are warranted to understand limits to agreement and extrapolation to individual-level diets. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42018103470.

Characterisation of Temporal Patterns in Step Count Behaviour from Smartphone App Data: An Unsupervised Machine Learning Approach.

The increasing ubiquity of smartphone data, with greater spatial and temporal coverage than achieved by traditional study designs, have the potential to provide insight into habitual physical activity patterns. This study implements and evaluates the utility of both K-means clustering and agglomerative hierarchical clustering methods in identifying weekly and yearlong physical activity behaviour trends. Characterising the demographics and choice of activity type within the identified clusters of behaviour. Across all seven clusters of seasonal activity behaviour identified, daylight saving was shown to play a key role in influencing behaviour, with increased activity in summer months. Investigation into weekly behaviours identified six clusters with varied roles, of weekday versus weekend, on the likelihood of meeting physical activity guidelines. Preferred type of physical activity likewise varied between clusters, with gender and age strongly associated with cluster membership. Key relationships are identified between weekly clusters and seasonal activity behaviour clusters, demonstrating how short-term behaviours contribute to longer-term activity patterns. Utilising unsupervised machine learning, this study demonstrates how the volume and richness of secondary app data can allow us to move away from aggregate measures of physical activity to better understand temporal variations in habitual physical activity behaviour.

Socio-demographic determinants of physical activity and app usage from smartphone data.

The increasing ubiquity of smartphones provides a potential new data source to capture physical activity behaviours. Though not designed as a research tool, these secondary data have the potential to capture a large population over a more extensive spatial area and with longer temporality than current methods afford. This paper uses one such secondary data source from a commercial app designed to incentivise activity. We explore the new insights these data provide, alongside the sociodemographic profile of those using physical activity apps, to gain insight into both physical activity behaviour and determinants of app usage in order to evaluate the suitability of the app in providing insights into the physical activity of the population. We find app usage to be higher in females, those aged 25-50, and users more likely to live in areas where a higher proportion of the population are of a lower socioeconomic status. We ascertain longer-term patterns of app usage with increasing age and more male users reaching physical activity guideline recommendations despite longer daily activity duration recorded by female users. Additionally, we identify key weekly and seasonal trends in physical activity. This is one of the first studies to utilise a large volume of secondary physical activity app data to co-investigate usage alongside activity behaviour captured.

Exploring the Geographic Variation in Fruit and Vegetable Purchasing Behaviour Using Supermarket Transaction Data.

The existence of dietary inequalities is well-known. Dietary behaviours are impacted by the food environment and are thus likely to follow a spatial pattern. Using 12 months of transaction records for around 50,000 'primary' supermarket loyalty card holders, this study explores fruit and vegetable purchasing at the neighbourhood level across the city of Leeds, England. Determinants of small-area-level fruit and vegetable purchasing were identified using multiple linear regression. Results show that fruit and vegetable purchasing is spatially clustered. Areas purchasing fewer fruit and vegetable portions typically had younger residents, were less affluent, and spent less per month with the retailer.

Safety and efficacy of volume-based feeding in critically ill, mechanically ventilated adults using the 'Protein & Energy Requirements Fed for Every Critically ill patient every Time' (PERFECT) protocol: a before-and-after study.

BACKGROUND: Underfeeding in critical illness is common and associated with poor outcomes. According to large prospective hospital studies, volume-based feeding (VBF) safely and effectively improves energy and protein delivery to critically ill patients compared to traditional rate-based feeding (RBF) and might improve patient outcomes. A before-and-after study was designed to evaluate the safety, efficacy and clinical outcomes associated with VBF compared to RBF in a single intensive care unit (ICU). METHODS: The sample included consecutively admitted critically ill adults, mechanically ventilated for at least 72 h and fed enterally for a minimum of 48 h. The first cohort (n = 46) was fed using RBF, the second (n = 46) using VBF, and observed for 7 days, or until extubation or death. Statistical comparison of percentage feed volume, energy and protein delivered, plus indices of feed intolerance, were the primary outcomes of interest. Secondary observations included ventilation period, mortality, and length of ICU stay (LOICUS). RESULTS: Groups were comparable in baseline clinical and demographic characteristics and nutrition practices. Volume delivered to the VBF group increased significantly by 11.2% (p ≤ 0.001), energy by 13.4% (p ≤ 0.001) and protein by 8.4% (p = 0.02), compared to the RBF group. In the VBF group, patients meeting > 90% of energy requirements increased significantly from 47.8 to 84.8% (p ≤ 0.001); those meeting > 90% of protein requirements changed from 56.5 to 73.9% (p = 0.134). VBF did not increase symptoms of feed intolerance. Adjusted binomial logistic regression found each additional 1% of prescribed feed delivered decreased the odds of vomiting by 0.942 (5.8%), 95% CI [0.900-0.985], p = 0.010. No differences in mortality or LOICUS were identified. Kaplan-Meier found a significantly increased extubation rate in patients receiving > 90% of protein requirements compared to those meeting < 80%, (p = 0.006). Adjusted Cox regression found the daily probability of being extubated tripled in patients receiving > 90% of their protein needs compared to the group receiving < 80%, hazard ratio 3.473, p = 0.021, 95% CI [1.205-10.014]. CONCLUSION: VBF safely and effectively increased the delivery of energy and protein to critically ill patients. Increased protein delivery may improve extubation rate which has positive patient-centred and financial implications, warranting larger confirmatory trials. This investigation adds weight to the ICU literature supporting VBF, and the growing evidence which advocates for enhanced protein delivery to improve patient outcomes.

The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial.

Background: p38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations. Objectives: These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations. Methods: The p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls. Volunteers aged 18-55 years were randomized into the lipopolysaccharide (LPS) challenge study, which investigated the effect of a single dose of AZD7624 vs placebo on inflammatory biomarkers. The Proof of Principle study randomized patients aged 40-85 years with a diagnosis of COPD for >1 year to AZD7624 or placebo to assess the effect of p38 inhibition in decreasing the rate of exacerbations. Results: The p38 isoform most relevant to lung inflammation was p38α, and AZD7624 specifically inhibited p38α and p38ß isoforms in human alveolar macrophages. Thirty volunteers were randomized in the LPS challenge study. AZD7624 reduced the increase from baseline in sputum neutrophils and TNF-α by 56.6% and 85.4%, respectively (p<0.001). In the 213 patients randomized into the Proof of Principle study, there was no statistically significant difference between AZD7624 and placebo when comparing the number of days to the first moderate or severe exacerbation or early dropout. Conclusion: Although p38α is upregulated in the lungs of COPD patients, AZD7624, an isoform-specific inhaled p38 MAPK inhibitor, failed to show any benefit in patients with COPD.

Realising the potential of various inhaled airway challenge agents through improved delivery to the lungs.

Inhaled airway challenges provoke bronchoconstriction in susceptible subjects and are a pivotal tool in the diagnosis and monitoring of obstructive lung diseases, both in the clinic and in the development of new respiratory medicines. This article reviews the main challenge agents that are in use today (methacholine, mannitol, adenosine, allergens, endotoxin) and emphasises the importance of controlling how these agents are administered. There is a danger that the optimal value of these challenge agents may not be realised due to suboptimal inhaled delivery; thus considerations for effective and reproducible challenge delivery are provided. This article seeks to increase awareness of the importance of precise delivery of inhaled agents used to challenge the airways for diagnosis and research, and is intended as a stepping stone towards much-needed standardisation and harmonisation in the administration of inhaled airway challenge agents.

One Filter, One Sample, and the N- and O-Glyco(proteo)me: Toward a System to Study Disorders of Protein Glycosylation.

A method has been developed for release/isolation of O-glycans from glycoproteins in whole cell lysates for mass spectrometric analysis. Cells are lysed in SDS, which is then exchanged for urea and ammonium bicarbonate in a centrifugal filter, before treating with NH4OH to release O-glycans. Following centrifugation, O-glycans are recovered in the filtrate. Sonication achieves O-glycan release in 1 h. Combining the established protocol for filter-aided N-glycan separation, here optimized for enhanced PNGase F efficiency, with the developed O-glycan release method allows analysis of both N- and O-glycans from one sample, in the same filter unit, from 0.5 to 1 million cells. The method is compatible with subsequent analysis of the residual protein by liquid chromatography-mass spectrometry (LC-MS) after glycan release. The medium throughput approach is amenable to analysis of biological replicates, offering a simple way to assess the often subtle changes to glycan profiles accompanying differentiation and disease progression, in a statistically robust way.

Are differences in travel time or distance to healthcare for adults in global north countries associated with an impact on health outcomes? A systematic review.

OBJECTIVES: To investigate whether there is an association between differences in travel time/travel distance to healthcare services and patients' health outcomes and assimilate the methodologies used to measure this. DESIGN: Systematic Review. We searched MEDLINE, Embase, Web of Science, Transport database, HMIC and EBM Reviews for studies up to 7 September 2016. Studies were excluded that included children (including maternity), emergency medical travel or countries classed as being in the global south. SETTINGS: A wide range of settings within primary and secondary care (these were not restricted in the search). RESULTS: 108 studies met the inclusion criteria. The results were mixed. 77% of the included studies identified evidence of a distance decay association, whereby patients living further away from healthcare facilities they needed to attend had worse health outcomes (eg, survival rates, length of stay in hospital and non-attendance at follow-up) than those who lived closer. 6 of the studies identified the reverse (a distance bias effect) whereby patients living at a greater distance had better health outcomes. The remaining 19 studies found no relationship. There was a large variation in the data available to the studies on the patients' geographical locations and the healthcare facilities attended, and the methods used to calculate travel times and distances were not consistent across studies. CONCLUSIONS: The review observed that a relationship between travelling further and having worse health outcomes cannot be ruled out and should be considered within the healthcare services location debate.

smokeSALUD: exploring the effect of demographic change on the smoking prevalence at municipality level in Austria.

BACKGROUND: Reducing the smoking population is still high on the policy agenda, as smoking leads to many preventable diseases, such as lung cancer, heart disease, diabetes, and more. In Austria, data on smoking prevalence only exists at the federal state level. This provides an interesting overview about the current health situation, but for regional planning authorities these data are often insufficient as they can hide pockets of high and low smoking prevalence in certain municipalities. METHODS: This paper presents a spatial-temporal change of estimated smokers for municipalities from 2001 and 2011. A synthetic dataset of smokers is built by combining individual large-scale survey data and small area census data using a deterministic spatial microsimulation approach. Statistical analysis, including chi-square test and binary logistic regression, are applied to find the best variables for the simulation model and to validate its results. RESULTS: As no easy-to-use spatial microsimulation software for non-programmers is available yet, a flexible web-based spatial microsimulation application for health decision support (called simSALUD) has been developed and used for these analyses. The results of the simulation show in general a decrease of smoking prevalence within municipalities between 2001 and 2011 and differences within areas are identified. These results are especially valuable to policy decision makers for future planning strategies. CONCLUSIONS: This case study shows the application of smokeSALUD to model the spatial-temporal changes in the smoking population in Austria between 2001 and 2011. This is important as no data on smoking exists at this geographical scale (municipality). However, spatial microsimulation models are useful tools to estimate small area health data and to overcome these problems. The simulations and analysis should support health decision makers to identify hot spots of smokers and this should help to show where to spend health resources best in order to reduce health inequalities.

Attenuated total reflection-Fourier transform infrared spectroscopic imaging of pharmaceuticals in microfluidic devices.

The poor aqueous solubility of many active pharmaceutical ingredients presents challenges for effective drug delivery. In this study, the combination of attenuated total reflection (ATR)-FTIR spectroscopic imaging with specifically designed polydimethylsiloxane microfluidic devices to study drug release from pharmaceutical formulations has been developed. First, the high-throughput analysis of the dissolution of micro-formulations studied under flowing conditions has been introduced using a model formulation of ibuprofen and polyethylene glycol. The behaviour and release of the drug was monitored in situ under different pH conditions. In contrast to the neutral solution, where both the drug and excipient dissolved at a similar rate, structural change from the molecularly dispersed to a crystalline form of ibuprofen was characterised in the obtained spectroscopic images and the corresponding ATR-FTIR spectra for the experiments carried out in the acidic medium. Further investigations into the behaviour of the drug after its release from formulations (i.e., dissolved drug) were also undertaken. Different solutions of sodium ibuprofen dissolved in a neutral medium were studied upon contact with acidic conditions. The phase transition from a dissolved species of sodium ibuprofen to the formation of solid crystalline ibuprofen was revealed in the microfluidic channels. This innovative approach could offer a promising platform for high-throughput analysis of a range of micro-formulations, which are of current interest due to the advent of 3D printed pharmaceutical and microparticulate delivery systems. Furthermore, the ability to study dissolved drug in solution under flowing conditions can be useful for the studies of the diffusion of drugs into tissues or live cells.

Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects.

BACKGROUND: Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response. METHODS: Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatments were the oral p38 MAPK inhibitor PH-797804 30 mg (study 1), PH-797804 30 mg and the inhaled p38 MAPK inhibitor PF-03715455 20 mg (study 2) and inhaled fluticasone propionate 500 µg (study 3). The primary endpoint was sputum neutrophil percentage. RESULTS: Sputum neutrophil percentage post-LPS challenge was significantly inhibited (15.1 and 15.3% reduction) by PH-797804 compared to placebo in studies 1 and 2 (p = 0.0096 and 0.0001, respectively), and by PF-03715455 (8.0% reduction, p = 0.031); fluticasone propionate had no effect. PH-797804 significantly inhibited the increase in inflammatory mediators (IL-6, MCP-1, MIP1ß and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1ß, CC16 and CRP levels in plasma, with PH-797804 having greater effects. Fluticasone propionate had no effect on sputum supernatant or plasma biomarkers. CONCLUSIONS: PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects.

Comparison of pharmaceutical formulations: ATR-FTIR spectroscopic imaging to study drug-carrier interactions.

Attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopic imaging has been used in combination with UV detection to study the release of a model poorly water-soluble drug, indomethacin, when formulated with selected drug carriers. Firstly, formulations of indomethacin and nicotinamide in varying weight ratios were studied since novel tablet dosage forms containing multi-drugs are of industrial interest. The in situ spectroscopic imaging measurements of the dissolving tablets showed that as the loading of indomethacin was increased, the rate of drug release changed from one that expressed first-order drug release to one which showed zero-order drug release. Two drug release mechanisms have been identified from the recorded spectroscopic images and UV dissolution profiles. To further validate these mechanisms, specific formulations containing the model drug and two other excipients, urea and mannitol, were studied. The formulations with urea showed similar first-order release, indicative of the drug-carrier interactions. Whereas, the indomethacin/mannitol formulations showed a zero-order release curve explained by disintegration of the tablet. ATR-FTIR spectroscopic imaging provided highly chemically specific information as well as the spatial distribution of the components during the dissolution process which has demonstrated the potential of this combined analytical setup to determine the mechanisms of drug release.