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In this research we present a low-cost system for breath acetone analysis based on UV-LED photoacoustic spectroscopy. We considered the end-tidal phase of exhalation, which represents the systemic concentrations of volatile organic compounds (VOCs) – providing clinically relevant information about the human health. This is achieved via the development of a CO2-triggered breath sampling system, which collected alveolar breath over several minutes in sterile and inert containers. A real-time mass spectrometer is coupled to serve as a reference device for calibration measurements and subsequent breath analysis. The new sensor system provided a 3σ detection limit of 8.3 ppbV and an NNEA of 1.4E-9 Wcm−1Hz−0.5. In terms of the performed breath analysis measurements, 12 out of 13 fell within the error margin of the photoacoustic measurement system, demonstrating the reliability of the measurements in the field.

Detection of volatile organic compounds in exhaled air is a promising approach to non-invasive and scalable gastric cancer screening. This work proposes a new approach for the detection of volatile organic compounds by analyzing odor-evoked calcium responses in the rat olfactory bulb. We estimate the feasibility of gastric cancer biomarker detection added to the exhaled air of healthy participants. Our detector consists of a convolutional encoder and a similarity-based classifier over encoder outputs. To minimize overfitting on a small available training set, we involve a pre-training where the encoder is trained on synthetic data representing spatiotemporal patterns similar to real calcium responses in the olfactory bulb. We estimate the classification accuracy of exhaled air samples by matching their encodings with encodings of calibration samples of two classes: 1) exhaled air and 2) a mixture of exhaled air with the cancer biomarker. On our data, the accuracy increased from 0.68 on real data up to 0.74 if pre-training on synthetic data is involved. Our work is focused on proving the feasibility of proposed new approach rather than on comparing its efficiency with existing methods. Such detection is often performed with an electronic nose, but its output becomes unstable over time due to a sensor drift. In contrast to the electronic nose, rats can robustly detect low concentrations of biomarkers over lifetime. The feasibility of gastric cancer biomarker detection in exhaled air by bio-hybrid system is shown. Pre-training of neural models for images analysis increases the accuracy of detection.

The application of electronic nose system as an instrument for exhaled air analysis for diagnosing various diseases (lung cancer, etc.) is one of the most rapidly developing areas of predictive medicine. However, a significant disadvantage of such systems is difficulty in production of identical multi-sensor systems because the sensors of the same type are not identical, that degrades the predictive ability. To solve this problem calibration transfer methods are used.This paper analyzes currently applied calibration transfer methods. A new approach to evaluate the effectiveness of calibration transfer methods for two multi-sensor systems is proposed and implemented. One- and three-component gas mixtures are taken for the analysis. In this work, four methods are used to adjust the sensor responses: UDS, UDSwoi, DS-L1R and DS-PLS2. Applicability of one-factor standardization methods (UDS and UDSwoi) is shown on the classification tasks: multi-class classification task of one-component gas mixtures and binary classification task of three-component gas mixtures. Multi-class classification of model one-component gas mixtures for UDS, UDSwoi with 4 calibration transfer samples provided the classification accuracy of 0.985 and 0.990, respectively. The binary classification of two three-component mixtures with different ratios of three VOCs within the 20% discrepancy limits, UDS, UDSwoi and DS-PLS2 achieved an error-free accuracy of 1.000.

Exhaled ammonia (NH3) is an essential noninvasive biomarker for disease diagnosis. In this study, an acetone-modifier positive photoionization ion mobility spectrometry (AM-PIMS) method was developed for accurate qualitative and quantitative analysis of exhaled NH3 with high selectivity and sensitivity. Acetone was introduced into the drift tube along with the drift gas as a modifier, and the characteristic NH3 product ion peak of (C3H6O)4NH4+ (K0 = 1.45 cm2/V·s) was obtained through the ion-molecule reaction with acetone reactant ions (C3H6O)2H+ (K0 = 1.87 cm2/V·s), which significantly increased the peak-to-peak resolution and improved the accuracy of exhaled NH3 qualitative identification. Moreover, the interference of high humidity and the memory effect of NH3 molecules were significantly reduced via online dilution and purging sampling, thus realizing breath-by-breath measurement. As a result, a wide quantitative range of 5.87–140.92 μmol/L with a response time of 40 ms was achieved, and the exhaled NH3 profile could be synchronized with the concentration curve of exhaled CO2. Finally, the analytical capacity of AM-PIMS was demonstrated by measuring the exhaled NH3 of healthy subjects, demonstrating its great potential for clinical disease diagnosis.

This article describes a fully optoelectronic system for measuring the H2O concentration and temperature of air exhaled from human lungs. A device consisting of both a laser hygrometer and an ultra-fast resistive thermometer. It was tested during an experiment with saturated water vapour, confirming its accuracy for measuring H2O concentration in air. Data, from a preliminary investigation of breath samples from anonymous adult volunteers, is presented.

Trace gas analysis in breath is challenging due to the vast number of different components. We present a highly sensitive quantum cascade laser based photoacoustic setup for breath analysis. Scanning the range between 8263 and 8270 nm with a spectral resolution of 48 pm, we are able to quantify acetone and ethanol within a typical breath matrix containing water and CO2. We photoacoustically acquired spectra within this region of mid-infra-red light and prove that those spectra do not suffer from non-spectral interferences. The purely additive behavior of a breath sample spectrum was verified by comparing it with the independently acquired single component spectra using Pearson and Spearman correlation coefficients. A previously presented simulation approach is improved and an error attribution study is presented. With a 3σ detection limit of 6.5 ppbv in terms of ethanol and 250 pptv regarding acetone, our system is among the best performing presented so far.

Infrared spectroscopy appears to be a promising analytical method for the metabolic analysis of breath. However, due to the presence of trace amounts in exhaled breath, the absorption strength of the metabolites remains extremely low. In such low detection limits, the nonlinear detection sensitivity of the infrared detector and electronic noise strongly modify the baseline of the acquired infrared spectra of breath. Fitting the reference molecular spectra with the baseline-modified spectral features of breath metabolites does not provide accurate identification. Therefore, baseline correction of the acquired infrared spectra of breath is the primary requirement for the success of breath-based infrared diagnosis. A selective spectral region-based, simple baseline correction method is proposed for the infrared spectroscopy of breath., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kiran Sankar Maiti reports a relationship with LMU Munich that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In this study, we aimed to assess the feasibility of re-collecting breath samples using the Centri® (Markes International, Bridgend, UK) followed by two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC×GC-TOFMS) analysis. The work was conducted in two main phases. In the first phase, we evaluated the re-collection performance by analyzing two sets of standards, including a Grob mix primary solution and a standard mixture of 20 selected volatile compounds (VCs) covering different classes of organic species commonly found in breath samples. The intra-day and inter-day precision (reported as relative standard deviation (RSD),%) for the re-collection of the Grob mix primary solution were in the range of 1 % to14 % and 3 % to12 %, respectively. The re-collection accuracy ranged from 78 % to 97 %. The intra-day RSD for the re-collection of the standard mixture of selected VCs was within 20 % for all compounds, except for acetone and nonane. The precision was within 25 % for all compounds, except for nonane, n-hexane, 1,4-dichlorobenzene, and decane, which exhibited less than 36 % RSD. The re-collection accuracy was in the range of 67 % to 129 %. In the second phase of the study, the re-collection performance in breath analysis was evaluated via five repetitive splitting and re-collection of six breath samples obtained from healthy adults, realizing a total of 30 breath analyses. Initially, we evaluated the re-collection performance by considering all features obtained from breath analysis and then focused on the 20 VCs commonly found in breath samples. The re-collection accuracy for total breath features ranged from 86 to 103 %, and the RSDs were in the range of 1.0 % to 10.4 %. For the selected VCs, the re-collection accuracy of all compounds, except for undecane and benzene, was in the range of 71 % to 132 %., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Breath composition analysis is a fast and non-invasive alternative to commonly used methods of detecting lung cancer, such as biopsy. One issue in the study of breath composition is the availability of appropriate sampling and sample-preparation methods that are able to fully capture the gas and droplet phases of exhaled breath. In this article, we detail the application of a filter-incorporated needle-trap device (NTD) to capture gaseous compounds and droplets in breath samples. In addition, a thin-film microextraction method was also employed to conduct extractions from only the gas phase. In comparing the NTD (total concentration) and TFME (free concentration) results, it is possible to obtain a more comprehensive view of the sample, as this approach captures both the free and droplet-bound concentrations, which can in turn provide a better characterization of the cancer. Furthermore, the developed devices were applied for the on-site sampling of lung cancer patients. The complete interpretation of the results and their relationship to the state of the disease and patient health status requires a large cohort of patients and considerable medical expertise; therefore, this study focuses on method development and the application of the proposed device for fast and sensitive on-site detection of biomarkers in patients.

Human exhaled breath contains various molecules that relate to human health and environmental exposures. There has been increasing interest in human breath analysis for exposure monitoring. This review focuses on the utilization of solid phase microextraction (SPME) for breath analysis of environmental and occupational exposures. Breath analysis of different types of exposures are summarized. The developments of SPME methods for breath analysis are highlighted. The limitations of the current studies and the prospects of breath analysis in exposure monitoring are discussed.

Background: Proton-transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS) is a promising tool for a rapid online determination of exhaled volatile organic compounds (eVOCs) profiles in patients with cystic fibrosis (CF)., Objective: To detect VOC breath signatures specific to adult patients with CF compared with controls using PTR-TOF-MS., Methods: 102 CF patients (54 M/48, mean age 25.6 ± 7.8 yrs) and 97 healthy controls (56 M/41F, mean age 25.8 ± 6.0 yrs) were examined. Samples from normal quiet breathing and forced expiratory maneuvers were analyzed with PTR-TOF-MS (Ionicon, Austria) to obtain VOC profiles listed as ions at various mass-to-charge ratios (m/z)., Results: PTR-TOF-MS analysis was able to detect 167 features in exhaled breath from CF patients and healthy controls. According to cluster analysis and LASSO regression, patients with CF and controls were separated. The most significant VOCs for CF were indole, phenol, dimethyl sulfide, and not indicated: m/z = 297.0720 ([C12H13N2O7 and C17H13O5]H + ), m/z = 281.0534 ([C19H7NO2, C12H11NO7 and C16H9O5]H + ) during five-fold cross-validation both in forced expiratory maneuver and in normal quiet breathing., Conclusion: PTR-TOF-MS is a promising method for determining the molecular composition of exhaled air specific to CF., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Breath exhaled hydrogen cyanide (HCN) has been identified to be associated with several respiratory diseases. Accurately distinguishing the concentration and release rate of different HCN sources is of great value in clinical research. However, there are still significant challenges due to the high adsorption and low concentration characteristics of exhaled HCN. In this study, a two-compartment kinetic model method based on negative photoionization mass spectrometry was developed to simultaneously determine the kinetic parameters including concentrations and release rates in the airways and alveoli. The influences of the sampling line diameter, length, and temperature on the response time of the sampling system were studied and optimized, achieving a response time of 0.2 s. The negative influence of oral cavity-released HCN was reduced by employing a strategy based on anatomical lung volume calculation. The calibration for HCN in the dynamic range of 0.5-100 ppbv and limit of detection (LOD) at 0.3 ppbv were achieved. Subsequently, the experiments of smoking, short-term passive smoking, and intake of bitter almonds were performed to examine the influences of endogenous and exogenous factors on the dynamic parameters of the model method. The results indicate that compared with steady-state concentration measurements, the kinetic parameters obtained using this model method can accurately and significantly reflect the changes in different HCN sources, highlighting its potential for HCN-related disease research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Early diagnosis of coronavirus disease 2019 (COVID-19) is of the utmost importance but remains challenging. The objective of the current study was to characterize exhaled breath from mechanically ventilated adults with COVID-19. Methods: In this prospective observational study, we used real-time, online, proton transfer reaction time-of-flight mass spectrometry to perform a metabolomic analysis of expired air from adults undergoing invasive mechanical ventilation in the intensive care unit due to severe COVID-19 or non-COVID-19 acute respiratory distress syndrome (ARDS). Findings: Between March 25th and June 25th, 2020, we included 40 patients with ARDS, of whom 28 had proven COVID-19. In a multivariate analysis, we identified a characteristic breathprint for COVID-19. We could differentiate between COVID-19 and non-COVID-19 ARDS with accuracy of 93% (sensitivity: 90%, specificity: 94%, area under the receiver operating characteristic curve: 0·94-0·98, after cross-validation). The four most prominent volatile compounds in COVID-19 patients were methylpent-2-enal, 2,4-octadiene 1-chloroheptane, and nonanal. Interpretation: The real-time, non-invasive detection of methylpent-2-enal, 2,4-octadiene 1-chloroheptane, and nonanal in exhaled breath may identify ARDS patients with COVID-19. Funding: The study was funded by Agence Nationale de la Recherche (SoftwAiR, ANR-18-CE45-0017 and RHU4 RECORDS, Programme d'Investissements d'Avenir, ANR-18-RHUS-0004), Région Île de France (SESAME 2016), and Fondation Foch.

• By analyzing the VOCs presents in our breath, we could identify if some components should not be present in our bodies, or their concentration is higher or lower than normal. • To collect breath samples for VOC analysis, we looked into the current available methodologies and, due to their high prices, tried to develop our own easy and cheap device. A simple single use Minigrip LDPE plastic bag was used in this work and its efficiency and performance were tested. • After breath collection, samples were analyzed using Thermal Desorption (TD) system, coupled with Gas Chromatography Mass Spectrometer (GC-MS).

Rapid in-situ chemical analysis of flowing gas streams is of interest in a wide range of applications but requires deconvolution of the time-scales associated with the analyte source concentration, its accumulation within a sampling chamber, and its detection by a sensor. A mathematical analysis is presented on the use of a flow-through sample chamber for rapid, in-situ breath analysis utilizing analyte diffusion through a Nafion membrane optode. We show that this approach yields apparently non-Fickian (anomalous or Case II) transport that varies from t1/2 to t as t → 0 with constant inlet concentration. Such behavior arises due to the transition from membrane-limited to sample chamber-limited transport dynamics depending on test conditions. The model is validated utilizing experimental data obtained from the color response associated with the Friedel-Craft acylation of acetone vapor with resorcinol reagent immobilized in Nafion membrane solid-state catalyst. Reduction of optode membrane thickness and increase in membrane humidification yield an optical response limited only by sample chamber material accumulation. At this limit, the exhaled breath signal for acetone obtained from a healthy individual is found to vary as t2 (apparently Super Case II transport). Utilizing a simplified material balance on the human lung, this observation is ascribed to a constant acetone exhalation rate as opposed to a constant exhaled acetone concentration. This conclusion is shown to have broad implications on the use of exhaled breath biomarkers for medical diagnosis, in particular, lung physiology and permeability.

This paper reports a procedure of building a functionalized reduced graphene oxide (rGO) library and an electronic nose based on the library. Functionalized rGO was prepared by reducing and modifying graphene oxide (GO) with chemically diverse amine ligands. We used the unmodified rGO and eight different functionalized rGO to build the chemiresistive sensor arrays in the electronic nose. Four potential cancer-related biomarkers in breath, ethanol, 2-ethylhexanol, nonanal and ethylbenzene, were used as the model volatile organic compounds (VOCs) analytes. The electronic nose showed linear responses to the model VOCs with high sensitivity of 25 ppm. Principal component analysis (PCA) results demonstrated the successful discrimination of the four model VOCs and binary VOC mixtures. The procedure of building the rGO library was simple and yielded consistent performance. We expected more versatile and sensitive electronic noses to be constructed based on the functionalized rGO library with potential applications in recognition and quantitative measurement of VOCs for health monitoring and disease diagnosis.

The growing number of prostate cancer cases is a real concern in modern society. Over 1.4 million new cases and about 400 thousand (>26%) deaths were registered worldwide in 2020 due to prostate cancer. The high mortality rate of prostate cancer is due to the lack of reliable early detection of the disease. Till now the most reliable diagnosis of cancer is tissue biopsy, which is an invasive process. A non-invasive or minimally invasive technique could lead to a diagnostic tool that will allow for saving or prolonging the lifespan of millions of lives. Metabolite-based diagnostics may have a better chance of early cancer detection. However, reliable detection techniques need to be developed. Infrared spectroscopy based gaseous-biofluid holds great promise towards the development of non-invasive diagnostics. A pilot study based on breath analysis by infrared spectroscopy showed promising results in distinguishing prostate cancer patients from healthy volunteers. Details of the spectral metabolic analysis are presented., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study demonstrates the adverse effects of water in exhaled breath samples on the accuracy of breath biomarker analysis when using gas chromatography. The presence of water in exhaled breath significantly modifies the retention times and peak areas of compounds, particularly for low-boiling, early eluting compounds. To tackle this issue, a two-step approach is introduced. The process begins with thorough desorption of the sorbent tube using a high split ratio and a short analysis duration, followed by a secondary analysis of the same tube. The efficacy of the new, straightforward approach was illustrated using humid breath samples and 57 compound standard mixture. This study highlights the importance of proper sample pretreatment and analysis to ensure reliable and accurate results in clinical research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: The burden of liver disease in the UK has risen dramatically and there is a need for improved diagnostics. Aims: To determine which breath volatiles are associated with the cirrhotic liver and hence diagnostically useful. Methods: A two-stage biomarker discovery procedure was used. Alveolar breath samples of 31 patients with cirrhosis and 30 healthy controls were mass spectrometrically analysed and compared (stage 1). 12 of these patients had their breath analysed after liver transplant (stage 2). Five patients were followed longitudinally as in-patients in the post-transplant period. Results: Seven volatiles were elevated in the breath of patients versus controls. Of these, five showed statistically significant decrease post-transplant: limonene, methanol, 2-pentanone, 2-butanone and carbon disulfide. On an individual basis limonene has the best diagnostic capability (the area under a receiver operating characteristic curve (AUROC) is 0.91), but this is improved by combining methanol, 2-pentanone and limonene (AUROC curve 0.95). Following transplant, limonene shows wash-out characteristics. Conclusions: Limonene, methanol and 2-pentanone are breath markers for a cirrhotic liver. This study raises the potential to investigate these volatiles as markers for early-stage liver disease. By monitoring the wash-out of limonene following transplant, graft liver function can be non-invasively assessed.

Breath-composition analysis is a well-established, non-invasive method for early disease diagnosis and investigating exposure history. However, this analytical approach is hampered by the aerosol nature of breath samples and/or low concentrations of volatile organic compounds. Conventionally, two separate methods have been applied to study gas phase and breath droplets, although these approaches are expensive and time-consuming. To address this issue, for the first time a needle-trap device packed with Carboxen, which served as a sorbent for the extraction of volatile analytes from the gas-phase, and electrospun polyacrylonitrile filter, which used to capture breath aerosol was applied to breath characterization. The performance of the developed device was subsequently compared to that of Carboxen-loaded thin-film microextraction, which was employed for the first time to extract free gas-phase components. Both methods were optimized, validated, and applied for the screening of breath samples obtained from volunteers. Obtained figures of merits are as follows: limits of detection (0.01-0.2 ng mL -1 ), recovery (81-108%) and repeatability (<13%). To investigate the effect of droplets, breath samples acquired with and without a face mask were compared. While both methods yielded similar results for the breath samples obtained with the mask, the needle-trap device was able to provide higher concentrations of volatile organic compounds for the samples acquired without a mask due to its enhanced ability to trap droplets. Additionally, tests were also conducted to investigate breath composition after accidental exposure to chemicals. The results of these tests revealed that polar compounds tended to partition to breath droplets and were eliminated from the body more quickly, while non-polar compounds tended to remain in the gas phase and were eliminated at a slower rate., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Aims: In this work, breath samples from clinically stable bronchiectasis patients with and without bronchial infections by Pseudomonas Aeruginosa- PA) were collected and chemically analysed to determine if they have clinical value in the monitoring of these patients., Materials and Methods: A cohort was recruited inviting bronchiectasis patients (25) and controls (9). Among the former group, 12 members were suffering PA infection. Breath samples were collected in Tedlar bags and analyzed by e-nose and Gas Chromatography-Mass Spectrometry (GC-MS). The obtained data were analyzed by chemometric methods to determine their discriminant power in regards to their health condition. Results were evaluated with blind samples., Results: Breath analysis by electronic nose successfully separated the three groups with an overall classification rate of 84% for the three-class classification problem. The best discrimination was obtained between control and bronchiectasis with PA infection samples 100% (CI 95% : 84-100%) on external validation and the results were confirmed by permutation tests. The discrimination analysis by GC-MS provided good results but did not reach proper statistical significance after a permutation test., Conclusions: Breath sample analysis by electronic nose followed by proper predictive models successfully differentiated between control, Bronchiectasis and Bronchiectasis PA samples., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: The chemical gas sensor array based electronic-nose (e-nose) devices with machine learning algorithms can detect and differentiate expelled breath samples of patients with various respiratory ailments and controls. It is by the recognition of levels and variations of volatile organic compounds (VOC) in the exhaled air. Here, we aimed to differentiate chronic obstructive pulmonary disease (COPD) and lung cancer from controls., Materials and Methods: This work presents the details of the developed e-nose system, selection of the study subjects, exhaled breath sampling method and detection, and the data analysis algorithms. The developed device is tested in 199 participants including 93 controls, 55 COPD patients, and 51 lung cancer patients. The main advantage of the device is robustness and portability and cost-effectiveness., Results: In the training phase and model validation phase, the ensemble learning method XGBoost outperformed the other two models. In the prediction of lung cancer, XGBoost method attained a classification accuracy of 79.31%. In COPD prediction also the same method had given the better results with 76.67% accuracy., Conclusion: The e-nose system developed with TGS gas sensors was portable, low cost, and gave a rapid response. It has been demonstrated that the VOC profiles of patients with pulmonary diseases and healthy controls are different and hence the e-nose system can be used as a potential diagnostic device for patients with lung diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cancers of the head and neck region are a severely disabling group of diseases with no method for early detection. Analysis of exhaled breath volatile organic compounds shows promise as biomarkers for early detection and disease monitoring. This article reviews breath analysis in the setting of head and neck cancer, with a practical focus on breath sampling techniques, detection technologies and valid data analysis methods. Title and abstract keyword searches were conducted on PubMed and Embase databases to identify English language studies without a time-period limitation. The main inclusion criteria were human studies comparing head and neck cancer patients to healthy controls using exhaled breath analysis. Multiple breath collection techniques, three major detection technologies and multiple data analysis methods were identified. However, the variability in techniques and lack of methodological standardization does not allow for adequate study replication or data pooling. Twenty-two volatile organic compounds identified in five studies have been reported to discriminate head and neck cancer patients from healthy controls. Breath analysis for detection of head and neck cancer shows promise as a non-invasive detection tool. However, methodological standardization is paramount for future research study design to provide the potential for translating these techniques into routine clinical use., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

When working with humid gaseous samples, the amount of water vapour collected in a needle trap along with volatile analytes may vary from sample to sample and decrease during the storage. This has a major impact on desorption efficiency and recovery. We propose the addition of a labelled internal standards to nullify the effect of variable humidity on the analytical performance of needle trap micro-extraction combined with gas chromatography mass spectrometry. Triple-bed (Divinylbenzene/Carbopack X/Carboxen 1000) and single-bed (Tenax GR) needles were tested with standard gaseous mixtures prepared at different relative humidity levels (85%, 50% and 10%). The standard mixtures contained twenty-five analytes representative of breath and ambient air constituents, including hydrocarbons, ketones, aldehydes, aromatics, and sulphurs, in the concentration range 0.1-700 ppbv. The two needles showed different behaviours, as recovery was independent of humidity for single-beds, whereas a low recovery (10-20%) was observed when triple-beds trapped very volatile compounds at low humidity (e.g. pentane and ethanol, 10% relative humidity. Triple-beds showed an almost quantitative recovery (>90%) of all the analytes at 50% and 85% relative humidity. This big difference was probably due to the reduced action of water vapour pressure during the desorption step. The addition of 6 D-acetone and 8 D-toluene to the sorbent material before gas sampling and the normalization of raw data nullified this effect, thereby lowering the variations of analyte recovery at different humidity levels down to 20%. Internal standards were also exploited to limit within 10-20% alterations in peak areas of very volatile compounds during needle storage at room temperature. This variation may results from a loss of water vapour either retained from the sorbent material and/or condensed on triple-bed needle walls. After normalization, the inter- and intra-day precision were halved to 5% and 10% in the case of single-beds, respectively, and to 15% and 20% with three-beds. The addition of an internal standard to the sorbent helps to keep the overall analytical procedure under control and improves the reliability of needle trap micro-extraction for the analysis of volatile organic compounds at ultra-trace levels., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Precision medicine has spurred new innovations in molecular pathology leading to recent advances in the analysis of exhaled breath as a non-invasive diagnostic tool. Volatile organic compounds (VOCs) detected in exhaled breath have the potential to reveal a wealth of chemical and metabolomic information. This study describes the development of a method for the analysis of breath, based on automated thermal desorption (TD) combined with flow modulated comprehensive two-dimensional gas chromatography (GC×GC) with dual flame ionisation and quadrupole mass spectrometric detection (FID and qMS). The constrained optimisation and analytical protocol was designed to meet the practical demands of a large-scale multi-site clinical study, while maintaining analytical rigour to produce high fidelity data. The results demonstrate a comprehensive method optimisation for the collection and analysis of breath VOCs by GC×GC, integral to the standardisation and integration of breath analysis within large clinical studies., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Lung cancer is the deadliest cancer in developed countries. To reduce its mortality rate, it is important to enhance our capability to detect it at earlier stages by developing early diagnostic methods. In that context, the analysis of exhaled breath is an interesting approach because of the simplicity of the medical act and its non-invasiveness. Thermal desorption comprehensive two-dimensional gas chromatography time of flight mass spectrometry (TD-GC × GC-TOFMS) has been used to characterize and compare the volatile content of human breath of lung cancer patients and healthy volunteers. On the sampling side, the contaminations induced by the bags membrane and further environmental migration of VOCs during and after the sampling have also been investigated. Over a realistic period of 6 h, the concentration of contaminants inside the bag can increase from 2 to 3 folds based on simulated breath samples. On the data processing side, Fisher ratio (FR) and random forest (RF) approaches were applied and compared in regards to their ability to reduce the data dimensionality and to extract the significant information. Both approaches allow to efficiently smooth the background signal and extract significant features (27 for FR and 17 for RF). Principal component analysis (PCA) was used to evaluate the clustering capacity of the different models. For both approaches, a separation along PC-1 was obtained with a variance score around 35%. The combined model provides a partial separation with a PC-1 score of 52%. This proof-of-concept study further confirms the potential of breath analysis for cancer detection but also underlines the importance of quality control over the full analytical procedure, including the processing of the data., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A historic soil contamination of chlorinated hydrocarbons from a former dry cleaning shop caused intrusion of vapors into a building currently used as bookshop. The aim of this study was to determine the indoor air quality and the uptake of soil contaminants and their degradation products. Samples of indoor air were collected over one week in the warm and one week in the cold season. Pre-shift and post-shift samples of end-exhaled air were collected from two employees. Chlorinated hydrocarbons were analyzed in indoor air and exhaled air samples using thermal desorption gas chromatography mass spectrometry (TD-GC-MS). Tetrachloroethylene (PER), and its degradation products trichloroethylene (TRI), 1,1-dichloroethylene (1,1-DCE), 1,2-cis-dichloroethylene (1,2-cis-DCE), 1,2-trans-dichloroethylene (1,2-trans-DCE), methylene chloride (MC) and vinyl chloride (VC) were determined in ambient air. PER was the prime contaminant with a week average (±sd) of 805.2 ± 598.6 μg/m 3 in June 2016 and 1031 ± 499.3 μg/m 3 in December 2017. MC, 1,2-cis-DCE and TRI were detected at concentrations below 2.3 μg/m 3 . 1,1-DCE and VC were not detected. In exhaled air PER, 1,1-DCE, and MC were detected in both June and December, whereas TRI, 1,2-cis-DCE and 1,2-trans-DCE were only detected on one or two days in the cold season. VC was not detected in exhaled air. For PER, the mean concentrations (±sd) in end-exhaled air increased from a five days (Mon-Fri) average pre-shift value of 22.2 ± 8.0 to a post-shift value of 52.6 ± 15.5 ng/L in the male shop owner (p < 0.01) and in the female cashier these values were 26.0 ± 3.6 and 63.6 ± 12.7 ng/L, respectively (p < 0.01). Intrusion of chlorinated soil contaminants resulted in contamination of indoor air above the current accepted indoor air level for PER of 250 μg/m 3 . For PER in end-exhaled air an accumulation over the workweek was not observed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The analysis of trace carbonyls including aldehydes and ketones is important for monitoring environmental air quality, determining toxicity of aerosol of electronic cigarette, and detecting diseases by breath analysis. This work reports investigation of a single microreactor chip with HClO 4 -acidified DNPH coating for capture and analysis of carbonyls in air and exhaled breath. Three aldehydes and three ketones were spiked into one liter synthetic air in Tedlar bags serving as gaseous carbonyl standard for characterization of capture efficiency (CE). The HClO 4 -acidified DNPH showed higher CE of carbonyls than conventionally-used acid including H 3 PO 4 and H 2 SO 4 acidified DNPH under the microreactor conditions. The microreactor conditions including HClO 4 to DNPH molar ratio, DNPH to carbonyls molar ratio, and gaseous sample flow rate through the microreactor were studied in detail and thereby optimized. Under the optimized conditions, 100% of CEs for aldehydes and above 80% for ketones were obtained. The microreactor chips were applied to determine acetone concentration in exhaled breath., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Interest in exhaled breath has grown considerably in recent years, as breath biosampling has shown promise for non-invasive disease diagnosis, therapeutic drug monitoring, and environmental exposure. Real time breath analysis can be accomplished via direct online mass spectrometry (MS)-based methods, which can provide more accurate and detailed data and an enhanced understanding of the temporal evolution of exhaled VOCs in the breath; however, the complicated chemical composition and large raw datasets involved in breath analysis have hindered the discovery of sources contributing to the exhaled VOCs. The positive matrix factorization (PMF) receptor model has been widely used for source apportionment in atmospheric studies. Since the exhaled VOCs contain compounds from various sources, such as alveolar air, mouth air and respiratory dead-space air, PMF may be also helpful for source apportionment of exhaled VOCs in the breath. Thus, this study explores the application of PMF in the pretreatment of direct breath measurement data. The results indicate that (i) endogenous compounds and background contaminants sources can be readily distinguished by PMF in data obtained from replicate measurements of human exhaled breath at single time points (~30 s/measurement), which may benefit both exhalome investigations and the identification of exposure biomarkers; (ii) sources resolved from online measurement data collected over longer periods (1.5 h) can be used to isolate the evolution of exhaled VOCs and investigate processes such as the pharmacokinetics of ketamine and its major metabolites. Therefore, PMF has shown promise for both data processing and subsequent data mining for the ambient MS-based breath analysis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A novel non-silicon-based micro-preconcentration device, as a pretreatment component in a portable gas chromatography system, was developed for the preconcentration one of the trace volatile organic compounds (VOCs) in the exhaled gases, which is one typical biomarker for the chronic liver disease (CLD). The device was designed as an array of manifold-shaped rectangular metal micro-channels with flat dimensions of 16 mm × 12.6 mm and the internal empty volume is 14.4 μL on the copper substrate. Instead of the non-silicon fabrication process, the traditional laser etching technology (LET) was optimized to etch micro-channels, and vacuum diffusion welding (VDW) was applied to form internal channels. The fabricated chip was filled with Carbopack X adsorbent. In the testing, the metal gas preconcentrator (MGP) was installed in a commercial GC (gas chromatography) and nitrogen was used as carrier gas and desorbed gas. With the MPG, up to 352 of concentration factor can be achieved for 10 ppb isoprene. The developed MGP, which has advantages of high strength, low cost, good thermal conductivities, can potentially be used for non-invasive screening of advanced liver fibrosis by monitoring isoprene concentrations in exhaled breath., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Tuberculosis (TB) remains a global public health malady that claims almost 1.8 million lives annually. Diagnosis of TB represents perhaps one of the most challenging aspects of tuberculosis control. Gold standards for diagnosis of active TB (culture and nucleic acid amplification) are sputum-dependent, however, in up to a third of TB cases, an adequate biological sputum sample is not readily available. The analysis of exhaled breath, as an alternative to sputum-dependent tests, has the potential to provide a simple, fast, and non-invasive, and ready-available diagnostic service that could positively change TB detection. Human breath has been evaluated in the setting of active tuberculosis using thermal desorption-comprehensive two-dimensional gas chromatography-time of flight mass spectrometry methodology. From the entire spectrum of volatile metabolites in breath, three random forest machine learning models were applied leading to the generation of a panel of 46 breath features. The twenty-two common features within each random forest model used were selected as a set that could distinguish subjects with confirmed pulmonary M. tuberculosis infection and people with other pathologies than TB., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Chromatographic studies on breath composition are aimed at finding volatile markers useful for medical diagnostics or in screening investigations. Studies leading to the development of screening breath tests are especially important for the diagnostics of chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). The aim of the presented study was to confirm diagnostic usefulness of chosen volatile compounds detected in breath, which are suggested as potential biomarkers of renal dysfunction and diabetes. Breath analysis were carried out in three groups: 10 healthy volunteers, 10 patients with CKD and 10 patients with CKD and T2DM. All exhaled air samples were analyzed using gas chromatograph (Agilent 6890GC) coupled with mass spectrometer (5975MSD). Thermal desorption was applied as the enrichment method. TMA was detected only in CKD patients. Higher breath concentrations of methanethiol (MeSH) were observed in CKD patients with coexisting diabetes than in patients with renal dysfunction only or in the healthy group. There was a tendency of increasing MeSH concentration in breath with increasing total glutathione in plasma (r=0.53, p=0.0026). Also, a trend of increasing dimethylsulfide (DMS) levels detected in breath was noticed with an increase of hydrogen sulfide concentration in plasma (r=0.74; p=0.00001) as well as with aspartate aminotransferase (AST), (r=0.61; p=0.001). The presented results suggest the possibility of applying TMA, MeSH, and DMS detection in breath as diagnostic methods., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This review provides an overview of volatile organic compounds (VOCs) which are considered lung cancer biomarkers for diagnostic breath analysis. It includes results of scientific publications from 1985 to 2015. The identified VOCs are listed and ranked according to their occurrence of nomination. The applied detection and sampling methods are specified but not evaluated. Possible reasons for the different results of the studies are stated. Among the most frequently emerging biomarkers are 2-butanone and 1-propanol as well as isoprene, ethylbenzene, styrene and hexanal. The outcome of this review may be helpful for the development of a lung cancer screening device., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: It is a legal requirement to supply a breath analysis sample when requested by Police at roadside checkpoints. The current device requires a 1L sample at 8L·min(-1). Court disputes commonly attribute respiratory disease for failure to produce a sample., Objective: To determine whether respiratory disease aetiology and/or severity precludes an adequate breath sample using a modern evidential breath analyser., Methods: Subjects performed breath analysis following standard Police procedure. Three efforts within 15min were allowed and any reasons for failure recorded., Results: 24 subjects with interstitial lung disease (ILD) and 26 subjects with chronic obstructive pulmonary disease (COPD) were studied and met minimum respiratory function criteria as per device specifications. 18 ILD subjects (75%) and 24 COPD subjects (92%) were able to provide a sample. All subjects with a vital capacity below 1.5L were unable to provide a sample., Discussion: In the balance of probabilities most patients with lung disease are able to supply an evidential breath sample. The exception is a very severe disease, particularly in volume limited patients., (Copyright © 2016 The Chartered Society of Forensic Sciences. Published by Elsevier Ireland Ltd. All rights reserved.)

At present, there is a growing concern about human quality of life. In particular, there is an awareness of the impact of volatile organic compounds (VOCs) on the environment and human health, so the monitoring of human exposure to VOCs is an increasingly urgent need. Biomonitoring is theoretically more accurate compared with traditional ambient air monitoring, and it plays an essential role in human environmental exposure assessment. Breath analysis is a biomonitoring method with many advantages, which is applicable to assessments of human exposure to a large number of VOCs. Techniques are being developed to improve the sensitivity and precision of breath analysis based on in-direct and direct measurements which will be reviewed in this paper. This paper briefly reviews the frequently used methods in both of these categories, specifically highlighting some promising new techniques. Furthermore, this review also provides theoretical background knowledge about the use of breath analysis as a biomonitoring tool for human exposure assessment. A review of the application of breath analysis to human exposure monitoring during last two decades is also provided according to occupational/non-occupational exposure. Obstacles and potential challenges in this field are also summarized. Based on the gradual improvements in the theoretical basis and technology reviewed in this paper, breath analysis is an enormous potential approach for the monitoring of human exposure to VOCs., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Breast cancer (BC) remains the most commonly diagnosed malignancy in women. We investigated 4 straight aldehydes in the exhaled breath as potential early BC diagnostic biomarkers., Methods: End-tailed breath were collected by Bio-VOC® sampler and assayed by gas chromatography-mass spectrometry. Kruskal-Wallis one-way analysis of variance test and binary logistic regression were used for data analysis. The diagnostic accuracies were evaluated by receiver operating characteristic curves. A predictive model/equation was generated using the 4 biomarkers and validated by leave-one-out cross-validation., Results: All four potential biomarkers demonstrated significant differences in concentrations between BC and healthy controls (HC) (p<0.05). The areas under the curves (AUCs) in HC vs BCI-II model using hexanal, heptanal, octanal, and nonanal were 0.816, 0.809, 0.731, and 0.830, respectively. The AUC for their combined use was 0.934 (sensitivity 91.7%, specificity 95.8%) in the early diagnosis of BC. The predictive model/equation exhibited good sensitivity (72.7%) and specificity (91.7%) in distinguishing between HC and BC (cross-validation: sensitivity 68.2% and specificity 91.7%)., Conclusions: The diagnostic values of 4 exhaled straight aldehydes as early diagnostic biomarkers for BC were successfully verified and the diagnostic accuracy improved in their combined use., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Coeliac disease (CD) is a common chronic inflammatory disorder of the small bowel induced in genetically susceptible people by the exposure to gliadin gluten. Even though several tests are available to assist the diagnosis, CD remains a biopsy-defined disorder, thus any non-invasive or less invasive diagnostic tool may be beneficial. The analysis of volatile metabolites in exhaled breath, given its non-invasive nature, is particularly promising as a screening tool of disease in symptomatic or non-symptomatic patients. In this preliminary study the proton transfer reaction time of flight mass spectrometry coupled to a buffered end-tidal on-line sampler to investigate metabolites in the exhaled breath of patients affected by coeliac disease under a gluten free diet was applied. Both H3O(+) or NO(+) were used as precursor ions. In our investigation no differences were found in the exhaled breath of CD patients compared to healthy controls. In this study, 33 subjects were enrolled: 16 patients with CD, all adhering a gluten free diet, and 17 healthy controls. CD patients did not show any symptom of the disease at the time of breath analysis; thus the absence of discrimination from healthy controls was not surprising., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Analyses of exhaled air by means of electronic noses offer a large diagnostic potential. Such analyses are non-invasive; samples can also be easily obtained from severely ill patients and repeated within short intervals. Lung cancer is the most deadly malignant tumor worldwide, and monitoring of lung cancer progression is of great importance and may help to decide best therapy. In this report, twenty-two patients with diagnosed lung cancer and ten healthy volunteers were studied using breath samples collected several times at certain intervals and analysed by an electronic nose. The samples were divided into three sub-groups; group d for survivor less than one year, group s for survivor more than a year and group h for the healthy volunteers. Prediction models based on partial least square and artificial neural nets could not classify the collected groups d, s and h, but separated well group d from group h. Using artificial neural net, group d could be separated from group s. Excellent predictions and stable models of survival day for group d were obtained, both based on partial least square and artificial neural nets, with correlation coefficients 0.981 and 0.985, respectively. Finally, the importance of consecutive measurements was shown., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The analysis of volatile compounds is an efficient method to appraise information about the chemical composition of liquids and solids. This principle is applied to several practical applications, such as food analysis where many important features (e.g. freshness) can be directly inferred from the analysis of volatile compounds. The same approach can also be applied to a human body where the volatile compounds, collected from the skin, the breath or in the headspace of fluids, might contain information that could be used to diagnose several kinds of diseases. In particular, breath is widely studied and many diseases can be potentially detected from breath analysis. The most fascinating property of breath analysis is the non-invasiveness of the sample collection. Solid-state sensors are considered the natural complement to breath analysis, matching the non-invasiveness with typical sensor features such as low-cost, easiness of use, portability, and the integration with the information networks. Sensors based breath analysis is then expected to dramatically extend the diagnostic capabilities enabling the screening of large populations for the early diagnosis of pathologies. In the last years there has been an increased attention to the development of sensors specifically aimed to this purpose. These investigations involve both specific sensors designed to detect individual compounds and non-specific sensors, operated in array configurations, aimed at clustering subjects according to their health conditions. In this paper, the recent significant applications of these sensors to breath analysis are reviewed and discussed., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Isoprene in human breath is said to be related to cholesterol metabolism, and the possibility of the correlations with some clinical parameters has been studied. However, at this stage, no clear benefit of breath isoprene has been reported for clinical diagnosis. In this work, isoprene and acetone concentrations were measured in the breath of healthy and obese subjects using a needle-type extraction device for subsequent analysis in gas chromatography-mass spectrometry (GC-MS) to investigate the possibility of these compounds as an indicator of possible diseases., Methods: After measuring intraday and interday variations of isoprene and acetone concentrations in breath samples of healthy subjects, their concentrations were also determined in 80 healthy and 17 obese subjects. In addition, correlation between these breath concentrations and the blood tests result was studied for these healthy and obese subjects., Results: The results indicated successful determination of breath isoprene and acetone in this work, however, no clear correlation was observed between these measured values and the blood test results., Conclusions: Breath isoprene concentration may not be a useful indicator for obesity or hypercholesterolemia., (Copyright © 2014 Elsevier B.V. All rights reserved.)