Detecting Coronary Artery Disease Using Exhaled Breath Analysis.

INTRODUCTION: Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide, and there is an unmet need for a simple, inexpensive, noninvasive tool aimed at CAD detection. The aim of this pilot study was to evaluate the possible use of breath analysis in detecting the presence of CAD. MATERIALS AND METHODS: In a prospective study, breath from patients with no history of CAD who presented with acute chest pain to the emergency room was sampled using a designated portable electronic nose (eNose) system. First, breath samples from 60 patients were analyzed and categorized as obstructive, nonobstructive, and no-CAD according to the actual presence and extent of CAD as was demonstrated on cardiac imaging (either computerized tomography angiography or coronary angiography). Classification models were built according to the results, and their diagnostic performance was then examined in a blinded manner on a new set of 25 patients. The data were compared with the actual results of coronary arteries evaluation. Sensitivity, specificity, and accuracy were calculated for each model. RESULTS: Obstructive CAD was correctly distinguished from nonobstructive and no-CAD with 89% sensitivity, 31% specificity, 83% negative predictive value (NPV), 42% positive predictive value (PPV), and 52% accuracy. In another model, any extent of CAD was successfully distinguished from no-CAD with 69% sensitivity, 67% specificity, 54% NPV, 79% PPV, and 68% accuracy. CONCLUSION: This proof-of-concept study shows that breath analysis has the potential to be used as a novel rapid, noninvasive diagnostic tool to help identify presence of CAD in patients with acute chest pain.

Sensing gastric cancer via point-of-care sensor breath analyzer.

BACKGROUND: Detection of disease by means of volatile organic compounds from breath samples using sensors is an attractive approach to fast, noninvasive and inexpensive diagnostics. However, these techniques are still limited to applications within the laboratory settings. Here, we report on the development and use of a fast, portable, and IoT-connected point-of-care device (so-called, SniffPhone) to detect and classify gastric cancer to potentially provide new qualitative solutions for cancer screening. METHODS: A validation study of patients with gastric cancer, patients with high-risk precancerous gastric lesions, and controls was conducted with 2 SniffPhone devices. Linear discriminant analysis (LDA) was used as a classifying model of the sensing signals obatined from the examined groups. For the testing step, an additional device was added. The study group included 274 patients: 94 with gastric cancer, 67 who were in the high-risk group, and 113 controls. RESULTS: The results of the test set showed a clear discrimination between patients with gastric cancer and controls using the 2-device LDA model (area under the curve, 93.8%; sensitivity, 100%; specificity, 87.5%; overall accuracy, 91.1%), and acceptable results were also achieved for patients with high-risk lesions (the corresponding values for dysplasia were 84.9%, 45.2%, 87.5%, and 65.9%, respectively). The test-phase analysis showed lower accuracies, though still clinically useful. CONCLUSION: Our results demonstrate that a portable breath sensor device could be useful in point-of-care settings. It shows a promise for detection of gastric cancer as well as for other types of disease. LAY SUMMARY: A portable sensor-based breath analyzer for detection of gastric cancer can be used in point-of-care settings. The results are transferrable between devices via advanced IoT technology. Both the hardware and software of the reported breath analyzer could be easily modified to enable detection and monitirng of other disease states.

Disease Detection with Molecular Biomarkers: From Chemistry of Body Fluids to Nature-Inspired Chemical Sensors.

This article aims to review nature-inspired chemical sensors for enabling fast, relatively inexpensive, and minimally (or non-) invasive diagnostics and follow-up of the health conditions. It can be achieved via monitoring of biomarkers and volatile biomarkers, that are excreted from one or combination of body fluids (breath, sweat, saliva, urine, seminal fluid, nipple aspirate fluid, tears, stool, blood, interstitial fluid, and cerebrospinal fluid). The first part of the review gives an updated compilation of the biomarkers linked with specific sickness and/or sampling origin. The other part of the review provides a didactic examination of the concepts and approaches related to the emerging chemistries, sensing materials, and transduction techniques used for biomarker-based medical evaluations. The strengths and pitfalls of each approach are discussed and criticized. Future perspective with relation to the information and communication era is presented and discussed.

Synergy between nanomaterials and volatile organic compounds for non-invasive medical evaluation.

This article is an overview of the present and ongoing developments in the field of nanomaterial-based sensors for enabling fast, relatively inexpensive and minimally (or non-) invasive diagnostics of health conditions with follow-up by detecting volatile organic compounds (VOCs) excreted from one or combination of human body fluids and tissues (e.g., blood, urine, breath, skin). Part of the review provides a didactic examination of the concepts and approaches related to emerging sensing materials and transduction techniques linked with the VOC-based non-invasive medical evaluations. We also present and discuss diverse characteristics of these innovative sensors, such as their mode of operation, sensitivity, selectivity and response time, as well as the major approaches proposed for enhancing their ability as hybrid sensors to afford multidimensional sensing and information-based sensing. The other parts of the review give an updated compilation of the past and currently available VOC-based sensors for disease diagnostics. This compilation summarizes all VOCs identified in relation to sickness and sampling origin that links these data with advanced nanomaterial-based sensing technologies. Both strength and pitfalls are discussed and criticized, particularly from the perspective of the information and communication era. Further ideas regarding improvement of sensors, sensor arrays, sensing devices and the proposed workflow are also included.

Assessment, origin, and implementation of breath volatile cancer markers.

A new non-invasive and potentially inexpensive frontier in the diagnosis of cancer relies on the detection of volatile organic compounds (VOCs) in exhaled breath samples. Breath can be sampled and analyzed in real-time, leading to fascinating and cost-effective clinical diagnostic procedures. Nevertheless, breath analysis is a very young field of research and faces challenges, mainly because the biochemical mechanisms behind the cancer-related VOCs are largely unknown. In this review, we present a list of 115 validated cancer-related VOCs published in the literature during the past decade, and classify them with respect to their "fat-to-blood" and "blood-to-air" partition coefficients. These partition coefficients provide an estimation of the relative concentrations of VOCs in alveolar breath, in blood and in the fat compartments of the human body. Additionally, we try to clarify controversial issues concerning possible experimental malpractice in the field, and propose ways to translate the basic science results as well as the mechanistic understanding to tools (sensors) that could serve as point-of-care diagnostics of cancer. We end this review with a conclusion and a future perspective.

Hybrid volatolomics and disease detection.

This Review presents a concise, but not exhaustive, didactic overview of some of the main concepts and approaches related to "volatolomics"-an emerging frontier for fast, risk-free, and potentially inexpensive diagnostics. It attempts to review the source and characteristics of volatolomics through the so-called volatile organic compounds (VOCs) emanating from cells and their microenvironment. It also reviews the existence of VOCs in several bodily fluids, including the cellular environment, blood, breath, skin, feces, urine, and saliva. Finally, the usefulness of volatolomics for diagnosis from a single bodily fluid, as well as ways to improve these diagnostic aspects by "hybrid" approaches that combine VOC profiles collected from two or more bodily fluids, will be discussed. The perspectives of this approach in developing the field of diagnostics to a new level are highlighted.

Non-contact immunological signaling for highly-efficient regulation of the transcriptional map of human monocytes.

The different immune system cells communicate and coordinate a response using a complex and evolved language of cytokines and chemokines. These cellular interactions carry out multiple functions in distinct cell types with numerous developmental outcomes. Despite the plethora of different cytokines and their cognate receptors, there is a restricted number of signal transducers and activators to control immune responses. Herein, we report on a new class of immunomodulatory signaling molecules based on volatile molecules (VMs, namely, volatile organic compounds [VOCs]), by which they can affect and/or control immune cell behavior and transcriptomic profile without any physical contact with other cells. The study demonstrates the role of VMs by analyzing non-contact cell communication between normal and cancerous lung cells and U937 monocytes, which are key players in the tumor microenvironment. Integrated transcriptome and proteome analyses showed the suggested regulatory role of VMs released from normal and cancer cells on neighboring monocytes in several molecular pathways, including PI3K/AKT, PPAR, and HIF-1. Presented data provide an initial platform for a new class of immunomodulatory molecules that can potentially mirror the genomic and proteomic profile of cells, thereby paving the way toward non-invasive immunomonitoring.

Real-time prognostic biomarkers for predicting in-hospital mortality and cardiac complications in COVID-19 patients.

Hospitalized patients with Coronavirus disease 2019 (COVID-19) are highly susceptible to in-hospital mortality and cardiac complications such as atrial arrhythmias (AA). However, the utilization of biomarkers such as potassium, B-type natriuretic peptide, albumin, and others for diagnosis or the prediction of in-hospital mortality and cardiac complications has not been well established. The study aims to investigate whether biomarkers can be utilized to predict mortality and cardiac complications among hospitalized COVID-19 patients. Data were collected from 6,927 hospitalized COVID-19 patients from March 1, 2020, to March 31, 2021 at one quaternary (Henry Ford Health) and five community hospital registries (Trinity Health Systems). A multivariable logistic regression prediction model was derived using a random sample of 70% for derivation and 30% for validation. Serum values, demographic variables, and comorbidities were used as input predictors. The primary outcome was in-hospital mortality, and the secondary outcome was onset of AA. The associations between predictor variables and outcomes are presented as odds ratio (OR) with 95% confidence intervals (CIs). Discrimination was assessed using area under ROC curve (AUC). Calibration was assessed using Brier score. The model predicted in-hospital mortality with an AUC of 90% [95% CI: 88%, 92%]. In addition, potassium showed promise as an independent prognostic biomarker that predicted both in-hospital mortality, with an AUC of 71.51% [95% Cl: 69.51%, 73.50%], and AA with AUC of 63.6% [95% Cl: 58.86%, 68.34%]. Within the test cohort, an increase of 1 mEq/L potassium was associated with an in-hospital mortality risk of 1.40 [95% CI: 1.14, 1.73] and a risk of new onset of AA of 1.55 [95% CI: 1.25, 1.93]. This cross-sectional study suggests that biomarkers can be used as prognostic variables for in-hospital mortality and onset of AA among hospitalized COVID-19 patients.

Biodegradable, Biocompatible, and Implantable Multifunctional Sensing Platform for Cardiac Monitoring.

Cardiac monitoring after heart surgeries is crucial for health maintenance and detecting postoperative complications early. However, current methods like rigid implants have limitations, as they require performing second complex surgeries for removal, increasing infection and inflammation risks, thus prompting research for improved sensing monitoring technologies. Herein, we introduce a nanosensor platform that is biodegradable, biocompatible, and integrated with multifunctions, suitable for use as implants for cardiac monitoring. The device has two electrochemical biosensors for sensing lactic acid and pH as well as a pressure sensor and a chemiresistor array for detecting volatile organic compounds. Its biocompatibility with myocytes has been tested in vitro, and its biodegradability and sensing function have been proven with ex vivo experiments using a three-dimensional (3D)-printed heart model and 3D-printed cardiac tissue patches. Moreover, an artificial intelligence-based predictive model was designed to fuse sensor data for more precise health assessment, making it a suitable candidate for clinical use. This sensing platform promises impactful applications in the realm of cardiac patient care, laying the foundation for advanced life-saving developments.

A nanomaterial-based breath test for short-term follow-up after lung tumor resection.

In this case study, we demonstrate the feasibility of nanomaterial-based sensors for identifying the breath-print of early-stage lung cancer (LC) and for short-term follow-up after LC-resection. Breath samples were collected from a small patient cohort prior to and after lung resection. Gas-chromatography/mass-spectrometry showed that five volatile organic compounds were significantly reduced after LC surgery. A nanomaterial-based sensor-array distinguished between pre-surgery and post-surgery LC states, as well as between pre-surgery LC and benign states. In contrast, the same sensor-array could neither distinguish between pre-surgery and post-surgery benign states, nor between LC and benign states after surgery. This indicates that the observed pattern is associated with the presence of malignant lung tumors. The proof-of-concept presented here has initiated a large-scale clinical study for post-surgery follow-up of LC patients. FROM THE CLINICAL EDITOR: Monitoring for tumor recurrence remains very challenging due to post-surgical and radiation therapy induced changes in target organs, which often renders standard radiological identification of recurrent malignancies inaccurate. In this paper a novel nanotechnology-based sensor array is used for identification of volatile organic compounds in exhaled air that enable identification of benign vs. malignant states.

Volatile fingerprints of cancer specific genetic mutations.

We report on a new concept for profiling genetic mutations of (lung) cancer cells, based on the detection of patterns of volatile organic compounds (VOCs) emitted from cell membranes, using an array of nanomaterial-based sensors. In this in-vitro pilot study we have derived a volatile fingerprint assay for representative genetic mutations in cancer cells that are known to be associated with targeted cancer therapy. Five VOCs were associated with the studied oncogenes, using complementary chemical analysis, and were discussed in terms of possible metabolic pathways. The reported approach could lead to the development of novel methods for guiding treatments, so that patients could benefit from safer, more timely and effective interventions that improve survival and quality of life while avoiding unnecessary invasive procedures. Studying clinical samples (tissue/blood/breath) will be required as next step in order to determine whether this cell-line study can be translated into a clinically useful tool. FROM THE CLINICAL EDITOR: In this novel study, a new concept for profiling genetic mutations of (lung) cancer cells is described, based on the detection of patterns of volatile organic compounds emitted from cell membranes, using an array of nano-gold based sensors.

Noninvasive Detection of Stress by Biochemical Profiles from the Skin.

Stress is a leading cause of several disease types, yet it is underdiagnosed as current diagnostic methods are mainly based on self-reporting and interviews that are highly subjective, inaccurate, and unsuitable for monitoring. Although some physiological measurements exist (e.g., heart rate variability and cortisol), there are no reliable biological tests that quantify the amount of stress and monitor it in real time. In this article, we report a novel way to measure stress quickly, noninvasively, and accurately. The overall detection approach is based on measuring volatile organic compounds (VOCs) emitted from the skin in response to stress. Sprague Dawley male rats (n = 16) were exposed to underwater trauma. Sixteen naive rats served as a control group (n = 16). VOCs were measured before, during, and after induction of the traumatic event, by gas chromatography linked with mass spectrometry determination and quantification, and an artificially intelligent nanoarray for easy, inexpensive, and portable sensing of the VOCs. An elevated plus maze during and after the induction of stress was used to evaluate the stress response of the rats, and machine learning was used for the development and validation of a computational stress model at each time point. A logistic model classifier with stepwise selection yielded a 66-88% accuracy in detecting stress with a single VOC (2-hydroxy-2-methyl-propanoic acid), and an SVM (support vector machine) model showed a 66-72% accuracy in detecting stress with the artificially intelligent nanoarray. The current study highlights the potential of VOCs as a noninvasive, automatic, and real-time stress predictor for mental health.

Continuous Monitoring of Psychosocial Stress by Non-Invasive Volatilomics.

Stress is becoming increasingly commonplace in modern times, making it important to have accurate and effective detection methods. Currently, detection methods such as self-evaluation and clinical questionnaires are subjective and unsuitable for long-term monitoring. There have been significant studies into biomarkers such as HRV, cortisol, electrocardiography, and blood biomarkers, but the use of multiple electrodes for electrocardiography or blood tests is impractical for real-time stress monitoring. To this end, there is a need for non-invasive sensors to monitor stress in real time. This study looks at the possibility of using breath and skin VOC fingerprinting as stress biomarkers. The Trier social stress test (TSST) was used to induce acute stress and HRV, cortisol, and anxiety levels were measured before, during, and after the test. GC-MS and sensor array were used to collect and measure VOCs. A prediction model found eight different stress-related VOCs with an accuracy of up to 78%, and a molecularly capped gold nanoparticle-based sensor revealed a significant difference in breath VOC fingerprints between the two groups. These stress-related VOCs either changed or returned to baseline after the stress induction, suggesting different metabolic pathways at different times. A correlation analysis revealed an association between VOCs and cortisol levels and a weak correlation with either HRV or anxiety levels, suggesting that VOCs may include complementary information in stress detection. This study shows the potential of VOCs as stress biomarkers, paving the way into developing a real-time, objective, non-invasive stress detection tool for well-being and early detection of stress-related diseases.

Liquid Biopsy-Based Volatile Organic Compounds from Blood and Urine and Their Combined Data Sets for Highly Accurate Detection of Cancer.

Liquid biopsy is seen as a prospective tool for cancer screening and tracking. However, the difficulty lies in effectively sieving, isolating, and overseeing cancer biomarkers from the backdrop of multiple disrupting cells and substances. The current study reports on the ability to perform liquid biopsy without the need to physically filter and/or isolate the cancer cells per se. This has been achieved through the detection and classification of volatile organic compounds (VOCs) emitted from the cancer cells found in the headspace of blood or urine samples or a combined data set of both. Spectrometric analysis shows that blood and urine contain complementary or overlapping VOC information on kidney cancer, gastric cancer, lung cancer, and fibrogastroscopy subjects. Based on this information, a nanomaterial-based chemical sensor array in conjugation with machine learning as well as data fusion of the signals achieved was carried out on various body fluids to assess the VOC profiles of cancer. The detection of VOC patterns by either Gas Chromatography-Mass Spectrometry (GC-MS) analysis or our sensor array achieved >90% accuracy, >80% sensitivity, and >80% specificity in different binary classification tasks. The hybrid approach, namely, analyzing the VOC datasets of blood and urine together, contributes an additional discrimination ability to the improvement (>3%) of the model's accuracy. The contribution of the hybrid approach for an additional discrimination ability to the improvement of the model's accuracy is examined and reported.

Breath Volatile Organic Compounds in Surveillance of Gastric Cancer Patients following Radical Surgical Management.

As of today, there is a lack of a perfect non-invasive test for the surveillance of patients for potential relapse following curative treatment. Breath volatile organic compounds (VOCs) have been demonstrated to be an accurate diagnostic tool for gastric cancer (GC) detection; here, we aimed to prove the yield of the markers in surveillance, i.e., following curative surgical management. Patients were sampled in regular intervals before and within 3 years following curative surgery for GC; gas chromatography-mass spectrometry (GC-MS) and nanosensor technologies were used for the VOC assessment. GC-MS measurements revealed a single VOC (14b-Pregnane) that significantly decreased at 12 months, and three VOCs (Isochiapin B, Dotriacontane, Threitol, 2-O-octyl-) that decreased at 18 months following surgery. The nanomaterial-based sensors S9 and S14 revealed changes in the breath VOC content 9 months after surgery. Our study results confirm the cancer origin of the particular VOCs, as well as suggest the value of breath VOC testing for cancer patient surveillance, either during the treatment phase or thereafter, for potential relapse.

Biodiagnostics in an era of global pandemics-From biosensing materials to data management.

The novel corona virus SARS-CoV-2 (COVID-19) has exposed the world to challenges never before seen in fast diagnostics, monitoring, and prevention of the outbreak. As a result, different approaches for fast diagnostic and screening are made and yet to find the ideal way. The current mini-review provides and examines evidence-based innovative and rapid chemical sensing and related biodiagnostic solutions to deal with infectious disease and related pandemic emergencies, which could offer the best possible care for the general population and improve the approachability of the pandemic information, insights, and surrounding contexts. The review discusses how integration of sensing devices with big data analysis, artificial Intelligence or machine learning, and clinical decision support system, could improve the accuracy of the recorded patterns of the disease conditions within an ocean of information. At the end, the mini-review provides a prospective on the requirements to improve our coping of the pandemic-related biodiagnostics as well as future opportunities.

Artificially Intelligent Nanoarray Detects Various Cancers by Liquid Biopsy of Volatile Markers.

Cancer is usually not symptomatic in its early stages. However, early detection can vastly improve prognosis. Liquid biopsy holds great promise for early detection, although it still suffers from many disadvantages, mainly searching for specific cancer biomarkers. Here, a new approach for liquid biopsies is proposed, based on volatile organic compound (VOC) patterns in the blood headspace. An artificial intelligence nanoarray based on a varied set of chemi-sensitive nano-based structured films is developed and used to detect and stage cancer. As a proof-of-concept, three cancer models are tested showing high incidence and mortality rates in the population: breast cancer, ovarian cancer, and pancreatic cancer. The nanoarray has >84% accuracy, >81% sensitivity, and >80% specificity for early detection and >97% accuracy, 100% sensitivity, and >88% specificity for metastasis detection. Complementary mass spectrometry analysis validates these results. The ability to analyze such a complex biological fluid as blood, while considering data of many VOCs at a time using the artificially intelligent nanoarray, increases the sensitivity of predictive models and leads to a potential efficient early diagnosis and disease-monitoring tool for cancer.

The Utility of Breath Analysis in the Diagnosis and Staging of Parkinson's Disease.

BACKGROUND: The analysis of volatile organic compounds (VOCs) collected in breath samples has the potential to be a rapid, non-invasive test to aid in the clinical diagnosis and tracking of chronic conditions such as Parkinson's disease (PD). OBJECTIVE: To assess the feasibility and utility of breath sample analysis done, both at point of collection in clinic and when sent away to be analyzed remotely, to diagnose, stratify and monitor disease course in a moderately large cohort of patients with PD. METHODS: Breath samples were collected from 177 people with PD and 37 healthy matched control individuals followed over time. Standard clinical data (MDS-UPDRS & cognitive assessments) from the PD patients were collected at the same time as the breath sample was taken, these measures were then correlated with the breath test analysis of exhaled VOCs. RESULTS: The breath test was able to distinguish patients with PD from healthy control participants and correlated with disease stage. The off-line system (remote analysis) gave good results with overall classification accuracies across a range of clinical measures of between 73.6% to 95.6%. The on-line (in clinic) system showed comparable results but with lower levels of correlation, varying between 33.5% to 82.4%. Chemical analysis identified 29 potential molecules that were different and which may relate to pathogenic pathways in PD. CONCLUSION: Breath analysis shows potential for PD diagnostics and monitoring. Both off-line and on-line sensor systems were easy to do and provided comparable results which will enable this technique to be easily adopted in clinic if larger studies confirm our findings.

Noninvasive Pregestational Genetic Testing of Embryos Using Smart Sensors Array.

Pregestational genetic testing of embryos is the conventional tool in detecting genetic disorders (fetal aneuploidy and monogenic disorders) for in vitro fertilization (IVF) procedures. The accepted clinical practice for genetic testing still depends on biopsy, which has the potential to harm the embryo. Noninvasive genetic prenatal testing has not yet been achieved. In this study, embryos with common genetic disorders created through IVF were tested with an artificially intelligent nanosensor array. Volatile organic compounds emitted by the culture fluid of embryos were analyzed with chemical gas sensors. The obtained results showed significant discrimination between the embryos with different genetic diseases and their wild-types. Embryos were obtained from the same clinical center for avoiding differences based on clinical and demographical characteristics. The achieved discrimination accuracy was 81% for PKD disease, 90% for FRAX disease, 85% for HOCM disease, 90% for BRCA disease, and 100% for HSCR disease. These proof-of-concept findings might launch the development of a noninvasive approach for early assessment of embryos by examining the culture fluid of the embryos, potentially enabling noninvasive diagnosis and screening of genetic diseases for IVF.

A Wearable Microneedle-Based Extended Gate Transistor for Real-Time Detection of Sodium in Interstitial Fluids.

Sodium is a prominent prognostic biomarker for assessing health status, such as dysnatremia. As of now, detection and monitoring of sodium levels in the human body is carried out by means of laborious and bulky laboratory equipmentand/or by offline analysis of various body fluids. Herein, an innovative stretchable, skin-conformal and fast-response microneedle extended-gate FET biosensor is reported for real-time detection of sodium in interstitial fluids for minimally invasive health monitoring along with high sensitivity, low limit of detection, excellent biocompatibility, and on-body mechanical stability. The integration of the reported device with a wireless-data transmitter and the Internet-of-Things cloud for real-time monitoring and long-term analysis is reported and discussed. This platform would eventually help bringing unlimited possibilities for effecient medical care and accurate clinical decision-making.