Non-invasive Disease Diagnosis Research Articles

Medical Diagnosis Using Volatile Organic Compounds Sensors

Volatile organic compounds (VOCs) are important biomarkers in exhaled breath or skin secretion of patients under various medical or pre-medical conditions. As such, VOCs have been explored as alternative biomarkers in the detection of diseases, including asthma, tuberculosis, and lung cancer. In this regard, a rapid, cost-effective, facile, and sample-free strategy is advantageous and critically needed for premedical screening, medical diagnosis, and health monitoring. In this review, we present an overview of the latest progress of using nanomaterial-based chemo-resistive VOC sensors for fast, real-time, and non-invasive diagnosis of diseases via detecting VOCs from exhaled breath and other sources from human body. The origin and emission of VOCs are summarized from human body, and the VOC signatures are discussed as related to specific disease. Targeting specific VOCs, chemoresistive sensors using different nanomaterials are reviewed in terms of their sensing performance metrics including sensitivity, selectivity, response/recovery time, and stability. Various strategies for improving VOC sensor performance are discussed, specifically on the material and signal processing-based approaches.

Challenges in Diagnosis and Prevention of Iatrogenic Endometriosis as a Long-Term Surgical Complication after C-Section.

Endometriosis is a gynecological condition caused by the development of endometrial tissue outside the uterine cavity. Naturally, it commonly occurs at locations such as the ovaries and pelvic peritoneum. However, ectopic endometrial tissue may be discovered outside of the typical sites, suggesting the possibility of iatrogenic seeding after gynecological operations. Based on this hypothesis, we developed a study aiming to establish the root cause of atypical implantation of endometrial foci, as the main end point, and to determine diagnostic features and risk factors for this condition, as a secondary target. The research followed a retrospective design, including a total of 126 patients with endometriosis who met the inclusion criteria. A group of 71 patients with a history of c-section was compared with a control group of patients with endometriosis and no history of c-section. Endometriosis that developed inside or in close proximity to surgical incisions of asymptomatic patients before surgical intervention was defined as iatrogenic endometriosis. Compared with patients who did not have a c-section, the c-section group had significantly more minimally invasive pelvic procedures and multiple adhesions and endometriosis foci at intraoperative look (52.1% vs. 34.5%, respectively 52.1% vs. 29.1%). The most common location for endometriosis lesions in patients with prior c-section was the abdominal wall (42.2% vs. 5.4%), although the size of foci was significantly smaller by size and weight (32.2 mm vs. 34.8 mm, respectively 48.6 g vs. 53.1 g). The abdominal wall endometriosis was significantly associated with minimally invasive pelvic procedures (correlation coefficient = 0.469, p-value = 0.001) and c-section (correlation coefficient = 0.523, p-value = 0.001). A multivariate regression analysis identified prior c-section as an independent risk factor for abdominal wall endometriosis (OR = 1.85, p-value < 0.001). We advocate for strict protocols to be implemented and followed during c-section and minimally invasive procedures involving the pelvic region to ensure minimum spillage of endometrial cells. Further research should be developed to determine the method of abdominal and surgical site irrigation that can significantly reduce the risk of implantation of viable endometrial cells. Understanding all details of iatrogenic endometriosis will lead to the development of non-invasive disease diagnosis and minimally invasive procedures that have the potential to reduce postoperative complications.

Calibration-free mid-infrared exhaled breath sensor based on BF-QEPAS for real-time ammonia measurements at ppb level

Breath analysis, compared with blood analysis, can enable real-time non-invasive diagnostics through quantification of exhaled biomarkers. Here, we demonstrate, for the first time, a calibration-free mid-infrared (MIR) exhaled breath sensor for real-time ammonia measurements at ppb-level, which can be used for the non-invasive diagnosis of liver and kidney diseases. The exhaled breath sensor employs a 10.359-μm MIR quantum cascade laser (QCL) to target a strong NH3 absorption line and adopts the beat-frequency quartz-enhanced photoacoustic technique (BF-QEPAS) to remove the requirements of calibration process and wavelength locking in the conventional QEPAS technique. By studying the adsorption-desorption effect and optimizing the modulation depth and modulation frequency of the sensor system, a detection limit of 9.5 ppb is achieved at an integration time of 3 ms. The ammonia content exhaled by 8 healthy volunteers is recorded and the real-time measurement results are analyzed. Compared with conventional QEPAS sensors, the proposed BF-QEPAS-based sensor offers higher sensitivity, faster response time, as well as no need for calibration and wavelength locking.

Selectivity of volatile organic compounds on the surface of zinc oxide nanosheets for gas sensors.

The detection of volatile organic compounds by gas sensors is of great interest for environmental quality monitoring and the early-stage and noninvasive diagnosis of diseases. Experiments found hexane, toluene, aniline, butanone, acetone, and propanol gases in the exhaled breath of patients suffering from COVID-19, lung cancer, and diabetes. However, no studies are available to systematically elucidate the selectivity of these gases on nanosheets of zinc oxide for chemiresistive and direct thermoelectric gas sensors. Therefore, this work performed the elucidation by studying the electronic, electrical, and thermal properties of the bilayered ZnO nanosheets with polar (0001) and non-polar (112̄0) surfaces under the adsorption of the gases. The interaction between the gases and the nanosheets belongs to two groups: electrostatic attraction and charge exchange. The second one occurs due to the peak resonance of the same type of orbitals between the substrates and the gases along the surface normal and the first one for the other cases. The characteristics of the Seebeck coefficient exhibited distinct selectivity of butanone and acetone.

Biofluids manipulation methods for liquid biopsy in minimally-invasive assays

The Liquid Biopsy (LB) is an opportunity for non-invasive diagnosis and prognosis of various diseases. To date, it isn't possible to consider that tissue biopsy can represent a pathology entirety. Then, body fluids are rich in a large number and variety of biomarkers and they can provide information about several diseases.•Recently, other biological fluids, easy to be collected are rising for their significant content of biomarkers and for the possibility to collect and manipulate them without the intervention of medical staff.•The management of biological fluids requires suitable storage methods. Temperature, storage time and physical stresses due to sample handling can lead to chemical and physical changes that may induce sample degradation and incorrect analysis.•The reliability of a diagnostic or screening test depends on its sensitivity and specificity. As the liquid biopsy is a 'snapshot' of a pathophysiological condition, it is crucial that its components do not degrade due to the improper handling of the body fluid.In this review, some handling methods of Saliva, Urine, Stool, Seminal Fluid, Tears and Sweat samples will be described, as well as protocols to facilitate the analysis of metabolites, nucleic acids, proteins and Extracellular Vesicles (EVs) from those unusual body fluids.

Масс-спектрометрические исследования состава газовыделения живых организмов

The quantitative and qualitative composition of volatile organic compounds (VOCs) of human exhaled air, the air environment of various types of entomopathogenic fungi (EPF) of the genus Lecanicillium, used as an alternative to chemical pesticides to protect plants from pests, cabbage moth caterpillars, as well as spined soldier bug from the shield family, was studied using a quadrupole mass spectrometer. The main components found were acetone, acetic acid, and isoprene. These components in human exhalation are significant indicators for non-invasive disease diagnosis. For the first time, sulfur dioxide was found in the composition of VOC EPF, as one of the possible repellents. The caterpillars of cabbage moth secrete exclusively acetic acid.

Mass spectrometric gas release composition studies of living organisms

The quantitative and qualitative composition of volatile organic compounds (VOCs) of human exhaled air, the air environment of various types of entomopathogenic fungi (EPF) of the genus Lecanicillium, used as an alternative to chemical pesticides to protect plants from pests, cabbage moth caterpillars, as well as spined soldier bug from the shield family, was studied using a quadrupole mass spectrometer. The main components found were acetone, acetic acid, and isoprene. These components in human exhalation are significant indicators for non-invasive disease diagnosis. For the first time, sulfur dioxide was found in the composition of VOC EPF, as one of the possible repellents. The caterpillars of cabbage moth secrete exclusively acetic acid. Keywords: mass spectrometry, volatile organic compounds analysis, exhaled air, entomopathogenic fungi, Mamestra brassicae L., Podisus maculiventris S.

A sandwich-based evanescent wave fluorescent biosensor for simple, real-time exosome detection†

Exosomes are regarded as a promising biomarker for the noninvasive diagnosis and treatment of diseases. The value of exosomes for medical research has promoted the search for a fast, efficient, and sensitive detection method. This study reported a sandwich-based evanescent wave fluorescent biosensor (S-EWFB) for exosome detection. A two-step strategy was implemented to take advantages of the simple binding of fluorescent probes with exosomes via the hydrophobic interaction between the cholesteryl and phospholipid bilayer membrane, as well as real-time detection on an evanescent wave liquid-solid interface based on CD63 aptamer-specific capture to form an exosome@fluorescence probe/aptamer sandwich structure. The one-to-many connection between exosomes and signal molecules and the aptamer-modified evanescent wave optical fiber detection platform reduced the detection limit of exosomes to 7.66 particles/mL, with a linear range of 47.5–4.75 × 106 particles/mL. The entire detection process was simple, rapid, and real-time and lasted about 1 h while requiring no separation and purification. Additionally, this platform showed excellent surface regeneration capability and exhibited good performance during the analysis of tumor and non-tumor-derived exosomes.

Postsynthetic functionalization of covalent organic frameworks for dual channel fluorescence diagnosis of two indicators related to Parkinson's disease

Exploring facile analytical technologies with high reliability and precision to quantify targets is significant but remains great challenge for disease diagnosis. Several signal transduction pathways have stimulated the development of various target analysis system. However, many systems are limited by the single channel/mechanism method, it could lead to false positive/negative results. Herein, a dual channel-driven fluorescence sensor was designed for simultaneously analysing homovanillic acid (HVA) and Al3+, two effective indicators for the diagnosis of Parkinson's disease (PD). With two steps of postsynthetic modification (PSM) strategy for covalent organic framework (COF) TpBD-(OH)2, the excellent luminescent material TpBD-(COOH)2@EuTTA (1) still maintained good structural stability, further prepared hydrogel had also been applied to dual channel detect two analytes related to PD. The fluorescence sensor showed turn-off fluorescence response to HVA, and exhibited ratiometric identification approach to Al3+. Simultaneous and quantitative detection with dual channel for two indicators can greatly improve the accuracy of the diagnosis of PD. This study not only provides feasible strategy for versatile functionalization of COFs, but also reveals promising perspectives for the future of non-invasive and accurate disease diagnosis.

Rapid and Simple Analysis of the Human Pepsin Secondary Structure Using a Portable Raman Spectrometer.

Human pepsin is a digestive protease that plays an important role in the human digestive system. The secondary structure of human pepsin determines its bioactivity. Therefore, an in-depth understanding of human pepsin secondary structure changes is particularly important for the further improvement of the efficiency of human pepsin biological function. However, the complexity and diversity of the human pepsin secondary structure make its analysis difficult. Herein, a convenient method has been developed to quickly detect the secondary structure of human pepsin using a portable Raman spectrometer. According to the change of surface-enhanced Raman spectroscopy (SERS) signal intensity and activity of human pepsin at different pH values, we analyze the change of the human pepsin secondary structure. The results show that the content of the β-sheet gradually increased with the increase in the pH in the active range, which is in good agreement with circular dichroism (CD) measurements. The change of the secondary structure improves the sensitivity of human pepsin SERS detection. Meanwhile, human pepsin is a commonly used disease marker for the noninvasive diagnosis of gastroesophageal reflux disease (GERD); the detection limit of human pepsin we obtained is 2 μg/mL by the abovementioned method. The real clinical detection scenario is also simulated by spiking pepsin solution in saliva, and the standard recovery rate is 80.7-92.3%. These results show the great prospect of our method in studying the protein secondary structure and furthermore promote the application of SERS in clinical diagnosis.

Prospects in non-invasive diagnosis of bronchial asthma-related gastroesophageal reflux disease: a single-stage open uncontrolled non-randomised observational study

Background . Respiratory symptoms of bronchial asthma (BA) comorbid with gastroesophageal reflux disease (GERD) may provoke duodenogastroesophageal reflux (DGER) via aggressive agents like pepsinogens and bilirubin. Objectives . A clinical and functional study of the saliva pepsinogen and bilirubin-associated BA-comorbid GERD for non-invasive DGER diagnosis. Methods. A total of 29 patients with an allergic BA phenotype, comorbid GERD and 50 , 2 ± 2 , 4 years mean age have been examined. Biochemical blood panel included bilirubin, C-reactive protein and allergen-specifi c IgE. Saliva bilirubin was estimated in colorimetry, and the pepsinogen-1, -2 content — in immunological tests. Grade A–D reflux oesophagitis (RO) in oesophagoscopy was assigned to erosive reflux disease, and grade N–M oesophageal mucosa (OM) lesions — to non-erosive reflux disease. External respiratory function (ERF) was assessed with forced expiratory volume (FEV 1 , L/s), forced vital capacity (FVC), Tiffeneau index (FEV 1 /FVC), pre- and post-berodual FEF 1 and FVC dynamics. Results. The BA–GERD patients were markedly polymorbid. Cough and chest tightness associated with age, and the tight chest rate — with a higher body mass index and lower FEV 1 /FVC. The association between higher pepsinogen-I and lower FEV 1 /FVC–FVC in response to inhaled berodual, as well as between higher saliva bilirubin and lower FVC–FEV 1 after berodual intake reflects a significant high-DGER effect on BA representation. Conclusion. In BA–GERD patients, saliva pepsinogen and bilirubin are biomarkers of both DGER and respiratory inflammation with bronchospasm.

Metabolomics Diagnosis of COVID-19 from Exhaled Breath Condensate.

Infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe respiratory tract damage and acute lung injury. Therefore, it is crucial to study breath-associated biofluids not only to investigate the breath’s biochemical changes caused by SARS-CoV-2 infection, but also to discover potential biomarkers for the development of new diagnostic tools. In the present study, we performed an untargeted metabolomics approach using a bidimensional gas chromatography mass spectrometer (GCxGC-TOFMS) on exhaled breath condensate (EBC) from COVID-19 patients and negative healthy subjects to identify new potential biomarkers for the noninvasive diagnosis and monitoring of the COVID-19 disease. The EBC analysis was further performed in patients with acute or acute-on-chronic cardiopulmonary edema (CPE) to assess the reliability of the identified biomarkers. Our findings demonstrated that an abundance of EBC fatty acids can be used to discriminate COVID-19 patients and that they may have a protective effect, thus suggesting their potential use as a preventive strategy against the infection.

Alterations of the Human Lung and Gut Microbiomes in Non-Small Cell Lung Carcinomas and Distant Metastasis.

ABSTRACTNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Although dysbiosis of the lung and gut microbiota have been associated with NSCLC, their relative contributions are unclear; in addition, their roles in distant metastasis (DM) are still illusive. We recruited in total 121 participants, including 87 newly diagnosed treatment-naive NSCLC patients of various stages and 34 healthy volunteers, and surveyed their fecal and sputum microbiota. We compared the microbial profiles between groups, identified microbial biomarkers, and generated machine learning models for distinguishing healthy individuals from patients with NSCLC and patients of various stages. We found significant perturbations of gut and sputum microbiota in patients with NSCLC and DM. A machine learning model combining both microbiota (combined model) performed better than an individual data set in patient stratification, with the highest area under the curve (AUC) value of 0.896. Sputum and gut microbiota both contributed to the combined model; in most cases, sputum-only models performed similar to the combined models. Several microbial biomarkers were shared by both microbiotas, indicating their similar roles at distinct body sites. Microbial biomarkers of distinct disease stages were mostly shared, suggesting biomarkers for DM could be acquired early. Furthermore, Pseudomonas aeruginosa, a species previously associated with wound infections, was significantly more abundant in brain metastasis, indicating that distinct types of DMs could have different microbes. Our results indicate that alterations of the sputum microbiota have stronger relationships with NSCLC and DM than the gut and strongly support the feasibility of metagenome-based noninvasive disease diagnosis and risk evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT03454685).IMPORTANCE Our survey on gut and sputum microbiota revealed that both were significantly disturbed in non-small cell lung cancer (NSCLC) and associated with distant metastasis (DM) while only the sputum microbiota was associated with non-DM NSCLC. The lung microbiota could therefore have a stronger association with (and thus may contribute more to) disease development than the gut microbiota. Mathematic models using both microbiotas performed better in patient stratification than using individual microbiota. Sputum models, however, performed similar to the combined models, suggesting a convenient, noninvasive diagnostic for NSCLC. Microbial biomarkers of distinct disease stages were mostly shared, suggesting that the same set of microbes were underlying disease progression, and the signals for distant metastasis could be acquired at early stages of the disease. Our results strongly support the feasibility of noninvasive diagnosis of NSCLC, including distant metastasis, are of clinical importance, and should warrant further research on the underlying molecular mechanisms.

Advances in the Noninvasive Diagnosis of Dry Eye Disease

Dry eye disease (DED) is a multifactorial disease that represents one of the most common ophthalmologic conditions encountered in everyday clinical practice. Traditional diagnostic tests for DED, such as subjective questionnaires, tear film break-up time and the Schirmer test, are often associated with poor reproducibility and reliability, which make the diagnosis, follow-up, and management of the disease challenging. New advances in imaging technologies enable objective and reproducible measurements of DED parameters, thus making the diagnosis a multimodal imaging-based process. The aim of this review is to summarize all the current and emerging diagnostic tools available for the diagnosis and monitoring of DED, such as non-invasive tear breakup time, thermography, anterior segment optical coherence tomography, meibography, interferometry, in vivo confocal microscopy, and optical quality assessment. Although there is not a gold standard imaging technique, new multi-imaging-integrated devices are precious instruments to help clinicians to better cope with the diagnostic complexity of DED.

Constructing a NIR fluorescent probe for ratiometric imaging viscosity in mice and detecting blood viscosity in folliculitis mice and peritonitis mice

For a variety of viscosity-related diseases, studying blood viscosity may be an ever so direct, simple, non-invasive as well as effective pre-diagnostic method. At present, the main cause for the insufficiently thorough studies on blood viscosity is the lack of tools that can not only self-calibrate but also shield the interference of bio-auto fluorescence from blood. Herein, we have judiciously designed and synthesized a new fluorescent probe Nile-TPE to tackle the above problem. This TBET structure based fluorescent probe possess numerous merits including near-infrared (NIR) emission, ratiometric response, lipid droplets positioning, wide emission peak spacing, etc. Besides the viscosity ratiometric imaging in vitro, probe Nile-TPE also realizes the ratiometric imaging viscosity in mice and detecting blood viscosity in peritonitis mice and folliculitis mice for the first time. And, importantly, this effective method requires only 10 μL of blood. Therefore, probe Nile-TPE furnishes a more accurate tool for non-invasive diagnosis of viscosity-related diseases.

(Invited) Miniaturized Gas Analysis Platform for Non-Invasive Disease Detection

Recently, non-invasive diagnosis of human diseases using gas samples from human has become increasingly important due to its simple way to make a person less reluctant. The exhaled breath or urine vapors from patients can contain VOCs, which have been reported to be clinically meaningful biomarkers. However, it is difficult to make a diagnosis accurately due to very low gas concentration level of disease related VOCs, which is 1~100 ppb level. To overcome the detection limit of various commercialized gas sensors or detectors, the preconcentration of gas samples from human is required. On the other hand, gas chromatography (GC), which is extensively applied for gas mixture analysis, is necessary to separate and identify the gas components.A miniaturized gas analysis platform for the analysis of the low concentration and multiple disease related VOCs has been developed using a micro gas preconcentrator chip, a micro gas chromatography chip, a thermal conductivity detector chip, etc. Its design and fabrication process will be introduced and its basic performance will be presented for various clinically important VOCs.

Feasibility of Noninvasive Diagnosis of Spinal Vascular Diseases Using Time-Resolved Angiography With Stochastic Trajectories.

Background and Purpose: To determine the feasibility of time-resolved angiography with stochastic trajectories (TWIST) in the diagnosis of spinal dural arteriovenous fistula (SDAVF) and perimedullary arteriovenous fistula (PAVF).Methods: A total of 11 negative patients with TWIST examination were retrospective analyzed and then 18 patients with suspected spinal vascular diseases underwent TWIST. For negative patients, Adamkiewicz artery (AKA), great anterior radiculomedullary vein (GARV) and anterior spinal artery (ASA) were retrospective analyzed. In patients, the results of TWIST were compared with those of DSA.Results: The displaying rates of the ASA, AKA and GARV in 11 negative patients were 100, 90.9, and 90.9%, respectively. The AKA and GARV were separated on TWIST. Of 18 patients, 11 and three were diagnosed with SDAVF and PAVF, respectively. The spinal cord vascular malformation diagnosed on TWIST was consistent with DSA with an excellent intermodality agreement (Kappa = 0.92, p < 0.001). The feeding artery and side of all 11 SDAVF patients were displayed on TWIST and the results were consistent with DSA. For PAVF patients, the feeding artery in two patients and the sides as displayed on TWIST were consistent with DSA.Conclusions: TWIST enables the differentiation of the spinal artery and vein and the differential diagnosis of SDAVF and PAVF.

Precise Modulation Strategies for Transcranial Magnetic Stimulation: Advances and Future Directions.

Transcranial magnetic stimulation (TMS) is a popular modulatory technique for the noninvasive diagnosis and therapy of neurological and psychiatric diseases. Unfortunately, current modulation strategies are only modestly effective. The literature provides strong evidence that the modulatory effects of TMS vary depending on device components and stimulation protocols. These differential effects are important when designing precise modulatory strategies for clinical or research applications. Developments in TMS have been accompanied by advances in combining TMS with neuroimaging techniques, including electroencephalography, functional near-infrared spectroscopy, functional magnetic resonance imaging, and positron emission tomography. Such studies appear particularly promising as they may not only allow us to probe affected brain areas during TMS but also seem to predict underlying research directions that may enable us to precisely target and remodel impaired cortices or circuits. However, few precise modulation strategies are available, and the long-term safety and efficacy of these strategies need to be confirmed. Here, we review the literature on possible technologies for precise modulation to highlight progress along with limitations with the goal of suggesting future directions for this field.

ZeNose/GO hybrid composite for detection of clinically relevant VOCs in lower respiratory tract (Case study using Carene)

The exhaled human breath profile offers immense potential for non-invasive disease diagnosis and biomarker discovery as it provides mechanistic insights of endogenously produced volatile organic compounds and metabolic pathways affected due to disease prognosis. We have developed a ZIF-8/GO hybrid composite for sensing carene vapor levels, which vary because of respiratory infections. The developed electrochemical sensor platform uses ZIF-8/GO for detection of the target analyte and offers advantage for gas sensing due to high electrochemical activity, surface area and porosity for diffusion. The ZIF-8/GO-modified sensor platform demonstrates high sensitivity and specificity for carene detection up to 100 parts-per-billion. The results led to the development of breathomics-enabled electrochemical strategy that can be used for Point-of-Care diagnostics. We envision that our platform for sensing carene can be used for the detection of lower respiratory tract-related infections such as ventilator associated pneumonia.

Carotid Sound Signal Artifact Detection based on Discrete Wavelet Transform Decomposition

Abstract Auscultation methods allow a non-invasive diagnosis of cardiovascular diseases like atherosclerosis based on blood flow sounds of the carotid arteries. Since this process is highly dependent on the clinician’s experience, it is of great interest to develop automated data processing techniques for objective assessment. We have recently proposed a computerassisted auscultation system that we use to acquire carotid blood flow sounds. In this work, we present an approach for detecting artifacts within the blood flow sound caused by swallowing or coughing events. For this purpose, we first decompose the signal using a discrete wavelet transform (DTW). Then, we compute an energy ratio between the DWT scales associated with the signal information with and without artifacts using a sliding window of 1 s length. Evaluation based on Kruskal-Wallis and Wilcoxon rank-sum tests shows a statistically significant difference (p-value&lt;.0001) between the signal with and without artifact. Therefore, the proposed method allows the identification of the studied signal artifacts.