Circadian assessment of heart failure using explainable deep learning and novel multi-parameter polar images.

BACKGROUND AND OBJECTIVE: Heart failure (HF) is a multi-faceted and life-threatening syndrome that affects more than 64.3 million people worldwide. Current gold-standard screening technique, echocardiography, neglects cardiovascular information regulated by the circadian rhythm and does not incorporate knowledge from patient profiles. In this study, we propose a novel multi-parameter approach to assess heart failure using heart rate variability (HRV) and patient clinical information. METHODS: In this approach, features from 24-hour HRV and clinical information were combined as a single polar image and fed to a 2D deep learning model to infer the HF condition. The edges of the polar image correspond to the timely variation of different features, each of which carries information on the function of the heart, and internal illustrates color-coded patient clinical information. RESULTS: Under a leave-one-subject-out cross-validation scheme and using 7,575 polar images from a multi-center cohort (American and Greek) of 303 coronary artery disease patients (median age: 58 years [50-65], median body mass index (BMI): 27.28 kg/m2 [24.91-29.41]), the model yielded mean values for the area under the receiver operating characteristics curve (AUC), sensitivity, specificity, normalized Matthews correlation coefficient (NMCC), and accuracy of 0.883, 90.68%, 95.19%, 0.93, and 92.62%, respectively. Moreover, interpretation of the model showed proper attention to key hourly intervals and clinical information for each HF stage. CONCLUSIONS: The proposed approach could be a powerful early HF screening tool and a supplemental circadian enhancement to echocardiography which sets the basis for next-generation personalized healthcare.

Point of Care Testing (POCT) in Psychopathology Using Fractal Analysis and Hilbert Huang Transform of Electroencephalogram (EEG).

Research has shown that relying only on self-reports for diagnosing psychiatric disorders does not yield accurate results at all times. The advances of technology as well as artificial intelligence and other machine learning algorithms have allowed the introduction of point of care testing (POCT) including EEG characterization and correlations with possible psychopathology. Nonlinear methods of EEG analysis have significant advantages over linear methods. Empirical mode decomposition (EMD) is a reliable nonlinear method of EEG pre-processing. In this chapter, we compare two existing EEG complexity measures - Higuchi fractal dimension (HFD) and sample entropy (SE), with our newly proposed method using Higuchi fractal dimension from the Hilbert Huang transform (HFD-HHT). We present an example using the three complexity measures on a 2-minute EEG recorded from a healthy 20-year-old male after signal pre-processing. Furthermore, we showed the usefulness of these complexity measures in the classification of major depressive disorder (MDD) with healthy controls. Our study is in line with previous research and has shown an increase in HFD and SE values in the full, alpha and beta frequency bands suggestive of an increase in EEG irregularity. Moreover, the HFD-HHT values decreased in those three bands for majority of electrodes which is suggestive of a decrease in irregularity in the frequency-time domain. We conclude that all three complexity measures can be vital features useful for EEG analysis which could be incorporated in POCT systems.

Box-Counting Fractal Analysis: A Primer for the Clinician.

This chapter lays out the elementary principles of fractal geometry underpinning much of the rest of this book. It assumes a minimal mathematical background, defines the key principles and terms in context, and outlines the basics of a fractal analysis method known as box counting and how it is used to perform fractal, lacunarity, and multifractal analyses. As a standalone reference, this chapter grounds the reader to be able to understand, evaluate, and apply essential methods to appreciate and heal the exquisitely detailed fractal geometry of the brain.

Morphology and Fractal-Based Classifications of Neurons and Microglia in Two and Three Dimensions.

Microglia and neurons live physically intertwined, intimately related structurally and functionally in a dynamic relationship in which microglia change continuously over a much shorter timescale than do neurons. Although microglia may unwind and depart from the neurons they attend under certain circumstances, in general, together both contribute to the fractal topology of the brain that defines its computational capabilities. Both neuronal and microglial morphologies are well-described using fractal analysis complementary to more traditional measures. For neurons, the fractal dimension has proved valuable for classifying dendritic branching and other neuronal features relevant to pathology and development. For microglia, fractal geometry has substantially contributed to classifying functional categories, where, in general, the more pathological the biological status, the lower the fractal dimension for individual cells, with some exceptions, including hyper-ramification. This chapter provides a review of the intimate relationships between neurons and microglia, by introducing 2D and 3D fractal analysis methodology and its applications in neuron-microglia function in health and disease.

ImageJ in Computational Fractal-Based Neuroscience: Pattern Extraction and Translational Research.

To explore questions asked in neuroscience, neuroscientists rely heavily on the tools available. One such toolset is ImageJ, open-source, free, biological digital image analysis software. Open-source software has matured alongside of fractal analysis in neuroscience, and today ImageJ is not a niche but a foundation relied on by a substantial number of neuroscientists for work in diverse fields including fractal analysis. This is largely owing to two features of open-source software leveraged in ImageJ and vital to vigorous neuroscience: customizability and collaboration. With those notions in mind, this chapter's aim is threefold: (1) it introduces ImageJ, (2) it outlines ways this software tool has influenced fractal analysis in neuroscience and shaped the questions researchers devote time to, and (3) it reviews a few examples of ways investigators have developed and used ImageJ for pattern extraction in fractal analysis. Throughout this chapter, the focus is on fostering a collaborative and creative mindset for translating knowledge of the fractal geometry of the brain into clinical reality.

Fractals in the Neurosciences: A Translational Geographical Approach.

The chapter presents three new fractal indices (fractal fragmentation index, fractal tentacularity index, and fractal anisotropy index) and normalized Kolmogorov complexity with proven applicability in geographic research, developed by the authors, and the possibility of their future use in neuroscience. The research demonstrates the relevance of fractal analysis in different fields and the basic concepts and principles of fractal geometry being sufficient for the development of models relevant to the studied reality. Also, the research highlighted the need to continue interdisciplinary research based on known fractal indicators, as well as the development of new analysis methods with the translational potential between fields.

Machine Learning for the Prediction of Depression Progression from Inflammation Markers.

Major depressive disorder is one of the major contributors to disability worldwide with an estimated prevalence of 4%. Depression is a heterogeneous disease often characterized by an undefined pathogenesis and multifactorial phenotype that complicate diagnosis and follow-up. Translational research and identification of objective biomarkers including inflammation can assist clinicians in diagnosing depression and disease progression. Investigating inflammation markers using machine learning methods combines recent understanding of the pathogenesis of depression associated with inflammatory changes as part of chronic disease progression that aims to highlight complex interactions. In this paper, 721 patients attending a diabetes health screening clinic (DiabHealth) were classified into no depression (none) to minimal depression (none-minimal), mild depression, and moderate to severe depression (moderate-severe) based on the Patient Health Questionnaire (PHQ-9). Logistic Regression, K-nearest Neighbors, Support Vector Machine, Random Forest, Multi-layer Perceptron, and Extreme Gradient Boosting were applied and compared to predict depression level from inflammatory marker data that included C-reactive protein (CRP), Interleukin (IL)-6, IL-1ß, IL-10, Complement Component 5a (C5a), D-Dimer, Monocyte Chemoattractant Protein (MCP)-1, and Insulin-like Growth Factor (IGF)-1. MCP-1 and IL-1ß were the most significant inflammatory markers for the classification performance of depression level. Extreme Gradient Boosting outperformed the models achieving the highest accuracy and Area Under the Receiver Operator Curve (AUC) of 0.89 and 0.95, respectively.Clinical Relevance- The findings of this study show the potential of machine learning models to aid in clinical practice, leading to a more objective assessment of depression level based on the involvement of MCP-1 and IL-1ß inflammatory markers with disease progression.

Classification of children with ADHD through task-related EEG recordings via Swarm-Decomposition-based Phase Locking Value.

Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder mainly affecting children. ADHD children brain activity is reported to present alterations from neurotypically developed children, yet establishment of an EEG biomarker, which is of high importance in clinical practice and research, has not been achieved. In this work, task-related EEG recordings from 61 ADHD and 60 age-matched non-ADHD children are analyzed to examine the underlying Cross-Frequency Coupling phenomena. The proposed framework introduces personalized brain rhythm extraction in the form of oscillatory modes via Swarm Decomposition, allowing for the transition from sensor-level connectivity to source-level connectivity. Oscillatory modes are then subjected to a phase locking value-based feature extraction and the efficiency of the extracted features in separating ADHD from non-ADHD individuals is evaluated by means of a nested 5-fold cross validation scheme. The experimental results of the proposed framework (Area Under the Receiver Operating Characteristics Curve-AUROC: 0.9166) when benchmarked against the commonly used filter-based brain rhythm extraction (AUROC: 0.8361) underscore its efficiency and demonstrate its overall superiority over other state-of-the-art functional connectivity approaches in this classification task for this dataset.Clinical relevance-This framework provides novel insights about brain regions of interest that are involved in ADHD task-related function and holds promise in providing objective ADHD biomarkers by extending classic sensor-level connectivity to source-level.

Oxidative Stress Biomarkers in Predictive Multi-Class Modeling of Depression Severity with Diabetes Mellitus, Cardiovascular Disease and Hypertension Comorbidity.

In this study, depression severity was defined by the Patient Health Questionnaire (PHQ-9) and five machine learning algorithms were applied to classify depression severity in the presence of diabetes mellitus (DM), cardiovascular disease (CVD), and hypertension (HT) utilizing oxidative stress (OS) biomarkers (8-isoprostane, 8-hydroxydeoxyguanosine, reduced glutathione and oxidized glutathione), demographic details, and medication for eight hundred and thirty participants. The results show that the Random Forest (RF) outperformed other classifiers with the highest accuracy of 92% in a 4-class depression classification when considering all OS biomarkers along with DM, CVD and HT. RF also achieved the highest accuracy of 91% in 3-class classification when studying depression in presence of DM only and an accuracy of 88% and 87% in 5-class classification when investigating depression with CVD and HT, respectively. Moreover, RF performed best in the 3-class depression model with an accuracy of 85% when examining depression severity in the presence of OS biomarkers only. Our findings suggest that depression severity can be accurately identified with RF as a base classifier and that OS is a major contributor to depression severity in the presence of comorbidities. Biomarker analysis can supplement DSM-5-based diagnostics as part of personalized medicine and especially as point of care testing has become available for many of the given OS biomarkers.Clinical Relevance- Depression is the most common form of psychiatric disorder that has an oxidative stress etiology. Current diagnosis relies primarily on the Diagnostic and Statistical Manual for Mental Disorders (DSM-5), which may be too general and not informative for optimal multi-comorbidity diagnostics and treatment. Understanding the role of oxidative stress associated with depression can provide additional information for timely detection, comprehensive assessment, and appropriate intervention of depression illness.

Heart Failure Assessment Using Multiparameter Polar Representations and Deep Learning.

Heart failure refers to the inability of the heart to pump enough amount of blood to the body. Nearly 7 million people die every year because of its complications. Current gold-standard screening techniques through echocardiography do not incorporate information about the circadian rhythm of the heart and clinical information of patients. In this vein, we propose a novel approach to integrate 24-hour heart rate variability (HRV) features and patient profile information in a single multi-parameter and color-coded polar representation. The proposed approach was validated by training a deep learning model from 7,575 generated images to predict heart failure groups, i.e., preserved, mid-range, and reduced left ventricular ejection fraction. The developed model had overall accuracy, sensitivity, and specificity of 93%, 88%, and 95%, respectively. Moreover, it had a high area under the receiver operating characteristics curve (AUROC) of 0.88 and an area under the precision-recalled curve (AUPR) of 0.79. The novel approach proposed in this study suggests a new protocol for assessing cardiovascular diseases to act as a complementary tool to echocardiography as it provides insights on the circadian rhythm of the heart and can be potentially personalized according to patient clinical profile information.Clinical relevance- Implementing polar representations with deep learning in clinical settings to supplement echocardiography leverages continuous monitoring of the heart's circadian rhythm and personalized cardiovascular medicine while reducing the burden on medical practitioners.

EEG-based Emotion Recognition Using Sub-Band Time-Delay Correlations.

Emotion recognition is a challenging task with many potential applications in psychology, psychiatry, and human-computer interaction (HCI). The use of time-delay information in the controlled time-delay stability (cTDS) algorithm can help to capture the temporal dynamics of EEG signals, including sub-band information and bi-directional coupling that can aid in emotion recognition and identification of specific connectivity patterns between brain rhythms. Incorporating EEG frequency bands can be used to design better emotion recognition systems. This paper evaluates the cTDS algorithm for binary classification tasks of arousal and valence using EEG sub-band signals. This method achieved a high accuracy of 91.1% for arousal and 91.7% for valence based on one electrode recording site at Fp1. The cTDS algorithm is a promising approach to analyzing brain network interactions. It can be particularly applicable to arousal and valence classification tasks, especially within a complex, multimodal feature space associated with understanding psychiatric disorders and HCI applications.

Multiscale Diffusion Entropy Analysis for the Detection of Crucial Events in Cardiac Pathology.

The significance of crucial events in explaining the dynamics of a physiological system has only been recently emerging. Crucial events are yet to be fully understood and implemented in clinical applications of physiological signal processing. This paper proposes the application of modified diffusion entropy (MDEA) and novel multiscale diffusion entropy analyses (MSDEA) on measuring the temporal complexity of the ECG time series to improve crucial events detection performance. Thirty samples of each of three groups of ECG datasets from PhysioNet with recordings of cardiac arrhythmia (ARR), congestive heart failure (CHF) and normal sinus rhythm (NSR) were analyzed using MDEA with stripes followed by MSDEA. Healthy NSR ECGs showed an approximate 15% greater inverse power law (IPL) and scaling δ indices than pathologic CHF and ARR signals. Additionally, the scaling indices for the pathologic groups showed higher standard deviations, indicating that crucial events determined by MDEA reveal latent differences in ECG complexity that could better be investigated across multiple time scales of temporally decomposed signals using MSDEA which combines multiscale entropy (MSE) and MDEA. Hence, MSDEA showed an improved, clearer discrimination between the healthy and pathological cardiac signals (p<0.0005) characterized by a range of NSR complexity indices twice the range of the pathological values associated with ARR and CHF across twenty temporal scales as well as more reliable trend lines (R2>=0.95).Clinical Relevance- This research proposes a novel and enhanced diagnostic discrimination across healthy and pathologic cardiac conditions based on biomedical signal processing of ECG recordings utilizing the principle of crucial events detection.

A Systematic Review of Gait Analysis in the Context of Multimodal Sensing Fusion and AI.

BACKGROUND: Neurological diseases are a leading cause of disability and mortality. Gait, or human walking, is a significant predictor of quality of life, morbidity, and mortality. Gait patterns and other kinematic, kinetic, and balance gait features are accurate and powerful diagnostic and prognostic tools. OBJECTIVE: This review article focuses on the applicability of gait analysis using fusion techniques and artificial intelligence (AI) models. The aim is to examine the significance of mixing several types of wearable and non-wearable sensor data and the impact of this combination on the performance of AI models. METHOD: In this systematic review, 66 studies using more than two modalities to record and analyze gait were identified. 40 studies incorporated multiple gait analysis modalities without the use of artificial intelligence to extract gait features such as kinematic, kinetic, margin of stability, temporal, and spatial gait parameters, as well as cerebral activity. Similarly, 26 studies analyzed gait data using multimodal fusion sensors and AI algorithms. RESULTS: The research summarized here demonstrates that the quality of gait analysis and the effectiveness of AI models can both benefit from the integration of data from many sensors. Meanwhile, the utilization of EMG signals in fusion data is especially advantageous. CONCLUSION: The findings of this review suggest that a smart, portable, wearable-based gait and balance assessment system can be developed using multimodal sensing of the most cutting-edge, clinically relevant tools and technology available. The information presented in this article may serve as a vital springboard for such development.

HLA class I associations with the severity of COVID-19 disease in the United Arab Emirates.

SARS-CoV-2 appears to induce diverse innate and adaptive immune responses, resulting in different clinical manifestations of COVID-19. Due to their function in presenting viral peptides and initiating the adaptive immune response, certain Human Leucocyte Antigen (HLA) alleles may influence the susceptibility to severe SARS-CoV-2 infection. In this study, 92 COVID-19 patients from 15 different nationalities, with mild (n = 30), moderate (n = 35), and severe (n = 27) SARS-CoV-2 infection, living in the United Arab Emirates (UAE) were genotyped for the Class I HLA -A, -C, and -B alleles using next-generation sequencing (NGS) between the period of May 2020 to June 2020. Alleles and inferred haplotype frequencies in the hospitalized patient group (those with moderate to severe disease, n = 62) were compared to non-hospitalized patients (mild or asymptomatic, n = 30). An interesting trend was noted between the severity of COVID-19 and the HLA-C*04 (P = 0.0077) as well as HLA-B*35 (P = 0.0051) alleles. The class I haplotype HLA-C*04-B*35 was also significantly associated (P = 0.0049). The involvement of inflammation, HLA-C*04, and HLA-B*35 in COVID-19 severity highlights the potential roles of both the adaptive and innate immune responses against SARS-CoV-2. Both alleles have been linked to several respiratory diseases, including pulmonary arterial hypertension along with infections caused by the coronavirus and influenza. This study, therefore, supports the potential use of HLA testing in prioritizing public healthcare interventions for patients at risk of COVID-19 infection and disease progression, in addition to providing personalized immunotherapeutic targets.

Assessing the Link between Diabetic Metabolic Dysregulation and Breast Cancer Progression.

Diabetes mellitus is a burdensome disease that affects various cellular functions through altered glucose metabolism. Several reports have linked diabetes to cancer development; however, the exact molecular mechanism of how diabetes-related traits contribute to cancer progression is not fully understood. The current study aimed to explore the molecular mechanism underlying the potential effect of hyperglycemia combined with hyperinsulinemia on the progression of breast cancer cells. To this end, gene dysregulation induced by the exposure of MCF7 breast cancer cells to hyperglycemia (HG), or a combination of hyperglycemia and hyperinsulinemia (HGI), was analyzed using a microarray gene expression assay. Hyperglycemia combined with hyperinsulinemia induced differential expression of 45 genes (greater than or equal to two-fold), which were not shared by other treatments. On the other hand, in silico analysis performed using a publicly available dataset (GEO: GSE150586) revealed differential upregulation of 15 genes in the breast tumor tissues of diabetic patients with breast cancer when compared with breast cancer patients with no diabetes. SLC26A11, ALDH1A3, MED20, PABPC4 and SCP2 were among the top upregulated genes in both microarray data and the in silico analysis. In conclusion, hyperglycemia combined with hyperinsulinemia caused a likely unique signature that contributes to acquiring more carcinogenic traits. Indeed, these findings might potentially add emphasis on how monitoring diabetes-related metabolic alteration as an adjunct to diabetes therapy is important in improving breast cancer outcomes. However, further detailed studies are required to decipher the role of the highlighted genes, in this study, in the pathogenesis of breast cancer in patients with a different glycemic index.

Corrigendum: Evolution, ecology, and zoonotic transmission of betacoronaviruses: a review.

[This corrects the article DOI: 10.3389/fvets.2021.644414.].

Inflammation, oxidative stress and mitochondrial dysfunction in the progression of type II diabetes mellitus with coexisting hypertension.

Introduction: Type II diabetes mellitus (T2DM) is a metabolic disorder that poses a serious health concern worldwide due to its rising prevalence. Hypertension (HT) is a frequent comorbidity of T2DM, with the co-occurrence of both conditions increasing the risk of diabetes-associated complications. Inflammation and oxidative stress (OS) have been identified as leading factors in the development and progression of both T2DM and HT. However, OS and inflammation processes associated with these two comorbidities are not fully understood. This study aimed to explore changes in the levels of plasma and urinary inflammatory and OS biomarkers, along with mitochondrial OS biomarkers connected to mitochondrial dysfunction (MitD). These markers may provide a more comprehensive perspective associated with disease progression from no diabetes, and prediabetes, to T2DM coexisting with HT in a cohort of patients attending a diabetes health clinic in Australia. Methods: Three-hundred and eighty-four participants were divided into four groups according to disease status: 210 healthy controls, 55 prediabetic patients, 32 T2DM, and 87 patients with T2DM and HT (T2DM+HT). Kruskal-Wallis and χ2 tests were conducted between the four groups to detect significant differences for numerical and categorical variables, respectively. Results and discussion: For the transition from prediabetes to T2DM, interleukin-10 (IL-10), C-reactive protein (CRP), 8-hydroxy-2'-deoxyguanosine (8-OHdG), humanin (HN), and p66Shc were the most discriminatory biomarkers, generally displaying elevated levels of inflammation and OS in T2DM, in addition to disrupted mitochondrial function as revealed by p66Shc and HN. Disease progression from T2DM to T2DM+HT indicated lower levels of inflammation and OS as revealed through IL-10, interleukin-6 (IL-6), interleukin-1ß (IL-1ß), 8-OHdG and oxidized glutathione (GSSG) levels, most likely due to antihypertensive medication use in the T2DM +HT patient group. The results also indicated better mitochondrial function in this group as shown through higher HN and lower p66Shc levels, which can also be attributed to medication use. However, monocyte chemoattractant protein-1 (MCP-1) levels appeared to be independent of medication, providing an effective biomarker even in the presence of medication use. The results of this study suggest that a more comprehensive review of inflammation and OS biomarkers is more effective in discriminating between the stages of T2DM progression in the presence or absence of HT. Our results further indicate the usefulness of medication use, especially with respect to the known involvement of inflammation and OS in disease progression, highlighting specific biomarkers during disease progression and therefore allowing a more targeted individualized treatment plan.

The convergence of traditional and digital biomarkers through AI-assisted biosensing: A new era in translational diagnostics?

Advances in consumer electronics, alongside the fields of microfluidics and nanotechnology have brought to the fore low-cost wearable/portable smart devices. Although numerous smart devices that track digital biomarkers have been successfully translated from bench-to-bedside, only a few follow the same fate when it comes to track traditional biomarkers. Current practices still involve laboratory-based tests, followed by blood collection, conducted in a clinical setting as they require trained personnel and specialized equipment. In fact, real-time, passive/active and robust sensing of physiological and behavioural data from patients that can feed artificial intelligence (AI)-based models can significantly improve decision-making, diagnosis and treatment at the point-of-procedure, by circumventing conventional methods of sampling, and in person investigation by expert pathologists, who are scarce in developing countries. This review brings together conventional and digital biomarker sensing through portable and autonomous miniaturized devices. We first summarise the technological advances in each field vs the current clinical practices and we conclude by merging the two worlds of traditional and digital biomarkers through AI/ML technologies to improve patient diagnosis and treatment. The fundamental role, limitations and prospects of AI in realizing this potential and enhancing the existing technologies to facilitate the development and clinical translation of "point-of-care" (POC) diagnostics is finally showcased.

Investigating the effects of beta-blockers on circadian heart rhythm using heart rate variability in ischemic heart disease with preserved ejection fraction.

Heart failure is characterized by sympathetic activation and parasympathetic withdrawal leading to an abnormal autonomic modulation. Beta-blockers (BB) inhibit overstimulation of the sympathetic system and are indicated in heart failure patients with reduced ejection fraction. However, the effect of beta-blocker therapy on heart failure with preserved ejection fraction (HFpEF) is unclear. ECGs of 73 patients with HFpEF > 55% were recruited. There were 56 patients in the BB group and 17 patients in the without BB (NBB) group. The HRV analysis was performed for the 24-h period using a window size of 1,4 and 8-h. HRV measures between day and night for both the groups were also compared. Percentage change in the BB group relative to the NBB group was used as a measure of difference. RMSSD (13.27%), pNN50 (2.44%), HF power (44.25%) and LF power (13.53%) showed an increase in the BB group relative to the NBB group during the day and were statistically significant between the two groups for periods associated with high cardiac risk during the morning hours. LF:HF ratio showed a decrease of 3.59% during the day. The relative increase in vagal modulated RMSSD, pNN50 and HF power with a decrease in LF:HF ratio show an improvement in the parasympathetic tone and an overall decreased risk of a cardiac event especially during the morning hours that is characterized by a sympathetic surge.

Corrigendum: Evolution, ecology, and zoonotic transmission of betacoronaviruses: A review.

[This corrects the article DOI: 10.3389/fvets.2021.644414.].