Early Prediction of Impending Exertional Heat Stroke With Wearable Multimodal Sensing and Anomaly Detection.

We employed wearable multimodal sensing (heart rate and triaxial accelerometry) with machine learning to enable early prediction of impending exertional heat stroke (EHS). US Army Rangers and Combat Engineers (N = 2,102) were instrumented while participating in rigorous 7-mile and 12-mile loaded rucksack timed marches. There were three EHS cases, and data from 478 Rangers were analyzed for model building and controls. The data-driven machine learning approach incorporated estimates of physiological strain (heart rate) and physical stress (estimated metabolic rate) trajectories, followed by reconstruction to obtain compressed representations which then fed into anomaly detection for EHS prediction. Impending EHS was predicted from 33 to 69 min before collapse. These findings demonstrate that low dimensional physiological stress to strain patterns with machine learning anomaly detection enables early prediction of impending EHS which will allow interventions that minimize or avoid pathophysiological sequelae. We describe how our approach can be expanded to other physical activities and enhanced with novel sensors.

Quantifying Rheumatoid Arthritis Disease Activity Using a Multimodal Sensing Knee Brace.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory syndrome that features painful and destructive joint disease. Aggressive disease-modifying treatment can result in reduced symptoms and protection from irreversible joint damage; however, assessment of treatment efficacy is currently based largely on subjective measures of patient and physician impressions. In this work, we address this compelling need to provide an accurate and quantitative capability for monitoring joint health in patients with RA. METHODS: Joint acoustic emissions (JAEs), electrical bioimpedance (EBI), and kinematics were measured noninvasively from 11 patients with RA over the course of three weeks using a custom multimodal sensing brace, resulting in 49 visits with JAE recordings and 43 with EBI recordings. Features derived from all sensing modalities were fed into a linear discriminant analysis (LDA) model to predict disease activity according to the validated disease activity index (the DAS28-ESR). Erythrocyte sedimentation rate (ESR) was predicted using ridge regression and classified into a high or low class using LDA. RESULTS: DAS28-ESR level was predicted with an area under the receiver operating characteristic curve (AUC) of 0.82. With JAEs alone, we were able to track intrasubject differences in the disease activity score as well as classify ESR level with an AUC of 0.93. The majority of patients reported both an interest and ability to use the brace at home for longitudinal monitoring. CONCLUSION: This work demonstrates the ability to detect RA disease activity using noninvasive sensing. SIGNIFICANCE: This system has the potential to improve RA disease activity monitoring by giving treating clinicians objective data that can be acquired independent of a face-to-face clinic visit.

Quantifying Signal Quality for Joint Acoustic Emissions Using Graph-Based Spectral Embedding.

We present a new method for quantifying signal quality of joint acoustic emissions (JAEs) from the knee during unloaded flexion/extension (F/E) exercises. For ten F/E cycles, JAEs were recorded, in a clinical setting, from 34 healthy knees and 13 with a meniscus tear (n=24 subjects). The recordings were first segmented by F/E cycle and described using time and frequency domain features. Using these features, a symmetric k-nearest neighbor graph was created and described using a spectral embedding. We show how the underlying community structure of JAEs was comparable across joint health levels and was highly affected by artifacts. Each F/E cycle was scored by its distance from a diverse set of manually annotated, clean templates and removed if above the artifact threshold. We validate this methodology by showing an improvement in the distinction between the JAEs of healthy and injured knees. Graph community factor (GCF) was used to detect the number of communities in each recording and describe the heterogeneity of JAEs from each knee. Before artifact removal, there was no significant difference between the healthy and injured groups due to the impact of artifacts on the community construction. Following implementation of artifact removal, we observed improvement in knee health classification. The GCF value for the meniscus tear group was significantly higher than the healthy group (p<0.01). With more JAE recordings being taken in the clinic and at home, this paper addresses the need for a robust artifact removal method which is necessary for an accurate description of joint health.

An Interpretable Experimental Data Augmentation Method to Improve Knee Health Classification Using Joint Acoustic Emissions.

The characteristics of joint acoustic emissions (JAEs) measured from the knee have been shown to contain information regarding underlying joint health. Researchers have developed methods to process JAE measurements and combined them with machine learning algorithms for knee injury diagnosis. While these methods are based on JAEs measured in controlled settings, we anticipate that JAE measurements could enable accessible and affordable diagnosis of acute knee injuries also in field-deployable settings. However, in such settings, the noise and interference would be greater than in sterile, laboratory environments, which could decrease the performance of existing knee health classification methods using JAEs. To address the need for an objective noise and interference detection method for JAE measurements as a step towards field-deployable settings, we propose a novel experimental data augmentation method to locate and then, remove the corrupted parts of JAEs measured in clinical settings. In the clinic, we recruited 30 participants, and collected data from both knees, totaling 60 knees (36 healthy and 24 injured knees) to be used subsequently for knee health classification. We also recruited 10 healthy participants to collect artifact and joint sounds (JS) click templates, which are audible, short duration and high amplitude JAEs from the knee. Spectral and temporal features were extracted, and clinical data was augmented in five-dimensional subspace by fusing the existing clinical dataset into experimentally collected templates. Then knee scores were calculated by training and testing a linear soft classifier utilizing leave-one-subject-out cross-validation (LOSO-CV). The area under the curve (AUC) was 0.76 for baseline performance without any window removal with a logistic regression classifier (sensitivity = 0.75, specificity = 0.78). We obtained an AUC of 0.86 with the proposed algorithm (sensitivity = 0.80, specificity = 0.89), and on average, 95% of all clinical data was used to achieve this performance. The proposed algorithm improved knee health classification performance by the added information through identification and collection of common artifact sources in JAE measurements. This method when combined with wearable systems could provide clinically relevant supplementary information for both underserved populations and individuals requiring point-of-injury diagnosis in field-deployable settings.

Digital Cardiovascular Biomarker Responses to Transcutaneous Cervical Vagus Nerve Stimulation: State-Space Modeling, Prediction, and Simulation.

BACKGROUND: Transcutaneous cervical vagus nerve stimulation (tcVNS) is a promising alternative to implantable stimulation of the vagus nerve. With demonstrated potential in myriad applications, ranging from systemic inflammation reduction to traumatic stress attenuation, closed-loop tcVNS during periods of risk could improve treatment efficacy and reduce ineffective delivery. However, achieving this requires a deeper understanding of biomarker changes over time. OBJECTIVE: The aim of the present study was to reveal the dynamics of relevant cardiovascular biomarkers, extracted from wearable sensing modalities, in response to tcVNS. METHODS: Twenty-four human subjects were recruited for a randomized double-blind clinical trial, for whom electrocardiography and photoplethysmography were used to measure heart rate and photoplethysmogram amplitude responses to tcVNS, respectively. Modeling these responses in state-space, we (1) compared the biomarkers in terms of their predictability and active vs sham differentiation, (2) studied the latency between stimulation onset and measurable effects, and (3) visualized the true and model-simulated biomarker responses to tcVNS. RESULTS: The models accurately predicted future heart rate and photoplethysmogram amplitude values with root mean square errors of approximately one-fifth the standard deviations of the data. Moreover, (1) the photoplethysmogram amplitude showed superior predictability (P=.03) and active vs sham separation compared to heart rate; (2) a consistent delay of greater than 5 seconds was found between tcVNS onset and cardiovascular effects; and (3) dynamic characteristics differentiated responses to tcVNS from the sham stimulation. CONCLUSIONS: This work furthers the state of the art by modeling pertinent biomarker responses to tcVNS. Through subsequent analysis, we discovered three key findings with implications related to (1) wearable sensing devices for bioelectronic medicine, (2) the dominant mechanism of action for tcVNS-induced effects on cardiovascular physiology, and (3) the existence of dynamic biomarker signatures that can be leveraged when titrating therapy in closed loop. TRIAL REGISTRATION: ClinicalTrials.gov NCT02992899; https://clinicaltrials.gov/ct2/show/NCT02992899. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1016/j.brs.2019.08.002.

Development of aquatic life criteria in China: viewpoint on the challenge.

While more developed countries have a well-established systems to develop water quality criteria (WQC), little research has been done on the adequacy of the current WQC to protect endemic species of China. In order to maintain the health of aquatic ecosystems in China, a series of projects to establish national WQC based on regional characteristics has recently been initiated. However, the establishment of a completely novel methodology would be costly and time consuming. Also, due to the similarities in physiologies and natural histories of classes of aquatic organisms, there is no reason to believe that WQC would not be sufficient to protect unique species in China. This review was undertaken to identify key outstanding issues regarding establishment of aquatic life criteria (ALC) to be applied in China, including prioritization of chemicals, test species, mode of action, field/semi-field data, and methods of aggregating the information and calculating the ALC. This was used to identify the principle issues that need to be addressed in order to better understand the methods for development of criteria for the protection of aquatic life and provide a reference to China and other developing countries committed to the establishment of their own WQC system.

Ecological risk of nonylphenol in China surface waters based on reproductive fitness.

It has been recognized that ecological risk assessment based on traditional endpoints of toxicity are unable to provide adequate protection because some chemicals may affect reproductive fitness of aquatic organisms at much lower concentrations. In this paper, predicted no effect concentrations (PNECs) for 4-nonylphenol (NP) were derived based either on endpoints of survival, development, and growth or on some nonlethal biomarkers of reproduction, biochemical and molecular biology data. The PNECs derived from reproductive lesion ranged from 0.12 to 0.60 µg NP L(-1), which was significantly lower than those derived from other endpoints. An assessment of ecological risks posed by NP to aquatic organisms in surface waters of China was conducted based on concentration levels of NP in 16 surface waters of 4 major river basins and PNECs derived from reproductive fitness by a tiered ecological risk assessment (ERA). The results showed that 14.2% and 76.5% of surface waters in China may have ecological risks resulting from reproductive fitness if the thresholds of protection for aquatic organisms were set up as 5% (HC5) and 1% (HC1), respectively. The risks were significantly greatest in the Yangtze River Basin than in other major river basins. In comparison with the risks assessed based on traditional endpoints, such as lethality, for those chemicals causing adverse effects on reproduction due to modulation of endocrine function, to be protective of ecosystem structure and function, lesser PNECs, based on sublethal effects of reproduction, were appropriate.

Gene expression in caged fish as indicators of contaminants exposure in tropical karstic water bodies.

Karstic areas in Yucatan are very permeable, which allows contaminants to move rapidly into the aquifer. In the present study, we evaluated gene expression of vitellogenin (VTG) and cytochrome P-450 1A (CYP1A) in caged juvenile zebrafish deployed for 15 days in 13 different water bodies, cenotes and aguadas, throughout karstic region of the Yucatan peninsula. Gene expression was evaluated using qRT-PCR. Results indicated induction of VTG in 7 water bodies with respect to reference cage. The highest relative VTG expression, about 3000 times higher than reference cage, was found in an aguada close to a cattle farm. CYP1A induction with respect to reference cage was observed in 3 water bodies, all of them located near villages or used for tourist activities. Pollutants and biomarkers of effect should be monitored in these water bodies in order to have a better understanding of the actual levels of pollutants that are present at Yucatan's aquifer and the potential risk to human and environmental health.

Derivation of predicted no effect concentrations (PNEC) for 2,4,6-trichlorophenol based on Chinese resident species.

2,4,6-Trichlorophenol (2,4,6-TCP) is a common chemical intermediate and a by-product of water chlorination and combustion processes, and is a priority pollutant of the aquatic environment in many countries. Although information on the toxicity of 2,4,6-TCP is available, there is a lack of information on the predicted no-effect concentration (PNEC) of 2,4,6-TCP, mainly due to the shortage of chronic and site-specific toxicity data. In the present study, acute and sub-chronic toxicity of 2,4,6-TCP on six different resident Chinese aquatic species were determined. PNEC values were calculated and compared by use of two approaches: assessment factor (AF) and species sensitivity distribution (SSD). Values for acute toxicity ranged from 1.1 mg L(-1) (Plagiognathops microlepis) to 42 mg L(-1) (Corbicula fluminea) and the sub-chronic no observed effect concentrations (NOECs) ranged from 0.05 mg L(-1) (Mylopharyngodon piceus) to 2.0 mg L(-1) (C. fluminea). PNECs obtained by the assessment factor approach with acute (AF=1000, 0.001 mg L(-1)) or chronic (AF=10, 0.005 mg L(-1)) toxicity data were one order of magnitude less than those from SSD methods (0.057 mg L(-1)). PNEC values calculated using SSD methods with a 50% certainty for 2,4,6-TCP was less than those obtained by use of the USEPA recommend final chronic value (FCV) method (0.097 mg L(-1)) and the one obtained by use of the USEPA recommend acute-to-chronic (ACR) methods (0.073 mg L(-1)). PNECs derived using AF methods were more protective and conservative than that derived using SSD methods.

A tiered ecological risk assessment of three chlorophenols in Chinese surface waters.

INTRODUCTION: The ecological risks posed by three chlorophenols (CPs), 2,4-dichlorophenol (2,4-DCP), 2,4,6-trichlorophenol (2,4,6-TCP), and pentachlorophenol (PCP) in Chinese surface waters were assessed. MATERIALS AND METHODS: This was achieved by applying a tiered ecological risk assessment (ERA) approach ranging from deterministic methods to probabilistic options to measured concentrations of CPs in surface water of seven major watersheds and three drainage regions in China and the chronic toxicity data for indigenous Chinese species. RESULTS AND DISCUSSION: The results show that the risks of three chlorophenols are ranked PCP>2,4-DCP≈2,4,6-TCP. PCP posed little ecological risk while 2,4-DCP and 2,4,6-TCP posed negligible or de minimis risk in Chinese surface water. However, the risks varied with different river basins, for example, PCP posed some ecological risk in the Yangtze, Huaihe, and Pearl Rivers. The magnitude of 2,4-DCP and 2,4,6-TCP pollution in North China was more serious than that in South China. CONCLUSION: The probabilistic risk assessment approach, which can provide more information for risk managers and decision makers, was favored over the screening-level single-value estimate method. However, the results from all tiers of the ERA methods in the framework were consistent with each other.

Menhaden oil administration to dogs treated with radiation for nasal tumors demonstrates lower levels of tissue eicosanoids.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or menhaden oil may reduce inflammatory eicosanoids (prostaglandin E2, thromboxane B2, leukotriene B4, and 11-dehydro thromboxane B2), matrix metalloproteinases (MMPs), and blood lactate in dogs with nasal carcinomas receiving radiation therapy. We hypothesized that menhaden oil would reduce inflammation from radiation damage and lower blood lactate levels in dogs with nasal carcinoma. In a randomized, double-blind, placebo-controlled clinical study, 12 dogs with malignant carcinomas of the nasal cavity were given dietary menhaden oil (DHA and EPA) or soybean oil (control) and then received radiation therapy. Megavoltage radiation was delivered in 18 fractions to a total dose of 56 Gy. Blood levels of DHA, EPA, insulin, glucose, lactic acid, and MMPs 2 and 9; resting energy expenditure; and inflammatory eicosanoids from nasal biopsies were measured throughout radiation therapy. Samples were obtained from each patient 1 week before the start of radiation therapy, at start of radiation, and 7, 18 (end of radiation therapy), and 42 days after radiation was initiated. Dogs that are fed with menhaden oil had significantly (P < .05) higher plasma concentration of DHA by 500% and EPA by 200% and had significantly lower tissue inflammatory eicosanoids and decreased resting energy expenditure by 20% when compared with controls. Increased plasma DHA was significantly associated (P < .05) with decreased plasma lactic acid and MMPs. These data may suggest that dietary fish oil could reduce some detrimental inflammatory eicosanoids and metabolic consequences of radiation therapy.

Biotransformation of 2,2',5,5'-tetrachlorobiphenyl (PCB 52) and 3,3',4,4'-tetrachlorobiphenyl (PCB 77) by liver microsomes from four species of sea turtles.

The rates of oxidative metabolism of two tetrachlorobiphenyl congeners were determined in hepatic microsomes from four species of sea turtles, green (Chelonia mydas), olive ridley (Lepidochelys olivacea), loggerhead (Caretta caretta), and hawksbill (Eretmochelys imbricata). Hydroxylation of 3,3',4,4'-tetrachlorobiphenyl (PCB 77), an ortho-meta unsubstituted rodent cytochrome P450 (P450) 1A substrate PCB, was not observed in sea turtle microsomes. Sea turtle microsomes hydroxylated 2,2',5,5'-tetrachlorobiphenyl (PCB 52), a meta-para unsubstituted rodent P450 family 2 substrate PCB, at rates ranging from less than 0.5 to 53 pmol/min/mg protein. The P450 inhibitor ketoconazole inhibited hydroxylation of PCB 52, supporting the role of P450 catalysis. Sea turtle PCB 52 hydroxlyation rates strongly correlated with immunodetected P450 family 2-like and less so with P450 family 3-like hepatic proteins. Testosterone 6ß-, 16α-, 16ß-hydroxylase activities were also significantly correlated with the expression of these enzymes, indicating that P450 family 2 or P450 family 3 proteins are responsible for PCB hydroxylation in sea turtles. This study indicated species-specific PCB biotransformation in sea turtles and preferential elimination of meta-para unsubstituted PCB congeners over ortho-meta unsubstituted PCB congeners consistent with PCB accumulation patterns observed in tissues of sea turtles.

The characterization of cytosolic glutathione transferase from four species of sea turtles: loggerhead (Caretta caretta), green (Chelonia mydas), olive ridley (Lepidochelys olivacea), and hawksbill (Eretmochelys imbricata).

Glutathione s-transferases (GST) play a critical role in the detoxification of exogenous and endogenous electrophiles, as well as the products of oxidative stress. As compared to mammals, GST activity has not been extensively characterized in reptiles. Throughout the globe, most sea turtle populations face the risk of extinction. Of the natural and anthropogenic threats to sea turtles, the effects of environmental chemicals and related biochemical mechanisms, such as GST catalyzed detoxification, are probably the least understood. In the present study, GST activity was characterized in four species of sea turtles with varied life histories and feeding strategies: loggerhead (Caretta caretta), green (Chelonia mydas), olive ridley (Lepidochelys olivacea), and hawksbill (Eretmochelys imbricata). Although similar GST kinetics was observed between species, rates of catalytic activities using class-specific substrates show inter- and intra-species variation. GST from the spongivorous hawksbill sea turtle shows 3-4.5 fold higher activity with the substrate 4-nitrobenzylchloride than the other 3 species. GST from the herbivorous green sea turtle shows 3 fold higher activity with the substrate ethacrynic acid than the carnivorous olive ridley sea turtle. The results of this study may provide insight into differences in biotransformation potential in the four species of sea turtles and the possible health impacts of contaminant biotransformation by sea turtles.

Global gene expression in a type 2 Gaucher disease brain.

Gaucher disease is a member of a family of inherited disorders called sphingolipidoses that among others includes Tay-Sachs and Sandhoff diseases. It is caused by the accumulation of glucosylceramide (glucocerebroside) due to deficient activity of the enzyme glucosylceramide-beta-glucosidase (glucocerebrosidase). As with other glycosphingolipidoses, severe neurodegeneration is present in types 2 and 3 Gaucher disease. We have used Serial Analysis of Gene Expression (SAGE) to characterize the gene expression profiles in brain of patients with glycosphingolipid storage diseases to understand the molecular details of neurodegeneration. In the current study we have determined the gene expression profile from the brain of a patient with type 2 Gaucher disease, the acute neuronopathic form of the disorder. We found that the expression profile of the type 2 Gaucher brain is significantly altered relative to the normal control brain profile. There were also differences when compared with profiles from Tay-Sachs and Sandhoff patients, in particular in levels of genes related to macrophage activation. Intriguingly we found that gamma-synuclein, a family member of proteins involved the pathogenesis of other neurodegenerative disorders, was elevated in the one Gaucher type 2 patient brain we examined.