Extracellular ATP drives systemic inflammation, tissue damage and mortality

Systemic inflammatory response syndromes (SIRS) may be caused by both infectious and sterile insults, such as trauma, ischemia-reperfusion or burns. They are characterized by early excessive inflammatory cytokine production and the endogenous release of several toxic and damaging molecules. These are necessary to fight and resolve the cause of SIRS, but often end up progressively damaging cells and tissues, leading to life-threatening multiple organ dysfunction syndrome (MODS). As inflammasome-dependent cytokines such as interleukin-1 beta are critically involved in the development of MODS and death in SIRS, and ATP is an essential activator of inflammasomes in vitro, we decided to analyze the ability of ATP removal to prevent excessive tissue damage and mortality in a murine LPS-induced inflammation model. Our results indeed indicate an important pro-inflammatory role for extracellular ATP. However, the effect of ATP is not restricted to inflammasome activation at all. Removing extracellular ATP with systemic apyrase treatment not only prevented IL-1 beta accumulation but also the production of inflammasome-independent cytokines such as TNF and IL-10. In addition, ATP removal also prevented systemic evidence of cellular disintegration, mitochondrial damage, apoptosis, intestinal barrier disruption and even mortality. Although blocking ATP receptors with the broad-spectrum P2 purinergic receptor antagonist suramin imitated certain beneficial effects of apyrase treatment, it could not prevent morbidity or mortality at all. We conclude that removal of systemic extracellular ATP could be a valuable strategy to dampen systemic inflammatory damage and toxicity in SIRS

CABE : a cloud-based acoustic beamforming emulator for FPGA-based sound source localization

Microphone arrays are gaining in popularity thanks to the availability of low-cost microphones. Applications including sonar, binaural hearing aid devices, acoustic indoor localization techniques and speech recognition are proposed by several research groups and companies. In most of the available implementations, the microphones utilized are assumed to offer an ideal response in a given frequency domain. Several toolboxes and software can be used to obtain a theoretical response of a microphone array with a given beamforming algorithm. However, a tool facilitating the design of a microphone array taking into account the non-ideal characteristics could not be found. Moreover, generating packages facilitating the implementation on Field Programmable Gate Arrays has, to our knowledge, not been carried out yet. Visualizing the responses in 2D and 3D also poses an engineering challenge. To alleviate these shortcomings, a scalable Cloud-based Acoustic Beamforming Emulator (CABE) is proposed. The non-ideal characteristics of microphones are considered during the computations and results are validated with acoustic data captured from microphones. It is also possible to generate hardware description language packages containing delay tables facilitating the implementation of Delay-and-Sum beamformers in embedded hardware. Truncation error analysis can also be carried out for fixed-point signal processing. The effects of disabling a given group of microphones within the microphone array can also be calculated. Results and packages can be visualized with a dedicated client application. Users can create and configure several parameters of an emulation, including sound source placement, the shape of the microphone array and the required signal processing flow. Depending on the user configuration, 2D and 3D graphs showing the beamforming results, waterfall diagrams and performance metrics can be generated by the client application. The emulations are also validated with captured data from existing microphone arrays.</jats:p

Multimodal biometric monitoring technologies drive the development of clinical assessments in the home environment

Biometric Monitoring Technologies (BioMeTs) attracted the attention of the health care community because of their user-friendly form factor and multi-sensor data collection capabilities. The potential benefits of multimodal remote monitoring for collecting comprehensive, longitudinal, and contextual datasets spans therapeutic areas, and both chronic and acute disease settings. Importantly, multimodal BioMeTs unlock the ability to generate rich context data to augment digital measures. Currently, the availability of devices is no longer the main factor limiting adoption but rather the ability to integrate fit-for-purpose BioMeTs reliably and safely into clinical care. We provide a critical review of the state of art for multimodal BioMeTs in clinical care and identify three unmet clinical needs: 1) expanding the abilities of existing ambulatory unimodal BioMeTs; 2) adapting standardized clinical test protocols ("spot checks'') for use under free living conditions; and 3) novel applications to manage rehabilitation and chronic diseases. As the field is still in an early and quickly evolving state, we make practical recommendations to 1) select appropriate BioMeTs; 2) develop composite digital measures; and 3) design interoperable software to ingest, process, delegate, and visualize the data when deploying novel clinical applications. Multimodal BioMeTs will drive the evolution from in-clinic assessments to at-home data collection with a focus on prevention, personalization, and long-term outcomes by empowering health care providers with knowledge, delivering convenience, and an improved standard of care to patients

Verification, Analytical Validation, and Clinical Validation (V3): The Foundation of Determining Fit-for-Purpose for Biometric Monitoring Technologies (BioMeTs)

Digital medicine is an interdisciplinary field, drawing together stakeholders with expertize in engineering, manufacturing, clinical science, data science, biostatistics, regulatory science, ethics, patient advocacy, and healthcare policy, to name a few. Although this diversity is undoubtedly valuable, it can lead to confusion regarding terminology and best practices. There are many instances, as we detail in this paper, where a single term is used by different groups to mean different things, as well as cases where multiple terms are used to describe essentially the same concept. Our intent is to clarify core terminology and best practices for the evaluation of Biometric Monitoring Technologies (BioMeTs), without unnecessarily introducing new terms. We focus on the evaluation of BioMeTs as fit-for-purpose for use in clinical trials. However, our intent is for this framework to be instructional to all users of digital measurement tools, regardless of setting or intended use. We propose and describe a three-component framework intended to provide a foundational evaluation framework for BioMeTs. This framework includes (1) verification, (2) analytical validation, and (3) clinical validation. We aim for this common vocabulary to enable more effective communication and collaboration, generate a common and meaningful evidence base for BioMeTs, and improve the accessibility of the digital medicine field

Citrulline supplementation improves organ perfusion and arginine availability under conditions with enhanced arginase activity

Enhanced arginase-induced arginine consumption is believed to play a key role in the pathogenesis of sickle cell disease-induced end organ failure. Enhancement of arginine availability with l-arginine supplementation exhibited less consistent results; however, l-citrulline, the precursor of l-arginine, may be a promising alternative. In this study, we determined the effects of l-citrulline compared to l-arginine supplementation on arginine-nitric oxide (NO) metabolism, arginine availability and microcirculation in a murine model with acutely-enhanced arginase activity. The effects were measured in six groups of mice (n = 8 each) injected intraperitoneally with sterile saline or arginase (1000 IE/mouse) with or without being separately injected with l-citrulline or l-arginine 1 h prior to assessment of the microcirculation with side stream dark-field (SDF)-imaging or in vivo NO-production with electron spin resonance (ESR) spectroscopy. Arginase injection caused a decrease in plasma and tissue arginine concentrations. l-arginine and l-citrulline supplementation both enhanced plasma and tissue arginine concentrations in arginase-injected mice. However, only the citrulline supplementation increased NO production and improved microcirculatory flow in arginase-injected mice. In conclusion, the present study provides for the first time in vivo experimental evidence that l-citrulline, and not l-arginine supplementation, improves the end organ microcirculation during conditions with acute arginase-induced arginine deficiency by increasing the NO concentration in tissues

Fit‐for‐Purpose Biometric Monitoring Technologies: Leveraging the Laboratory Biomarker Experience

Biometric Monitoring Technologies (BioMeTs) are becoming increasingly common to aid data collection in clinical trials and practice. The state of BioMeTs, and associated digitally measured biomarkers, is highly reminiscent of the field of laboratory biomarkers two decades ago. In this review, we have summarized and leveraged historical perspectives, and lessons learned from laboratory biomarkers as they apply to BioMeTs. Both categories share common features, including goals and roles in biomedical research, definitions, and many elements of the biomarker qualification framework. They can also be classified based on the underlying technology, each with distinct features and performance characteristics, which require bench and human experimentation testing phases. In contrast to laboratory biomarkers, digitally measured biomarkers require prospective data collection for purposes of analytical validation in human subjects, lack well-established and widely accepted performance characteristics, require human factor testing and, for many applications, access to raw (sample-level) data. Novel methods to handle large volumes of data, as well as security and data rights requirements add to the complexity of this emerging field. Our review highlights the need for a common framework with appropriate vocabulary and standardized approaches to evaluate digitally measured biomarkers, including defining performance characteristics and acceptance criteria. Additionally, the need for human factor testing drives early patient engagement during technology development. Finally, the use of BioMeTs requires a relatively high degree of technology literacy among both study participants and healthcare professionals. Transparency of data generation and the need for novel analytical and statistical tools creates opportunities for precompetitive collaborations

Complex dynamics in systemic inflammation : quantification of coupling and targeting of the nitric oxide-soluble guanylate cyclase axis

Sepsis and septic shock are associated with high mortality rates and the majority of sepsis patients die due to complications of multiple organ dysfunction. The nitric oxide (NO) – soluble guanylate cyclase (sGC) axis is centrally involved in the homeodynamics of the (micro)circulation and cardiac function. Malfunctioning of this pathway can lead to failure of end-organ perfusion and cytopathic hypoxia, culminating in progressive multiple organ dysfunction and death. Although the pathway has been linked to detrimental effects in the pathogenesis of sepsis, the emerging consensus is that functional NO/sGC signaling is a prerequisite for microcirculatory and cardiac function, and thus stabilization of end-organ function during sepsis-induced systemic inflammation. Therefore we examined the feasibility of pharmacological targeting of sGC in a murine endotoxic shock model. The sGC activator BAY 58-2667 (cinaciguat) will specifically reactivate sGC that was exposed to oxidative stress and can prevent morbidity, cardiomyocyte apoptosis, and mortality when administered as a late therapeutic treatment. However, treatment was restricted to an optimal time window: administration of BAY 58-2667 too early after the sepsis-inducing challenge exacerbated mortality, indicating that the dynamics of the redox status of sGC were changing as a function of oxidative stress during the progression of endotoxic shock, and emphasizing the highly bivalent function of the pathway. We hypothesize that treatment with BAY 58-2667 in this optimal window specifically reestablished microcirculatory flow in hypoxic capillary beds by vasodilation, anti-platelet aggregation, anti-leukocyte adhesion, and cardioprotective effects. Together, these effects should lead to improved perfusion, decreased (cytopathic) hypoxia, and subsequently, improved organ function and survival. In addition, the effect of BAY 58-2667 on inter-organ coupling was quantified via variability of beat-to-beat dynamics. We identified improvements in unifractal dynamics and increased spectral power in the low frequency band acutely post-treatment. The latter is indicative for increased sympathetic input to the sinus node of the heart. Furthermore, a large number of measures of beat-to-beat variability were examined in a murine tumor necrosis factor (TNF) and endotoxic shock model. Our results indicate that analysis of beat-to-beat dynamics at high temporal resolution via multiscale entropy (MSE), a measure of complex dynamics, can predict outcome very early after the initial challenge, in contrast to other variability parameters, absolute heart rate, or blood pressure. Because the output of the MSE algorithm is a complex aggregate of multiscalar information, we developed a more clinically relevant MSE scoring method that amplifies the relevant features of an MSE profile, and summarizes that information in simple scoring components that can be easily followed as a function of time. Thus, quantification of multiscale complexity in physiological time series appears to be representative for the underlying complex regulation of the organism, the degree of loss of inter-organ coupling, and can be highly sensitive and specific for detecting state changes linked to disease, as demonstrated in these murine models. Preliminary results indicate that this is also possible in more complex sepsis models, as well as intensive care patients. Finally, we also showed that the hypersensitivity of MK2-deficient mice to TNF is likely caused by defects in the stress fiber response and/or failure of certain granulocytes to extravasate