In a porcine model of implantable pacemakers for pediatric unilateral diaphragm paralysis, the phrenic nerve is the best target.

BACKGROUND: A frequent complication of Fontan operations is unilateral diaphragmatic paresis, which leads to hemodynamic deterioration of the Fontan circulation. A potential new therapeutic option is the unilateral diaphragmatic pacemaker. In this study, we investigated the most effective stimulation location for a potential fully implantable system in a porcine model. METHODS: Five pigs (20.8 ± 0.95 kg) underwent implantation of a customized cuff electrode placed around the right phrenic nerve. A bipolar myocardial pacing electrode was sutured adjacent to the motor point and peripherally at the costophrenic angle (peripheral diaphragmatic muscle). The electrodes were stimulated 30 times per minute with a pulse duration of 200 µs and a stimulation time of 300 ms. Current intensity was the only variable changed during the experiment. RESULTS: Effective stimulation occurred at 0.26 ± 0.024 mA at the phrenic nerve and 7 ± 1.22 mA at the motor point, a significant difference in amperage (p = 0.005). Even with a maximum stimulation of 10 mA at the peripheral diaphragm muscle, however, no effective stimulation was observed. CONCLUSION: The phrenic nerve seems to be the best location for direct stimulation by a unilateral thoracic diaphragm pacemaker in terms of the required amperage level in a porcine model.

Photoannealing of Microtissues Creates High-Density Capillary Network Containing Living Matter in a Volumetric-Independent Manner.

The vascular tree is crucial for the survival and function of large living tissues. Despite breakthroughs in 3D bioprinting to endow engineered tissues with large blood vessels, there is currently no approach to engineer high-density capillary networks into living tissues in a scalable manner. Here, photoannealing of living microtissue (PALM) is presented as a scalable strategy to engineer capillary-rich tissues. Specifically, in-air microfluidics is used to produce living microtissues composed of cell-laden microgels in ultrahigh throughput, which can be photoannealed into a monolithic living matter. Annealed microtissues inherently give rise to an open and interconnected pore network within the resulting living matter. Interestingly, utilizing soft microgels enables microgel deformation, which leads to the uniform formation of capillary-sized pores. Importantly, the ultrahigh throughput nature underlying the microtissue formation uniquely facilitates scalable production of living tissues of clinically relevant sizes (>1 cm3 ) with an integrated high-density capillary network. In short, PALM generates monolithic, microporous, modular tissues that meet the previously unsolved need for large engineered tissues containing high-density vascular networks, which is anticipated to advance the fields of engineered organs, regenerative medicine, and drug screening.

Proof of concept of an accelerometer as a trigger for unilateral diaphragmatic pacing: a porcine model.

BACKGROUND: Unilateral diaphragmatic paralysis in patients with univentricular heart is a known complication after pediatric cardiac surgery. Because diaphragmatic excursion has a significant influence on perfusion of the pulmonary arteries and hemodynamics in these patients, unilateral loss of function leads to multiple complications. The current treatment of choice, diaphragmatic plication, does not lead to a full return of function. A unilateral diaphragmatic pacemaker has shown potential as a new treatment option. In this study, we investigated an accelerometer as a trigger for a unilateral diaphragm pacemaker (closed-loop system). METHODS: Seven pigs (mean weight 20.7 ± 2.25 kg) each were implanted with a customized accelerometer on the right diaphragmatic dome. Accelerometer recordings (mV) of the diaphragmatic excursion of the right diaphragm were compared with findings using established methods (fluoroscopy [mm]; ultrasound, M-mode [cm]). For detection of the amplitude of diaphragmatic excursions, the diaphragm was stimulated with increasing amperage by a cuff electrode implanted around the right phrenic nerve. RESULTS: Results with the different techniques for measuring diaphragmatic excursions showed correlations between accelerometer and fluoroscopy values (correlation coefficient 0.800, P < 0.001), accelerometer and ultrasound values (0.883, P < 0.001), and fluoroscopy and ultrasound values (0.816, P < 0.001). CONCLUSION: The accelerometer is a valid method for detecting diaphragmatic excursion and can be used as a trigger for a unilateral diaphragmatic pacemaker.

Estimates of the permeability of extra-cellular pathways through the astrocyte endfoot sheath.

BACKGROUND: Astrocyte endfoot processes are believed to cover all micro-vessels in the brain cortex and may play a significant role in fluid and substance transport into and out of the brain parenchyma. Detailed fluid mechanical models of diffusive and advective transport in the brain are promising tools to investigate theories of transport. METHODS: We derive theoretical estimates of astrocyte endfoot sheath permeability for advective and diffusive transport and its variation in microvascular networks from mouse brain cortex. The networks are based on recently published experimental data and generated endfoot patterns are based on Voronoi tessellations of the perivascular surface. We estimate corrections for projection errors in previously published data. RESULTS: We provide structural-functional relationships between vessel radius and resistance that can be directly used in flow and transport simulations. We estimate endfoot sheath filtration coefficients in the range [Formula: see text] to [Formula: see text], diffusion membrane coefficients for small solutes in the range [Formula: see text] to [Formula: see text], and gap area fractions in the range 0.2-0.6%, based on a inter-endfoot gap width of 20 nm. CONCLUSIONS: The astrocyte endfoot sheath surrounding microvessels forms a secondary barrier to extra-cellular transport, separating the extra-cellular space of the parenchyma and the perivascular space outside the endothelial layer. The filtration and membrane diffusion coefficients of the endfoot sheath are estimated to be an order of magnitude lower than those of the extra-cellular matrix while being two orders of magnitude higher than those of the vessel wall.

Non-task expert physicians benefit from correct explainable AI advice when reviewing X-rays.

Artificial intelligence (AI)-generated clinical advice is becoming more prevalent in healthcare. However, the impact of AI-generated advice on physicians' decision-making is underexplored. In this study, physicians received X-rays with correct diagnostic advice and were asked to make a diagnosis, rate the advice's quality, and judge their own confidence. We manipulated whether the advice came with or without a visual annotation on the X-rays, and whether it was labeled as coming from an AI or a human radiologist. Overall, receiving annotated advice from an AI resulted in the highest diagnostic accuracy. Physicians rated the quality of AI advice higher than human advice. We did not find a strong effect of either manipulation on participants' confidence. The magnitude of the effects varied between task experts and non-task experts, with the latter benefiting considerably from correct explainable AI advice. These findings raise important considerations for the deployment of diagnostic advice in healthcare.

Pump-less, recirculating organ-on-a-chip (rOoC) platform.

We developed a novel, pump-less directional flow recirculating organ-on-a-chip (rOoC) platform that creates controlled unidirectional gravity-driven flow by a combination of a 3D-tilting system and an optimized microfluidic layout. The rOoC platform was assembled utilizing a layer-to-layer fabrication technology based on thermoplastic materials. It features two organoid compartments supported by two independent perfusion channels and separated by a hydrogel barrier. We developed a computational model to predict wall shear stress values and then measured the flow rate in the microfluidic channels with micro-Particle-Image-Velocimetry (µPIV). The suitability of the rOoC for functional culture of endothelial cells was tested using HUVECs seeded in the perfusion channels. HUVECs aligned in response to the directional flow, formed a barrier and were able to sprout into the organoid compartments. Next, we demonstrated the viability of human stem-cell derived liver organoids in the organoid compartments. Finally, we show the possibility to circulate immune cells in the microfluidic channels that retain viability without being trapped or activated. The rOoC platform allows growing and connecting of two or more tissue or organ representations on-chip with the possibility of applying gradients, endothelial barriers, microvasculature and circulating cells independent of external tubing and support systems.

Monitoring of wearing and occlusion times with smart shutter glasses-A proof of concept.

PURPOSE: To develop and evaluate an electronic glasses frame for smart liquid crystal shutter glasses that monitors wearing and occlusion times to potentially improve therapy adherence in amblyopia therapy of children. METHODS: The first generation of an electronic glasses frame for adults was further developed, miniaturized and functionally tested in a proof of concept study on a small group of healthy children. Seven healthy children (4 females, 3 males, 2-9 years) were enrolled in the study. The subjects were instructed to wear the smart shutter glasses and to record their activities in daily life. Averaged and individual results were calculated for the precision of wearing position detection and activity recognition. Also, the proper execution of the configured occlusion pattern was observed. RESULTS: The first generation of an electronic glasses frame for smart liquid crystal shutter glasses in a miniaturized form factor for children. A key element is the implementation of the adaptive shutter operation and of smart algorithms for real-time therapy monitoring. In the proof of concept study, these algorithms monitored the state of wearing position, the wearer's activity and the configured occlusion pattern. The average agreement of the detected states of wearing position was 72.6%. The average activity recognition match was 77.3%. The removal of the glasses was 100% correctly detected and the occlusion was 100% halted when active motion was recognized. CONCLUSION: The assembled smart shutter glasses for children are suitable for demonstrating the feasibility of continuous therapy monitoring by calculating wearing and occlusion times due to smart algorithms for wearing position detection, activity recognition, and occlusion monitoring. However, further research and studies are necessary to optimize the individual fit and performance of this wearable therapeutic device.

Context-sensitive smart glasses monitoring wear position and activity for therapy compliance-A proof of concept.

PURPOSE: To improve the acceptance and compliance of treatment of amblyopia, the aim of this study was to show that it is feasible to design an electronic frame for context-sensitive liquid crystal glasses, which can measure the state of wear position in a robust manner and detect distinct motion patterns for activity recognition. METHODS: Different temple designs with integrated temperature and capacitive sensors were developed to realize the detection of the state of wear position to distinguish three states (correct position/wrong position/glasses taken off). The electronic glasses frame was further designed as a tool for accelerometer data acquisition, which was used for algorithm development for activity classification. For this purpose, training data of 20 voluntary healthy adult subjects (5 females, 15 males) were recorded and a 10-fold cross-validation was computed for classifier selection. In order to perform functional testing of the electronic glasses frame, a proof of concept study was performed in a small group of healthy adults. Four healthy adult subjects (2 females, 2 males) were included to wear the electronic glasses frame and to protocol their activities in their everyday life according to a defined test protocol. Individual and averaged results for the precision of the state of wear position detection and of the activity recognition were calculated. RESULTS: Context-sensitive control algorithms were developed which detected the state of wear position and activity in a proof of concept. The pilot study revealed an average of 91.4% agreement of the detected states of wear position. The activity recognition match was 82.2% when applying an additional filter criterion. Removing the glasses was always detected 100% correctly. CONCLUSION: The principles investigated are suitable for detecting the glasses' state of wear position and for recognizing the wearer´s activity in a smart glasses concept.

Call for Participation: Collaborative Benchmarking of Functional-Structural Root Architecture Models. The Case of Root Water Uptake.

Three-dimensional models of root growth, architecture and function are becoming important tools that aid the design of agricultural management schemes and the selection of beneficial root traits. However, while benchmarking is common in many disciplines that use numerical models, such as natural and engineering sciences, functional-structural root architecture models have never been systematically compared. The following reasons might induce disagreement between the simulation results of different models: different representation of root growth, sink term of root water and solute uptake and representation of the rhizosphere. Presently, the extent of discrepancies is unknown, and a framework for quantitatively comparing functional-structural root architecture models is required. We propose, in a first step, to define benchmarking scenarios that test individual components of complex models: root architecture, water flow in soil and water flow in roots. While the latter two will focus mainly on comparing numerical aspects, the root architectural models have to be compared at a conceptual level as they generally differ in process representation. Therefore, defining common inputs that allow recreating reference root systems in all models will be a key challenge. In a second step, benchmarking scenarios for the coupled problems are defined. We expect that the results of step 1 will enable us to better interpret differences found in step 2. This benchmarking will result in a better understanding of the different models and contribute toward improving them. Improved models will allow us to simulate various scenarios with greater confidence and avoid bugs, numerical errors or conceptual misunderstandings. This work will set a standard for future model development.

A multiscale subvoxel perfusion model to estimate diffusive capillary wall conductivity in multiple sclerosis lesions from perfusion MRI data.

We propose a new mathematical model to learn capillary leakage coefficients from dynamic susceptibility contrast MRI data. To this end, we derive an embedded mixed-dimension flow and transport model for brain tissue perfusion on a subvoxel scale. This model is used to obtain the contrast agent concentration distribution in a single MRI voxel during a perfusion MRI sequence. We further present a magnetic resonance signal model for the considered sequence including a model for local susceptibility effects. This allows modeling MR signal-time curves that can be compared with clinical MRI data. The proposed model can be used as a forward model in the inverse modeling problem of inferring model parameters such as the diffusive capillary wall conductivity. Acute multiple sclerosis lesions are associated with a breach in the integrity of the blood-brain barrier. Applying the model to perfusion MR data of a patient with acute multiple sclerosis lesions, we conclude that diffusive capillary wall conductivity is a good indicator for characterizing activity of lesions, even if other patient-specific model parameters are not well-known.

Basic Structure of Melanoidins Formed in the Maillard Reaction of 3-Deoxyglucosone and γ-Aminobutyric Acid.

Melanoidins are formed in foods during processing through the Maillard reaction between carbohydrates and amino compounds. The aim of this study was to draw conclusions about the formation mechanism and the structure of melanoidins formed at low water contents and low temperatures. In the Maillard reaction of d-glucose and γ-aminobutyric acid at low water contents 3-deoxyglucosone is the most important intermediate. Therefore, we used the reaction of 3-deoxyglucosone with γ-aminobutyric acid or ß-alanine as a simplified model system. The degradation of 3-deoxyglucosone and the color formation of the formed melanoidins were determined. In addition, the reaction mixture was analyzed with high-resolution mass spectrometry and a Kendrick analysis was applied. Oligomers consisting of up to four molecules of 3-deoxyglucosone and three amino acids and their respective dehydration products with furanoidic structure were detected. The melanoidin structure of C-C linked monomeric units postulated by Kroh et al. could be confirmed.

2-Deoxyglucosone: A New C6-α-Dicarbonyl Compound in the Maillard Reaction of d-Fructose with γ-Aminobutyric Acid.

In this study, α-dicarbonyl compounds consisting of a backbone with six carbon atoms resulting from the Maillard reaction of d-fructose with γ-aminobutyric acid were determined. The reaction was carried out under mild reaction conditions at 50 °C and water contents between 0 and 90%. A thus far unknown α-dicarbonyl compound was found as the main product in the first 24 h at water contents below 50%. After isolation of its stable quinoxaline derivative, it was possible to identify the compound as 2-deoxy-d- glycero-hexo-3,4-diulose (2-deoxyglucosone). For the first time, the four C6-α-dicarbonyl compounds, 1-deoxyglucosone, 2-deoxyglucosone, 3-deoxyglucosone, and 4-deoxyglucosone, could be identified in the Maillard reaction of a hexose at the same time. This indicates the formation of a 2,3-eneaminol from the Schiff base of d-fructose and the formation of 2-amino-2-deoxy-3-ketose as an alternative to the Heyns product.

Can words hurt? Patient-provider interactions during invasive procedures.

Patients are often prepared for procedural discomforts with descriptions of pain or undesirable experiences. This practice is thought to be compassionate and helpful, but there is little data on the effect of such communicative behavior. This study assesses how such descriptions affect patients' pain and anxiety during medical procedures. The interactions of patients with their healthcare providers during interventional radiological procedures were videotaped during a previously reported 3-arm prospective randomized trial assessing the efficacy of self-hypnotic relaxation. One hundred and fifty-nine videos of the standard care and attention control arms were reviewed. All statements that described painful or undesirable experiences as warning before potentially noxious stimuli or as expression of sympathy afterwards were recorded. Patients' ratings of pain and anxiety on 0-10 numerical scales (0=No Pain, No Anxiety at All and 10=Worst Pain Possible, Terrified) after the painful event and/or sympathizing statement were the basis for this study. Warning the patient in terms of pain or undesirable experiences resulted in greater pain (P<0.05) and greater anxiety (P<0.001) than not doing so. Sympathizing with the patient in such terms after a painful event did not increase reported pain, but resulted in greater anxiety (P<0.05). Contrary to common belief, warning or sympathizing using language that refers to negative experiences may not make patients feel better. This conclusion has implications for the training in medical communication skills and suggests the need for randomized trials testing different patient-practioner interactions.