Publications

Functional precision medicine (FPM) has emerged as a new approach to improve cancer treatment. Despite its potential, FPM assays present important limitations such as the number of cells and trained personnel required. To overcome these impediments, here we describe a novel microfluidic platform that can be used to perform FPM assays, optimizing the use of primary cancer cells and simplifying the process by using microfluidics to automatize the process.© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.

JTD Keywords: Bioassay, Biological assay, Cancer treatment, Functional assays, Lab-on-a-chip devices, Microfluidics, Personalized medicine, Precision medicine

Using nanoparticles (NPs) in drug delivery has exhibited promising therapeutic potential in various cancer types. Nevertheless, several challenges must be addressed, including the formation of the protein corona, reduced targeting efficiency and specificity, potential immune responses, and issues related to NP penetration and distribution within 3-dimensional tissues. To tackle these challenges, we have successfully integrated iron oxide nanoparticles into neuroblastoma-derived extracellular vesicles (EVs) using the parental labeling method. We first developed a tissue-engineered (TE) neuroblastoma model, confirming the viability and proliferation of neuroblastoma cells for at least 12 days, supporting its utility for EV isolation. Importantly, EVs from long-term cultures exhibited no differences compared to short-term cultures. Concurrently, we designed Rhodamine (Rh) and Polyacrylic acid (PAA)-functionalized magnetite nanoparticles (Fe3O4@PAA-Rh) with high crystallinity, purity, and superparamagnetic properties (average size: 9.2 +/- 2.5 nm). We then investigated the internalization of Fe3O4@PAA-Rh nanoparticles within neuroblastoma cells within the TE model. Maximum accumulation was observed overnight while ensuring robust cell viability. However, nanoparticle internalization was low. Taking advantage of the enhanced glucose metabolism exhibited by cancer cells, glucose (Glc)-functionalized nanoparticles (Fe3O4@PAA-Rh-Glc) were synthesized, showing superior cell uptake within the 3D model without inducing toxicity. These glucose-modified nanoparticles were selected for parental labeling of the TE models, showing effective NP encapsulation into EVs. Our research introduces innovative approaches to advance NP delivery, by partially addressing the challenges associated with 3D systems, optimizing internalization, and enhancing NP stability and specificity through EV-based carriers. Also, our findings hold the promise of more precise and effective cancer therapies while minimizing potential side effects.

JTD Keywords: Biomimetic models, Extracellular vesicles, Iron oxide nanoparticles, Neuroblastoma, Precision medicine

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with survival rates exceeding 85%. However, 15% of patients will relapse; consequently, their survival rates decrease to below 50%. Therefore, several research and innovation studies are focusing on pediatric relapsed or refractory ALL (R/R ALL). Driven by this context and following the European strategic plan to implement precision medicine equitably, the Relapsed ALL Network (ReALLNet) was launched under the umbrella of SEHOP in 2021, aiming to connect bedside patient care with expert groups in R/R ALL in an interdisciplinary and multicentric network. To achieve this objective, a board consisting of experts in diagnosis, management, preclinical research, and clinical trials has been established. The requirements of treatment centers have been evaluated, and the available oncogenomic and functional study resources have been assessed and organized. A shipping platform has been developed to process samples requiring study derivation, and an integrated diagnostic committee has been established to report results. These biological data, as well as patient outcomes, are collected in a national registry. Additionally, samples from all patients are stored in a biobank. This comprehensive repository of data and samples is expected to foster an environment where preclinical researchers and data scientists can seek to meet the complex needs of this challenging population. This proof of concept aims to demonstrate that a network-based organization, such as that embodied by ReALLNet, provides the ideal niche for the equitable and efficient implementation of "what's next" in the management of children with R/R ALL.© 2023 Velasco, Bautista, Rubio, Aguilar, Rives, Dapena, Pérez, Ramirez, Saiz-Ladera, Izquierdo, Escudero, Camós, Vega-Garcia, Ortega, Hidalgo-Gómez, Palacio, Menéndez, Bueno, Montero, Romecín, Zazo, Alvarez, Parras, Ortega-Sabater, Chulián, Rosa, Cirillo, García, García, Manzano-Muñoz, Minguela and Fuster.

JTD Keywords: artificial intelligence, cancer registry, children, discovery, functional assay, outcomes, precision medicine, risk-factors, Artificial intelligence, B-cell precursor, Cancer registry, Functional assay, Precision medicine, Relapsed acute lymphoblastic leukemia

The endosomal sorting complex required for transport (ESCRT) is a multi-protein machinery involved in several membrane remodeling processes. Different approaches have been used to resolve how ESCRT proteins scission membranes. However, the underlying mechanisms generating membrane deformations are still a matter of debate. Here, giant unilamellar vesicles, microfluidic technology, and micropipette aspiration are combined to continuously follow the ESCRT-III-mediated membrane remodeling on the single-vesicle level for the first time. With this approach, we identify different mechanisms by which a minimal set of three ESCRT-III proteins from Entamoeba histolytica reshape the membrane. These proteins modulate the membrane stiffness and spontaneous curvature to regulate bud size and generate intraluminal vesicles even in the absence of ATP. We demonstrate that the bud stability depends on the protein concentration and membrane tension. The approaches introduced here should open the road to diverse applications in synthetic biology for establishing artificial cells with several membrane compartments.© 2022 The Author(s).

JTD Keywords: bilayer, curvature, diffusion-coefficients, identification, membrane-scission, phase-diagram, reveals, sorting complex, structural basis, Biophysics, Biotechnology, Cell biology, Giant vesicles, Membranes

Breathing pattern has been shown to be different in chronic obstructive pulmonary disease (COPD) patients compared to healthy controls during rest and walking. In this study we evaluated respiratory parameters and the breathing variability of COPD patients as a function of their severity. Thoracic bioimpedance was acquired on 66 COPD patients during the performance of the six-minute walk test (6MWT), as well as 5 minutes before and after the test while the patients were seated, i.e. resting and recovery phases. The patients were classified by their level of airflow limitation into moderate and severe groups. We characterized the breathing patterns by evaluating common respiratory parameters using only wearable bioimpedance. Specifically, we computed the median and the coefficient of variation of the parameters during the three phases of the protocol, and evaluated the statistical differences between the two COPD severity groups. We observed significant differences between the COPD severity groups only during the sitting phases, whereas the behavior during the 6MWT was similar. Particularly, we observed an inverse relationship between breathing pattern variability and COPD severity, which may indicate that the most severely diseased patients had a more restricted breathing compared to the moderate patients.

JTD Keywords: 6mwt, activation, breathing pattern, burden, chronic obstructive pulmonary disease, exercise, muscles, pressure, pulmonary, signals, variability, volumes, wearables, Bioimpedance, Impedance pneumography

Precision medicine is starting to incorporate functional assays to evaluate anticancer agents on patient-isolated tissues or cells to select for the most effective. Among these new technologies, dynamic BH3 profiling (DBP) has emerged and extensively been used to predict treatment efficacy in different types of cancer. DBP uses synthetic BH3 peptides to measure early apoptotic events ('priming') and anticipate therapy-induced cell death leading to tumor elimination. This predictive functional assay presents multiple advantages but a critical limitation: the cell number requirement, that limits drug screening on patient samples, especially in solid tumors. To solve this problem, we developed an innovative microfluidic-based DBP (µDBP) device that overcomes tissue limitations on primary samples. We used microfluidic chips to generate a gradient of BIM BH3 peptide, compared it with the standard flow cytometry based DBP, and tested different anticancer treatments. We first examined this new technology's predictive capacity using gastrointestinal stromal tumor (GIST) cell lines, by comparing imatinib sensitive and resistant cells, and we could detect differences in apoptotic priming and anticipate cytotoxicity. We then validated µDBP on a refractory GIST patient sample and identified that the combination of dactolisib and venetoclax increased apoptotic priming. In summary, this new technology could represent an important advance for precision medicine by providing a fast, easy-to-use and scalable microfluidic device to perform DBP in situ as a routine assay to identify the best treatment for cancer patients.© 2022. The Author(s).

JTD Keywords: biomarkers, cancer drugs, chemotherapy, chip, models, platform, sensitivity, strategy, tumor-cells, Precision medicine

Identification of asymptomatic patients at higher risk for suffering cardiac events remains controversial and challenging in Brugada syndrome (BS). In this work, we proposed an ECG-based classifier to predict BS-related symptoms, by merging the most predictive electrophysiological features derived from the ventricular depolarization and repolarization periods, along with autonomic-related markers. The initial feature space included local and dynamic ECG markers, assessed during a physical exercise test performed in 110 BS patients (25 symptomatic). Morphological, temporal and spatial properties quantifying the ECG dynamic response to exercise and recovery were considered. Our model was obtained by proposing a two-stage feature selection process that combined a resampled-based regularization approach with a wrapper model assessment for balancing, simplicity and performance. For the classification step, an ensemble was constructed by several logistic regression base classifiers, whose outputs were fused using a performance-based weighted average. The most relevant predictors corresponded to the repolarization interval, followed by two autonomic markers and two other makers of depolarization dynamics. Our classifier allowed for the identification of novel symptom-related markers from autonomic and dynamic ECG responses during exercise testing, suggesting the need for multifactorial risk stratification approaches in order to predict future cardiac events in asymptomatic BS patients.

JTD Keywords: brugada syndrome, depolarization disorders, ensemble classifier, heart-rate recovery, Acute myocardial-ischemia, Autonomics, Brugada syndrome, Brugadum syndrome, Cardiac death, Depolarization, Depolarization disorder, Depolarization disorders, Dynamic ecg, Electrocardiography, Electrophysiology, Ensemble classifier, Ensemble-classifier, Events, Exercise, Forecasting, Heart, Heart-rate, Heart-rate recovery, Prognosis, Qrs, Quantification, Recovery, Repolarization, Sudden cardiac death

Single-molecule localization microscopy (SMLM) is a powerful super-resolution technique for elucidating structure and dynamics in the life- and material sciences. Simultaneously acquiring spectral information (spectrally resolved SMLM, sSMLM) has been hampered by several challenges: an increased complexity of the optical detection pathway, lower accessible emitter densities, and compromised spatio-spectral resolution. Here we present a single-component, low-cost implementation of sSMLM that addresses these challenges. Using a low-dispersion transmission grating positioned close to the image plane, the +1stdiffraction order is minimally elongated and is analyzed using existing single-molecule localization algorithms. The distance between the 0th and 1st order provides accurate information on the spectral properties of individual emitters. This method enables a 5-fold higher emitter density while discriminating between fluorophores whose peak emissions are less than 15 nm apart. Our approach can find widespread use in single-molecule applications that rely on distinguishing spectrally different fluorophores under low photon conditions.

JTD Keywords: cells, multicolor imaging, nanoscopy, particle tracking, point accumulation for imaging in nanoscale topography (paint), precision, single-molecule fo?rster resonance energy transfer (smfret), stochastic optical reconstruction microscopy (storm), Diffraction-limit, Multicolor imaging, Point accumulation for imaging in nanoscale topography (paint), Single-molecule förster resonance energy transfer (smfret), Single-molecule spectroscopy, Stochastic optical reconstruction microscopy (storm)

Chronic obstructive pulmonary disease (COPD) requires a multifactorial assessment, evaluating the airflow limitation and symptoms of the patients. The 6-min walk test (6MWT) is commonly used to evaluate the functional exercise capacity in these patients. This study aims to propose a novel predictive model of the major 6MWT outcomes for COPD assessment, without physical performance measurements.Cardiopulmonary and clinical parameters were obtained from fifty COPD patients. These parameters were used as inputs of a Bayesian network (BN), which integrated three multivariate models including the 6-min walking distance (6MWD), the maximum HR (HRmax) after the walking, and the HR decay 3 min after (HRR3). The use of BN allows the assessment of the patients' status by predicting the 6MWT outcomes, but also inferring disease severity parameters based on actual patient's 6MWT outcomes.Firstly, the correlation obtained between the estimated and actual 6MWT measures was strong (R = 0.84, MAPE = 8.10% for HRmax) and moderate (R = 0.58, MAPE = 15.43% for 6MWD and R = 0.58, MAPE = 32.49% for HRR3), improving the classical methods to estimate 6MWD. Secondly, the classification of disease severity showed an accuracy of 78.3% using three severity groups, which increased up to 84.4% for two defined severity groups.We propose a powerful two-way assessment tool for COPD patients, capable of predicting 6MWT outcomes without the need for an actual walking exercise. This model-based tool opens the way to implement a continuous monitoring system for COPD patients at home and to provide more personalized care.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

JTD Keywords: 6mwt, bayesian networks, copd, distance, exercise capacity, physical capacity, reference equations, severity, survival, wearables, 6mwt, Heart-rate recovery, Wearables

Moderate exercise has well-founded benefits in cardiovascular health. However, increasing, yet controversial, evidence suggests that extremely trained athletes may not be protected from cardiovascular events as much as moderately trained individuals. In our rodent model, intensive but not moderate training promoted aorta and carotid stiffening and elastic lamina ruptures, tunica media thickening of intramyocardial arteries, and an imbalance between vasoconstrictor and relaxation agents. An up-regulation of angiotensin-converter enzyme, miR-212, miR-132, and miR-146b might account for this deleterious remodeling. Most changes remained after a 4-week detraining. In conclusion, our results suggest that intensive training blunts the benefits of moderate exercise. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

JTD Keywords: atherosclerosis, cacs, coronary artery calcium score, cad, coronary artery disease, coronary artery disease, cv, cardiovascular, endurance exercise, extreme sport, mmp9, matrix metalloproteinase 9, no, nitric oxide, phe, phenylephrine, vsmc, vascular smooth muscle cell, Age, Atherosclerosis, Cacs, coronary artery calcium score, Cad, coronary artery disease, Coronary artery disease, Coronary atherosclerosis, Cv, cardiovascular, Disease, Endurance exercise, Extreme sport, Metalloproteinases, Micrornas, Mmp9, matrix metalloproteinase 9, No, nitric oxide, Phe, phenylephrine, Physical-activity, Prevalence, Rats, Relevance, Risk, Vascular stiffening, Vsmc, vascular smooth muscle cell

Large doses of movement practice have been shown to restore upper extremities' motor function in a significant subset of individuals post-stroke. However, such large doses are both difficult to implement in the clinic and highly inefficient. In addition, an important reduction in upper extremity function and use is commonly seen following rehabilitation-induced gains, resulting in “rehabilitation in vain”. For those with mild to moderate sensorimotor impairment, the limited spontaneous use of the more affected limb during activities of daily living has been previously proposed to cause a decline of motor function, initiating a vicious cycle of recovery, in which non-use and poor performance reinforce each other. Here, we review computational, experimental, and clinical studies that support the view that if arm use is raised above an effective threshold, one enters a virtuous cycle in which arm use and function can reinforce each other via self-practice in the wild. If not, one enters a vicious cycle of declining arm use and function. In turn, and in line with best practice therapy recommendations, this virtuous/vicious cycle model advocates for a paradigm shift in neurorehabilitation whereby rehabilitation be embedded in activities of daily living such that self-practice with the aid of wearable technology that reminds and motivates can enhance paretic limb use of those who possess adequate residual sensorimotor capacity. Altogether, this model points to a user-centered approach to recovery post-stroke that is tailored to the participant's level of arm use and designed to motivate and engage in self-practice through progressive success in accomplishing meaningful activities in the wild. Copyright © 2022 Ballester, Winstein and Schweighofer.

JTD Keywords: compensatory movement, computational neurorehabilitation, decision-making, individuals, learned non-use, learned nonuse, monkeys, neurorehabilitation, recovery, rehabilitation, stroke, stroke patients, wearable sensors, wrist, Arm movement, Article, Cerebrovascular accident, Clinical decision making, Clinical practice, Clinical study, Compensatory movement, Computational neurorehabilitation, Computer model, Daily life activity, Decision-making, Experimental study, Human, Induced movement therapy, Learned non-use, Musculoskeletal function, Neurorehabilitation, Paresis, Sensorimotor function, Stroke, Stroke rehabilitation, User-centered design, Vicious cycle, Virtuous cycle, Wearable sensors

Abstract Critical dynamics, characterized by scale-free neuronal avalanches, is thought to underlie optimal function in the sensory cortices by maximizing information transmission, capacity, and dynamic range. In contrast, deviations from criticality have not yet been considered to support any cognitive processes. Nonetheless, neocortical areas related to working memory and decision-making seem to rely on long-lasting periods of ignition-like persistent firing. Such firing patterns are reminiscent of supercritical states where runaway excitation dominates the circuit dynamics. In addition, a macroscopic gradient of the relative density of Somatostatin (SST+) and Parvalbumin (PV+) inhibitory interneurons throughout the cortical hierarchy has been suggested to determine the functional specialization of low- versus high-order cortex. These observations thus raise the question of whether persistent activity in high-order areas results from the intrinsic features of the neocortical circuitry. We used an attractor model of the canonical cortical circuit performing a perceptual decision-making task to address this question. Our model reproduces the known saddle-node bifurcation where persistent activity emerges, merely by increasing the SST+/PV+ ratio while keeping the input and recurrent excitation constant. The regime beyond such a phase transition renders the circuit increasingly sensitive to random fluctuations of the inputs -i.e., chaotic-, defining an optimal SST+/PV+ ratio around the edge-of-chaos. Further, we show that both the optimal SST+/PV+ ratio and the region of the phase transition decrease monotonically with increasing input noise. This suggests that cortical circuits regulate their intrinsic dynamics via inhibitory interneurons to attain optimal sensitivity in the face of varying uncertainty. Hence, on the one hand, we link the emergence of supercritical dynamics at the edge-of-chaos to the gradient of the SST+/PV+ ratio along the cortical hierarchy, and, on the other hand, explain the behavioral effects of the differential regulation of SST+ and PV+ interneurons by neuromodulators like acetylcholine in the presence of input uncertainty.

JTD Keywords: attractor model, cortex, cortical networks, edge-of-chaos, model, nmda receptors, Attractor model, Cortical hierarchies, Decision making, Dynamics, Edge of chaos, Edge-of-chaos, High-order, Higher-order, Inhibitory interneurons, Neurons, Optimal decision making, Persistent activities, Persistent activity, Supercritical, Supercriticality

Multiple targeted therapies are currently explored for pediatric and young adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treatment. However, this new armamentarium of therapies faces an old problem: choosing the right treatment for each patient. The lack of predictive biomarkers is particularly worrying for pediatric patients since it impairs the implementation of new treatments in the clinic. In this study, we used the functional assay dynamic BH3 profiling (DBP) to evaluate two new treatments for BCP-ALL that could improve clinical outcome, especially for relapsed patients. We found that the MEK inhibitor trametinib and the multi-target tyrosine kinase inhibitor sunitinib exquisitely increased apoptotic priming in an NRAS-mutant and in a KMT2A-rearranged cell line presenting a high expression of FLT3, respectively. Following these observations, we sought to study potential adaptations to these treatments. Indeed, we identified with DBP anti-apoptotic changes in the BCL-2 family after treatment, particularly involving MCL-1 – a pro-survival strategy previously observed in adult cancers. To overcome this adaptation, we employed the BH3 mimetic S63845, a specific MCL-1 inhibitor, and evaluated its sequential addition to both kinase inhibitors to overcome resistance. We observed that the metronomic combination of both drugs with S63845 was synergistic and showed an increased efficacy compared to single agents. Similar observations were made in BCP-ALL KMT2A-rearranged PDX cells in response to sunitinib, showing an analogous DBP profile to the SEM cell line. These findings demonstrate that rational sequences of targeted agents with BH3 mimetics, now extensively explored in clinical trials, may improve treatment effectiveness by overcoming anti-apoptotic adaptations in BCP-ALL.

JTD Keywords: apoptosis, bh3 mimetics, cancer, dependence, increases, kinase inhibition, pediatric leukemia, precision medicine, resistance, sensitivity, targeted therapies, tumor-cells, venetoclax, Apoptosis, Bcl-2 family proteins, Bh3 mimetics, Pediatric leukemia, Resistance, Targeted therapies

A new methodology for the pH-triggered degradation of polymers or for the release of drugs under visible light irradiation based on the cyclization of ortho-hydroxy-cinnamates (oHC) to coumarins is described. The key oHC structural motif can be readily incorporated into the rational design of novel photocleavable polymers via click chemistry. This main-chain moiety undergoes a fast photocleavage when irradiated with 455 nm light provided that a suitable base is added. A series of polyethylene glycol-alt-ortho-hydroxy cinnamate (polyethylene glycol (PEG)(n)-alt-oHC)-based polymers are synthesized and the time-dependent visible-light initiated cleavage of the photoactive monomer and polymer is investigated in solution by a variety of spectroscopic and chromatographic techniques. The photo-degradation behavior of the water-soluble poly(PEG(2000)-alt-oHC) is investigated within a broad pH range (pH = 2.1-11.8), demonstrating fast degradation at pH 11.8, while the stability of the polymer is greatly enhanced at pH 2.1. Moreover, the neat polymer shows long-term stability under daylight conditions, thus allowing its storage without special precautions. In addition, two water-soluble PEG-based drug-carrier molecules (mPEG(2000)-oHC-benzhydrol/phenol) are synthesized and used for drug delivery studies, monitoring the process by UV-vis spectroscopy in an ON/OFF intermittent manner.

JTD Keywords: coumarins, drug delivery, e/z-double bond isomerization, o-hydroxy cinnamates, polymer degradation, Aliphatic compounds, Antioxidant activity, Antitumor, Chromatographic techniques, Chromatography, Cis/trans isomerization, Controlled drug delivery, Coumarin derivatives, Coumarins, Drug delivery, Drug delivery system, E/z-double bond isomerization, Films, Hydrogels, Image enhancement, Light, Long term stability, O-hydroxy cinnamates, Particles, Photoactive monomers, Photodegradation, Polyethylene glycols, Polyethylenes, Polymer degradation, Responsive polymers, Salts, Structural motifs, Synthesis (chemical), Targeted drug delivery, Visible light photocatalysis, Visible-light irradiation

Flexible electrochemical sensors based on electroactive materials have emerged as powerful analytical tools for biomedical applications requiring bioanalytes detection. Within this context, 3D printing is a remarkable technology for developing electrochemical devices, due to no design constraints, waste minimization, and batch manufacturing with high reproducibility. However, the fabrication of 3D printed electrodes is still limited by the in-house fabrication of conductive filaments, which requires the mixture of the electroactive material with melted of thermoplastic polymer (e.g., polylactic acid, PLA). Herein, a simple approach is presented for preparing electrochemical dopamine (DA) biosensors. Specifically, the surface of 3D-printed PLA specimens, which exhibit an elastic modulus and a tensile strength of 3.7 +/- 0.3 GPa and 47 +/- 1 MPa, respectively, is activated applying a 0.5 m NaOH solution for 30 min and, subsequently, poly(3,4-ethylenedioxythiophene) is polymerized in situ using aqueous solvent. The detection of DA with the produced sensors has been demonstrated by cyclic voltammetry, differential pulse voltammetry, and chronoamperometry. In summary, the obtained results reflect that low-cost electrochemical sensors, which are widely used in medicine and biotechnology, can be rapidly fabricated using the proposed approach that, although based on additive manufacturing, does not require the preparation of conductive filaments.

JTD Keywords: 3d printers, Additive manufacturing, Amines, Batch manufacturing, Biomedical applications, Chronoamperometry, Conducting polymer, Conducting polymers, Conductive filaments, Conservation, Cyclic voltammetry, Differential pulse voltammetry, Electroactive material, Electrochemical biosensor, Electrochemical devices, Electrochemical sensors, Electrodes, Electron emission, Flexible electrode, High reproducibility, Medical applications, Neurophysiology, Poly-3 ,4-ethylenedioxythiophene, Polyesters, Polylactic aci, Sodium hydroxide, Tensile strength, Thermoplastic polymer

The puropse of this study was to evaluate associations of cisterna chyli (CCh) diameter with portal hemodynamics and the influence of TIPS-creation in cirrhotic patients. 93 cirrhotic patients (57 male, mean age 59 years) received CT prior to TIPS-creation. 38/93 additionally underwent post-interventional CT. CCh-diameter was measured. After categorization into patients with and without large venous collaterals (i.e. > 6 mm), data were analyzed regarding associations between CCh-diameter, clinical and portal-hemodynamic parameters and diameter-changes after TIPS-creation. Patient survival post-TIPS was analyzed. Median portosystemic pressure-gradient decreased from 20 to 9 mmHg after TIPS-creation. Large venous collaterals were observed in 59 patients. In 69/93 patients (74.2%) the CCh was detectable. Mean pre-interventional diameter was 9.4 ± 2.7 mm (large collaterals: 8.7 ± 2.0 mm, no large collaterals: 10.7 ± 3.2 mm, p = 0.003). CCh-diameter correlated strongly with pre-TIPS portal-pressure (Rs = 0.685, p = 0.0001), moderately with portosystemic-gradient (Rs = 0.524, p = 0.006), liver shear-wave-elastography (Rs = 0.597, p = 0.004) and spleen size (Rs = 0.501, p = 0.01) in patients without large collaterals, but not in patients with large collaterals. Post-TIPS CCh-diameter decreased significantly from 10.2 ± 2.8 mm to 8.3 ± 3.0 mm (p < 0.001). Patients without a detectable CCh on CT survived significantly shorter. The diameter of the CCh is associated with portal-pressure and decreases after TIPS-creation in cirrhotic patients, reflecting a portal decompression mechanism via the lymphatic system. Lack of larger central lymphatics detectable on CT may be associated with shorter survival.

JTD Keywords: circulation, cisterna chyli, fluid, hepatic cirrhosis, shear-wave elastography, thoracic-duct, vessels, Significant portal-hypertension

Enzyme-powered nanomotors are an exciting technology for biomedical applications due to their ability to navigate within biological environments using endogenous fuels. However, limited studies into their collective behavior and demonstrations of tracking enzyme nanomotors in vivo have hindered progress toward their clinical translation. Here, we report the swarming behavior of urease-powered nanomotors and its tracking using positron emission tomography (PET), both in vitro and in vivo. For that, mesoporous silica nanoparticles containing urease enzymes and gold nanoparticles were used as nanomotors. To image them, nanomotors were radiolabeled with either I on gold nanoparticles or F-labeled prosthetic group to urease. In vitro experiments showed enhanced fluid mixing and collective migration of nanomotors, demonstrating higher capability to swim across complex paths inside microfabricated phantoms, compared with inactive nanomotors. In vivo intravenous administration in mice confirmed their biocompatibility at the administered dose and the suitability of PET to quantitatively track nanomotors in vivo. Furthermore, nanomotors were administered directly into the bladder of mice by intravesical injection. When injected with the fuel, urea, a homogeneous distribution was observed even after the entrance of fresh urine. By contrast, control experiments using nonmotile nanomotors (i.e., without fuel or without urease) resulted in sustained phase separation, indicating that the nanomotors’ self-propulsion promotes convection and mixing in living reservoirs. Active collective dynamics, together with the medical imaging tracking, constitute a key milestone and a step forward in the field of biomedical nanorobotics, paving the way toward their use in theranostic applications. 124 18

JTD Keywords: cell, reversal, silica nanoparticles, size, step, transport, Administration, intravesical, Animals, Equipment design, Female, Gold, Metal nanoparticles, Mice, Mice, inbred c57bl, Motion, Phantoms, imaging, Positron emission tomography computed tomography, Precision medicine, Propelled micromotors, Robotics, Translational research, biomedical, Urease, Urinary bladder

Background: Home hospitalization is widely accepted as a cost-effective alternative to conventional hospitalization for selected patients. A recent analysis of the home hospitalization and early discharge (HH/ED) program at Hospital Clínic de Barcelona over a 10-year period demonstrated high levels of acceptance by patients and professionals, as well as health value-based generation at the provider and health-system levels. However, health risk assessment was identified as an unmet need with the potential to enhance clinical decision making. Objective: The objective of this study is to generate and assess predictive models of mortality and in-hospital admission at entry and at HH/ED discharge. Methods: Predictive modeling of mortality and in-hospital admission was done in 2 different scenarios: at entry into the HH/ED program and at discharge, from January 2009 to December 2015. Multisource predictive variables, including standard clinical data, patients’ functional features, and population health risk assessment, were considered. Results: We studied 1925 HH/ED patients by applying a random forest classifier, as it showed the best performance. Average results of the area under the receiver operating characteristic curve (AUROC; sensitivity/specificity) for the prediction of mortality were 0.88 (0.81/0.76) and 0.89 (0.81/0.81) at entry and at home hospitalization discharge, respectively; the AUROC (sensitivity/specificity) values for in-hospital admission were 0.71 (0.67/0.64) and 0.70 (0.71/0.61) at entry and at home hospitalization discharge, respectively. Conclusions: The results showed potential for feeding clinical decision support systems aimed at supporting health professionals for inclusion of candidates into the HH/ED program, and have the capacity to guide transitions toward community-based care at HH discharge.

JTD Keywords: Home hospitalization, Health risk assessment, Predictive modeling, Chronic care, Integrated care, Modeling, Hospitalization, Health risk, Prediction, Mortality, Clinical decision support

Perceptual decision-making in the brain is commonly modeled as a competition among tuned cortical populations receiving stimulation according to their perceptual evidence. However, the contribution of evidence on the decision-making process changes through time. In this regard, the mechanisms controlling the sensitivity to perceptual evidence remain unknown. Here we explore this issue by using a biologically constrained model of the neocortex performing a dual-choice perceptual discrimination task. We combine mutual and global GABAergic inhibition, which are differentially regulated by acetylcholine (ACh), a neuromodulator linked to enhanced stimulus discriminability. We find that, while mutual inhibition determines the phase-space separation between two stable attractors representing each stimulus, global inhibition controls the formation of a chaotic attractor in-between the two, effectively protecting the weakest stimulus. Hence, under low ACh levels, where global inhibition dominates, the decision-making process is chaotic and less determined by the difference between perceptual evidences. On the contrary, under high ACh levels, where mutual inhibition dominates, the network becomes very sensitive to small differences between stimuli. Our results are in line with the putative role of ACh in enhanced stimulus discriminability and suggest that ACh levels control the sensitivity to sensory inputs by regulating the amount of chaos.

JTD Keywords: Acetylcholine, Cortical model, Decision-making, Chaos

We present a new computational framework for modeling moral decision-making in artificial agents based on the notion of ‘Machine Morality as Cooperation’. This framework integrates recent advances from cross-disciplinary moral decision-making literature into a single architecture. We build upon previous work outlining cognitive elements that an artificial agent would need for exhibiting latent morality, and we extend it by providing a computational realization of the cognitive architecture of such an agent. Our work has implications for cognitive and social robotics. Recent studies in human neuroimaging have pointed to three different decision-making processes, Pavlovian, model-free and model-based, that are defined by distinct neural substrates in the brain. Here, we describe how computational models of these three cognitive processes can be implemented in a single cognitive architecture by using the distributed and hierarchical organization proposed by the DAC theoretical framework. Moreover, we propose that a pro-social drive to cooperate exists at the Pavlovian level that can also bias the rest of the decision system, thus extending current state-of-the-art descriptive models based on harm-aversion.

JTD Keywords: Morality, Moral decision-making, Computational models, Cognitive architectures, Cognitive robotics, Human-robot interaction

When learning new environments, rats often pause at decision points and look back and forth over their possible trajectories as if they were imagining the future outcome of their actions, a behavior termed “Vicarious trial and error” (VTE). As the animal learns the environmental configuration, rats change from deliberative to habitual behavior, and VTE tends to disappear, suggesting a functional relevance in the early stages of learning. Despite the extensive research on spatial navigation, learning and VTE in the rat model, fewer studies have focused on humans. Here, we tested whether head-scanning behaviors that humans typically exhibit during spatial navigation are as predictive of spatial learning as in the rat. Subjects performed a goal-oriented virtual navigation task in a symmetric environment. Spatial learning was assessed through the analysis of trajectories, timings, and head orientations, under habitual and deliberative spatial navigation conditions. As expected, we found that trajectory length and duration decreased with the trial number, implying that subjects learned the spatial configuration of the environment over trials. Interestingly, IdPhi (a standard metric of VTE) also decreased with the trial number, suggesting that humans benefit from the same head-orientation scanning behavior as rats at spatial decision-points. Moreover, IdPhi captured exclusively at the first decision-point of each trial, was correlated with trial trajectory duration and length. Our findings demonstrate that in VTE is a signature of the stage of spatial learning in humans, and can be used to predict performance in navigation tasks with high accuracy.

JTD Keywords: Deliberation, Habitual, Hippocampus, Navigation, Spatial decision-making

We aimed to biomechanically evaluate the effect of the supraspinatus tendon on tuberosity stability using two different reverse shoulder arthroplasty (RSA) models for complex proximal humeral fractures (PHFs).

JTD Keywords: Tuberosity reconstruction, Reverse shoulder arthroplasty, Supraspinatus, Cadaveric study, Rotator cuff excision, Complex proximal humeral fractures

This book constitutes the proceedings of the 7th International Conference on Biomimetic and Biohybrid Systems, Living Machines 2018, held in Paris, France, in July 2018. The 40 full and 18 short papers presented in this volume were carefully reviewed and selected from 60 submissions. The theme of the conference targeted at the intersection of research on novel life-like technologies inspired by the scientific investigation of biological systems, biomimetics, and research that seeks to interface biological and artificial systems to create biohybrid systems.

JTD Keywords: Artificial neural network, Bio-actuators, Bio-robotics, Biohybrid systems, Biomimetics, Bipedal robots, Earthoworm-like robots, Robotics, Decision-making, Tactile sensing, Soft robots, Locomotion, Insects, Sensors, Actuators, Robots, Artificial intelligence, Neural networks, Motion planning, Learning algorithms

We have developed a new liquid chromatography-electrospray ionization tandem mass spectrometry methodology based on 2-picolylamine derivatization and positive ion mode detection for abscisic acid (ABA) identification. The selected reaction leads to the formation of an amide derivative which contains a highly active pyridyl group. The enhanced ionization allows for a 700-fold increase over commonly monitored unmodified ABA, which in turn leads to excellent limits of detection and quantification values of 0.03 and 0.15 ng mL-1, respectively. This method has been validated in the highly complex matrix of a red blood cell extract. In spite of the high sensitivity achieved, ABA could not be detected in Plasmodium falciparum-infected red blood cells, suggesting that, if present, it will be found either in ultratrace amounts or as brief bursts at defined time points within the intraerythrocytic cycle and/or in the form of a biosynthetic analogue.

JTD Keywords: Abscisic acid, Apicomplexa, Liquid chromatography-electrospray ionization tandem mass spectrometry, Malaria, Picolylamine, Plasmodium falciparum

In this paper, we present a new Multi-Agent System for reduction of the bullwhip effect in fuzzy supply chains. First, we show that a supply chain that uses an optimal ordering policy without data sharing among echelons still suffers from the bullwhip effect. Then, we propose the multi-agent solution to manage and reduce the bullwhip effect. The proposed multi-agent system includes four different types of agents in which each agent has its own list of actions. The proposed Multi-agent System applies a new Tabu Search algorithm for fuzzy rule generation, and a new data filtering algorithm for extraction of the bullwhip-free data from supply chain data warehouse. We validate the multi-agent system under different conditions and discuss how the system responds to different factors. The results show that the proposed multi-agent system reduces the bullwhip effect significantly in a rational time.

JTD Keywords: Bullwhip effect, Bullwhip-free data, Decentralized decision making, Fuzzy rule base, Fuzzy supply chain, Fuzzy time series, Multi-agent system, Supply chain management

In this paper, the problem of time alignment is revisited by adopting an ensemble-based approach with all signals jointly aligned. It is shown that the maximization of an eigenvalue ratio is synonymous to maximizing the signal-to-jitter-and-noise ratio. Since optimization of this criterion is extremely time consuming, a relaxed optimization procedure is introduced which converges much more quickly. Using simulations based on respiratory flow signals, the results suggest that the time delay error variance of the new method is much lower than that obtained with the well-known Woody’s method.

JTD Keywords: Time alignment, Signal ensemble, Subsample precision, Eigenvalue decomposition

P-type copper indium diselenide (CuInSe2) films have been prepared onto ITO substrates by an electrodeposition method, that sequentially applies potential pulses at the deposition potential of each element Cu, Se and In, and then step it back in cyclically to induce the solid state reaction between the elements. Two electrolyte concentrations as well as three different pulse durations were assessed. The resulting films were compared with those deposited at fixed electrode potentials. As-grown films are nanocrystalline and have an E-g similar to 0.95 eV. Raman spectroscopy shows that Se and Cu-Se contents decrease while pulse duration increases and electrolyte concentration decreases. Cu-Se phases are even absent for films grown at the low electrolyte concentration. These results represent a great improvement in the film phase purity reducing the need of post-deposition treatments.

JTD Keywords: CIS, Pulsed electrodeposition, Raman, Solar cells

A new method for obtaining a three-dimensional volumetric reconstruction from a set of views improving the classical Shape from Silhouette method (SFS) is presented. SFS approaches can be easily accelerated through hardware and software techniques but they are very sensible to errors arising during calibration and segmentation processes so they present difficulties when dealing with real images. This paper proposes a new algorithm which uses the information about pixel segmentation uncertainty contained in each view in order to get a reliable 3D reconstruction of the scene. Aggregation of the projected uncertainties permits to classify scene's voxels by means of a decision rule but also makes it possible to create a three-dimensional confidence map of the scene. As a consequence, the regions where more information is needed can be foreseen. Sample reconstructions from real image sets are presented and evaluated.

JTD Keywords: Calibration, Image classification, Image reconstruction, Image segmentation, 3D reconstruction, Calibration process, Decision rule, Hardware technique, Pixel segmentation, Pixel-level certainty measures, Scene voxel classification, Segmentation process, Shape from silhouette method, Software technique, Three-dimensional confidence map, Three-dimensional volumetric reconstruction