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This paper advocates for a constructivist approach to symbiosis to restore human-centredness in the governance of Symbiotic Artificial Intelligence (SAI). Challenging rigid, deterministic foundational methods warns against the risk of divorcing ethics from mere adherence to moral principles. Instead, it calls for a shift towards a distributed, contextual, relational, and dialectical structure to embody human-centredness. Through an analysis of the SAI landscape and its interplay between social and technological factors, the paper argues for a reconceptualisation of theoretical foundation and human responsibility within the socio-technical perspective. Chapter 2 delves into foundational issues of SAI, questioning the application of biological categories and proposing patterns of SAI based on definitions of intelligent life. Chapter 3 explores the potential of a constructivist approach, emphasising flexibility and context awareness, and presents a framework for understanding and evaluating SAI systems, components of an evolving methodology.

AbstractObjectiveThe Wheel of Cardiovascular Health Diet was recently elaborated based on current nutritional recommendations for healthy eating and was made for person-centered nutritional counseling, thus it may be an interesting tool to improve food awareness. However, its validity is yet to be tested. We hypothesized that the self-perception of patients diagnosed with chronic diseases, evaluated by the Wheel of Cardiovascular Health Diet, is satisfactory in assessing the quality of their diets, compared with the Healthy Eating Index-2020.MethodsThis is a cross-sectional analysis of adults with uncontrolled hypertension or type 2 diabetes. The patients answered the Wheel of Cardiovascular Health Diet, and then, based on the food frequency questionnaire, we analyzed the Healthy Eating Index-2020.ResultsA total of 330 patients were included in the study: 91.5% had hypertension, 58.5% had type 2 diabetes, and the median age was 58 (50–65) years. The mean difference observed between the percentage of the graphic area assessed by the patients’ self-perception from the Wheel of Cardiovascular Health Diet and Healthy Eating Index-2020 was −10.0% (95%CI −35.3 to 15.3), and a moderate correlation was observed. Linear Regression models showed that a 10-point increase in patients’ self-perception in the Wheel of Cardiovascular Health Diet is associated with a 2.9% increase (95%CI 2.08 to 3.70) in the diet quality by the Healthy Eating Index-2020 and is associated with lower BMI values: β = −0.42 kg/m2(95%CI −0.83 to −0.01).ConclusionThe Wheel of Cardiovascular Health Diet performed satisfactorily regarding validity and reliability by BMI and was associated with higher overall dietary quality, with the Healthy Eating Index-2020 as a relative reference.

In this paper, a condition monitoring system for railway track geometry is presented. The methodology has been designed for high-speed application, where the train travels at the maximum allowed speed for most of the trip. The system is designed to rely on acceleration data recorded by in-service vehicles to provide estimations of the track longitudinal level, based on pre-built regression models. It exploits synthetic indicators sampled over predefined track sections 100 m long. Different predictors are considered, computed both from acceleration data and from track geometry measured by the diagnostic train. The proposed modelling strategy allows distinguishing between isolated and distributed defects that populate the railway track as well as reproducing the evolution over time of the maximum longitudinal level registered in the considered track section; moreover, also accurate predictions of the defect amplitude are made. The results have been validated against track geometry data recorded by the diagnostic train during a monitoring period of 2 years. It is proven that the proposed system could support current maintenance strategies, providing a continuous flow of data to monitor the track infrastructure.

This study introduces a model predictive control methodology to determine optimal measures for mitigating air pollution, assisting Local Authorities in policy development. Anchored in an auto-regressive model, it analyzes dynamic air quality patterns over a defined timeframe using daily observed pollutant concentration, meteorological variables, and estimated emission data. Employing model predictive control methodology, the approach aims to optimize daily emission reductions. Evaluated in Milan, a heavily polluted European city, the findings highlight the methodology's potential as a robust tool for Local Authorities, enabling informed decisions in crafting efficient air quality management strategies, in the specific context ofNO2.

CD8+T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+T cell effector function, with potential implications for cancer immunotherapy.

This study presents a novel data-driven approach designed to address the intricate link between climate change and agriculture, focusing on rice farming in Southeast Asia. By using advanced modelling and optimization tools, namely ARX models and Model Predictive Control, it aims to control the temperature anomaly across fifteen world’s subregions. Using ARX models to downscale the global temperature anomaly, the approach allows the evaluation of local climate effects. The methodology is applied to evaluate the impact of climate change on rice production in Southeast Asia, projecting potential outcomes under different emission scenarios. By optimizing greenhouse gas emissions, particularly carbon dioxide and methane, the goal is to keep the temperature anomaly below critical thresholds, ensuring resilient rice production, supporting food security, and minimizing economic and social costs.

Shoulder rehabilitation is considered one of the most effective treatments for restoring functional abilities, reducing shoulder pain, and enabling the leading of an active life, improving mobility, strength, and endurance. However, the burdens of travel and time may prevent patients from taking part in such rehabilitation programs. The increased availability of wearable sensors and the development of machine learning (ML) algorithm has shown the feasibility of remote home-based rehabilitation therapy. In this study, we proposed a wearable system based on three magneto-inertial sensors to classify shoulder rehabilitation exercises. The classification has been performed by five different supervised ML algorithms [i.e., k-nearest neighbors (k-NNs), support vector machine (SVM), Naïve Bayes (NB), decision tree (DT), and random forest (RF)] to find out the most performant one. The feasibility of the wearable system was assessed on 19 healthy subjects during six rehabilitation exercises. Each exercise was performed six times, for a total of 684 samples. The data were analyzed and classified using the five mentioned classification models. Performances of the algorithms in accurately classifying exercise activity were evaluated with the k-fold cross-validation method and the nested validation method. The results demonstrated the effectiveness of the proposed algorithms in recognizing all the exercises. Features derived from acceleration, angular velocity, and orientation data were shown to reach the optimal predictive accuracies. Future work should focus on evaluating the performance of such systems on data acquired on patients with musculoskeletal disorders and on the inclusion of more shoulder rehabilitation exercises in the protocol.

Biomaterials able to promote neuronal development and neurite outgrowth are highly desired in neural tissue engineering for the repair of damaged or disrupted neural tissue and restoring the axonal connection. For this purpose, the use of either electroactive or micro- and nanostructured materials has been separately investigated. Here, the use of a nanomodulated conductive poly(3,4-ethylendioxithiophene) poly(styrenesulfonate) (PEDOT/PSS) substrate that exhibits instructive topographical and electrical cues at the same time was investigated for the first time. In particular, thin films featuring grooves with sizes comparable with those of neuronal neurites (NanoPEDOT) were fabricated by electrochemical polymerization of PEDOT/PSS on a nanomodulated polycarbonate template. The ability of NanoPEDOT to support neuronal development and direct neurite outgrowth was demonstrated by assessing cell viability and proliferation, expression of neuronal markers, average neurite length, and direction of neuroblastoma N2A cells induced to differentiate on this novel support. In addition to the beneficial effect of the nanogrooved topography, a 30% increase was shown in the average length of neurites when differentiating cells were subjected to an electrical stimulation of a few microamperes for 6 h. The results reported here suggest a favorable effect on the neuronal development of the synergistic combination of nanotopography and electrical stimulation, supporting the use of NanoPEDOT in neural tissue engineering to promote physical and functional reconnection of impaired neural networks.

Purpose: To compare procedural complications in patients undergoing atherectomy plus angioplasty (A+A) and plain balloon angioplasty (POBA).Materials and Methods: Patients in the Vascular Quality Initiative (VQI) registry undergoing first-time peripheral vascular intervention (PVI) were included. Those undergoing aortoiliac or pedal interventions, primary stenting, or hybrid procedures were excluded. Patients were stratified by lesion location (femoropopliteal [FP] or tibial [TIB]). The primary outcomes were target vessel dissection, distal embolization, and provisional stent placement. Secondary outcomes included postoperative complications and the need for subsequent interventions.Results: 12 499 patients undergoing FP (49.6% A+A) and 6736 patients undergoing TIB (17.0% A+A) interventions were identified. In the FP group, A+A was associated with greater intraoperative target vessel dissection (4.5% vs 2.6%, p<0.001), distal embolization (1.5% vs 0.7%, p =0.001), and provisional stent placement (1.5% vs 0%, p<0.001); and greater postoperative target vessel dissection (4.2% vs 2.0%, p<0.001) and distal embolization (0.9% vs 0.4%, p=0.034). In the TIB group, A+A was associated with fewer intraoperative vessel dissection (0.8% vs 2.3%, p=0.011) but greater provisional stent placement (0.3% vs 0%, p<0.001). TIB A+A was also associated with higher rates of technical success (97.6% vs 95.1%, p<0.001).Conclusions: Atherectomy was associated with increased procedural-related complications in femoropopliteal, but not in tibial vessels. Future studies addressing lesion morphology, device design, and technique may help define its role in peripheral vascular interventions.

Children are increasingly discharged directly from the PICU. Transitions have been recognized as a period of increased patient and caregiver stress and risk of adverse events. No study has evaluated patient and caregiver outcomes after direct discharge from the PICU. This study aimed to explore the family’s experiences with discharge directly home (DDH) from the PICU.This exploratory mixed-methods study was conducted in the PICU of the Institution is Sainte-Justine Hospital from February to July 2021. We included families of children expected to be DDH within 12 hours. Semistructured interviews were conducted at discharge, followed by telephone interviews 7 and 28 days post-PICU discharge. We measured comfort on a 5-point Likert scale and screened for anxiety using the Generalized Anxiety Disorder-7 tool.Families of 25 patients were interviewed. Thematic analysis of the interviews revealed several themes, such as feeling stress and anxiety, feeling confident, anticipating home care, and needing support. These findings complemented the quantitative findings; the median comfort score was 4 (comfortable) (interquartile range 4–5) and 8 (interquartile range 4–12) for the Generalized Anxiety Disorder-7 on the day of discharge, with 16 reporting clinically significant anxiety. In the 28-day study period, 2 patients were readmitted and 6 had visited the emergency department.Despite feelings of anxiety, many families felt comfortable with DDH from the PICU. Increasing our understanding of the patient and family experiences of discharge from the PICU will help to better support these patients and their families during transition.

This article deals with a network of computing agents aiming to solve an online optimization problem in a distributed fashion, i.e., by means of local computation and communication, without any central coordinator. We propose the gradient tracking with an adaptive momentum estimation (GTAdam) distributed algorithm, which combines a gradient tracking mechanism with first- and second-order momentum estimates of the gradient. The algorithm is analyzed in the online setting for strongly convex cost functions with Lipschitz continuous gradients. We provide an upper bound for the dynamic regret given by a term related to the initial conditions and another term related to the temporal variations of the objective functions. Moreover, a linear convergence rate is guaranteed in the static setup. The algorithm is tested on a time-varying classification problem, on a (moving) target localization problem, and in a stochastic optimization setup from image classification. In these numerical experiments from multiagent learning, GTAdam outperforms state-of-the-art distributed optimization methods.

An upper anterior tooth of Cosmopolitodus hastalis (Elasmobranchii: Lamnidae) from Burdigalian strata of the shallow-marine Chilcatay Formation exposed at Zamaca (East Pisco Basin, Peru) exhibits the remarkable occurrence of a serrated bite mark consistent with Linichnus serratus (Praedichnia: Machichnidae). In marine successions of Cenozoic age, traces belonging to the ichnogenus Linichnus are typically found occurring on the bones of marine mammals and interpreted as due to predation or scavenging by sharks provided with smooth-edged (Linichnus bromleyi) or denticulated (L. serratus) teeth. Only a few fossil shark teeth exist preserving serrated bite marks, all of which have been interpreted as due to self-biting, which may occur when a shark loses a tooth while feeding and accidentally bites into it. Since C. hastalis is a smooth-toothed species, self-biting cannot explain our unusual find of L. serratus, which in turn may either reflect some kind of trophic interaction between large carnivorous sharks (with a late juvenile or young adult C. hastalis being fed upon by another elasmobranch, possibly a large-sized carcharhinid) or testify to accidental biting during multispecies shark scavenging on the carcass of a third organism that did not get preserved alongside the bitten tooth.

An adaptive surface that can sense and respond to environmental stimuli is integral to smart functional materials. Here, we report pH-responsive anchoring systems onto the poly(ethylene glycol) (PEG) corona of polymer vesicles. The hydrophobic anchor, pyrene, is reversibly inserted into the PEG corona through the reversible protonation of its covalently linked pH-sensing group. Depending on the pKaof the sensor, the pH-responsive region is engineered from acidic to neutral and basic conditions. The switchable electrostatic repulsion between the sensors contributes to the responsive anchoring behavior. Our findings provide a new responsive binding chemistry for the creation of smart nanomedicine and a nanoreactor.

In Canada, Medical Assistance in Dying (MAiD) is legal for many Canadians based on several criteria, though minors who are deemed sufficiently capable to make medical decisions (i.e. mature minors) remain ineligible. In this article, we provide insight into recent philosophical and legal evidence related to MAiD for mature minors. We begin by providing an overview of literature pertaining to MAiD for mature minors in particular (including evidence from Belgium and the Netherlands), followed by a discussion on the lessons that can be learnt from Canada’s MAiD implementation process (in general) and other forms of paediatric end-of-life care. As a whole, we aim to highlight some key takeaway messages for health leaders to consider as deliberations on MAiD for mature minors continue.

Health care professionals experience moral distress when they cannot act based on their moral beliefs because of perceived constraints. Moral distress prevalence is high among critical care (ICU) clinicians, but varies significantly between and within professions.

Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes1. As plaques lack innervation, the effects of neuronal control on atherosclerosis remain unclear. However, the immune system responds to plaques by forming leukocyte infiltrates in the outer connective tissue coat of arteries (the adventitia)2–6. Here, because the peripheral nervous system uses the adventitia as its principal conduit to reach distant targets7–9, we postulated that the peripheral nervous system may directly interact with diseased arteries. Unexpectedly, widespread neuroimmune cardiovascular interfaces (NICIs) arose in mouse and human atherosclerosis-diseased adventitia segments showed expanded axon networks, including growth cones at axon endings near immune cells and media smooth muscle cells. Mouse NICIs established a structural artery–brain circuit (ABC): abdominal adventitia nociceptive afferents10–14entered the central nervous system through spinal cord T6–T13dorsal root ganglia and were traced to higher brain regions, including the parabrachial and central amygdala neurons; and sympathetic efferent neurons projected from medullary and hypothalamic neurons to the adventitia through spinal intermediolateral neurons and both coeliac and sympathetic chain ganglia. Moreover, ABC peripheral nervous system components were activated: splenic sympathetic and coeliac vagus nerve activities increased in parallel to disease progression, whereas coeliac ganglionectomy led to the disintegration of adventitial NICIs, reduced disease progression and enhanced plaque stability. Thus, the peripheral nervous system uses NICIs to assemble a structural ABC, and therapeutic intervention in the ABC attenuates atherosclerosis.

A stringent test of the accuracy of empirical force fields is reproducing the phase diagram of bulk phases and mixtures. Exploring the phase diagram of mixtures requires the detection of phase boundaries and critical points. In contrast to most solid–liquid transitions, in which a global order parameter (average density) can be used to discriminate between two phases, some demixing transitions entail relatively subtle changes in the local environment of each molecule. In such cases, finite sampling errors and finite-size effects make the identification of trends in local order parameters extremely challenging. Here we analyze one such example, namely a methanol/hexane mixture, and compute several local and global structural properties. We simulate the system at various temperatures and study the structural changes associated with demixing. We show that despite a seemingly continuous transformation between mixed and demixed states, the topological properties of the H-bond network change abruptly as the system crosses the demixing line. In particular, by using spectral clustering, we show that the distribution of cluster sizes develops a fat tail (as expected from percolation theory) in the vicinity of the critical point. We illustrate a simple criterion to identify this behavior, which results from the emergence of large system-spanning clusters from a collection of aggregates. We further tested the spectral clustering analysis on a Lennard–Jones system as a standard example of a system with no H-bonds, and also, in this case, we were able to detect the demixing transition.

The pathway for supramolecular fiber formation is coupled with the underlying order of the self-assembling molecules. Here, we report on atomistic molecular dynamics simulations to characterize the initial stages of the self-assembly of a model drug amphiphile in an aqueous solution. We perform two-dimensional metadynamics calculations to characterize the assembly space of this model drug amphiphile─Tubustecan, TT1. TT1 is composed of the hydrophobic anticancer drug, Camptothecin (CPT), conjugated to a hydrophilic polyethylene glycol (PEG) chain. We find that the aromatic stacking of CPT drives the formation of a higher-density liquid droplet. This droplet elongates and can form a higher-ordered supramolecular assembly upon reorganizing and forming an interface and additional aromatic stacking of the drugs. We show that novel reaction coordinates tailored to this class of molecules are essential in capturing the underlying degree of molecular order upon assembly. This approach can be refined and extended to characterize the supramolecular assembly pathway of other molecules containing aromatic compounds.

ABSTRACTNPPA/atrial natriuretic peptide (natriuretic peptide type A) exerts critical pleiotropic effects in the cardiovascular system, limiting cardiomyocyte hypertrophy and death, reducing cardiac fibrosis and promoting vascular integrity. However, the molecular mechanisms underlying these beneficial effects still need to be clarified. We demonstrated for the first time that macroautophagy/autophagy is involved in the local protective effects of NPPA in cardiomyocytes (CMs), both in vitro and in vivo. Exogenous NPPA rapidly activates autophagy in CMs through NPR1/type A natriuretic peptide receptor and PRKG/protein kinase G signaling and also increases cardiac autophagy in mice. Remarkably, endogenous NPPA is secreted by CMs in response to glucose deprivation or hypoxia, thereby stimulating autophagy through autocrine/paracrine mechanisms. NPPA preserves cell viability and reduces hypertrophy in response to stress through autophagy activation. In vivo, we found that Nppaknockout mice undergoing ischemia-reperfusion (I/R) show increased infarct size and reduced autophagy. Reactivation of autophagy by Tat-Beclin D11 limits I/R injury. We also found that the protective effects of NPPA in reducing infarct size are abrogated in the presence of autophagy inhibition. Mechanistically, we found that NPPA stimulates autophagy through the activation of TFEB (transcription factor EB). Our data suggest that NPPA is a novel extracellular regulator of autophagy in the heart.

Prevention of infection and propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a high priority in the Coronavirus Disease 2019 (COVID-19) pandemic. Here we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin-converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 spike protein, thereby inhibiting viral entry, infectivity and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and, thus, the spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model and, thus, provide a novel avenue to pursue therapy.

While rail freight transportation is gradually becoming a crucial asset in the context of decarbonization of the transport sector, new standards and requirements in this field aim at improving the safety and reliability of freight vehicles and the infrastructure. From this perspective, Condition Monitoring and Condition Based Maintenance are becoming essential tools to improve systems reliability through the use of in-service instrumented vehicles. On the contrary of high-speed applications, freight trains are actually not provided with any monitoring systems able to carry out this kind of analyses. In this context, an innovative hybrid monitoring system composed by wireless sensor nodes and a gateway was developed to be suitably mounted on a freight wagon. Sensor nodes, power supplied by solar energy, are able to carry out synthetic indices from vibration measurements, while the gateway acquires correlated GPS and odometry information. In order to take advantage of the acquired data, a software based on a geo-localization algorithm created for high-speed applications was developed in order to correlate vibration data to the railway line mileage. A field campaign allowed to test the system on a real freight wagon and to acquire many experimental data. Using the collected experimental data, in the paper is shown how the developed software can be used to perform diagnostic activities of the infrastructure. Moreover, it is demonstrated that relying on the only GPS information is sufficient to get enough accurate georeferenced data for freight trains applications. This paves the way to the future development of a completely wireless system able to perform condition monitoring of both the vehicle and the infrastructure minimizing the impact on the vehicle.

This article focuses on an online version of the emerging distributed constrained aggregative optimization framework, which is particularly suited for applications arising in cooperative robotics. Agents in a network want to minimize the sum of local cost functions, each one depending both on a local optimization variable, subject to a local constraint, and on an aggregated version of all the variables (e.g., the mean). We focus on a challenging online scenario in which the cost, the aggregation functions, and the constraints can all change over time, thus enlarging the class of captured applications. Inspired by an existing scheme, we propose a distributed algorithm with constant step size, named projected aggregative tracking, to solve the online optimization problem. We prove that the dynamic regret is bounded by a constant term and a term related to time variations. Moreover, in the static case (i.e., with constant cost and constraints), the solution estimates are proved to converge with a linear rate to the optimal solution. Finally, numerical examples show the efficacy of the proposed approach on a robotic surveillance scenario.

Objectives: To evaluate the 1-year effectiveness and safety of the XEN45, either alone or in combination with phacoemulsification, in glaucoma patients. Methods: This multicentre, prospective, observational study included consecutive eyes of glaucoma patients from the Italian XEN-Glaucoma Treatment Registry (XEN-GTR) who underwent XEN45 alone or in combination with phacoemulsification, with at least 1 year of follow-up. Surgical success was defined as intraocular pressure (IOP) &lt; 18 mmHg and ≥20% reduction from preoperative IOP, over 1 year of follow-up. Results: Two hundred thirty-nine eyes (239 patients) were analyzed, 144 (60.2%) eyes in the XEN-solo and 95 (39.8%) eyes in the XEN+Phaco groups. One hundred-sixty-eight (70.3%) eyes achieved overall success, without statistically significant differences between study groups (p= 0.07). Preoperative IOP dropped from a median (IQR) of 23.0 (20.0–26.0) mmHg to 14.0 (12.0–16.0) mmHg at month 12 (p&lt; 0.001), with overall 39.9 ± 18.3% IOP reduction. The mean number of preoperative ocular hypotensive medications (OHM) was significantly reduced from 2.7 ± 0.9 to 0.5 ± 0.9 at month 12 (p&lt; 0.001). Preoperative IOP &lt; 15 mmHg (HR: 6.63; 95%CI: 2.61–16.84, p&lt; 0.001) and temporal position of the surgeon (HR: 4.25; 95%CI: 2.62–6.88, p&lt; 0.001) were significantly associated with surgery failure. One hundred-forty-six (61.1%) eyes had no intraoperative complications, whereas 91 (38.1%) and 56 (23.4%) eyes experienced at least one complication, respectively early (&lt; month 1) and late (≥ month 1), all self-limiting or successfully treated without sequelae. Needling occurred in 55 (23.0%) eyes at least once during follow-up. Conclusion: Over 1-year follow-up, XEN45 alone or in combination with phacoemulsification, had comparable success rates and effectively and safely lowered IOP and the need for OHM.

Systemic inflammation has been suggested to have a pivotal role in atherothrombosis, but the factors that trigger systemic inflammation have not been fully elucidated. Lipopolysaccharide (LPS) is a component of the membrane of Gram-negative bacteria present in the gut that can translocate into the systemic circulation, causing non-septic, low-grade endotoxaemia. Gut dysbiosis is a major determinant of low-grade endotoxaemia via dysfunction of the intestinal barrier scaffold, which is a prerequisite for LPS translocation into the systemic circulation. Experimental studies have demonstrated that LPS is present in atherosclerotic arteries but not in normal arteries. In atherosclerotic plaques, LPS promotes a pro-inflammatory status that can lead to plaque instability and thrombus formation. Low-grade endotoxaemia affects several cell types, including leukocytes, platelets and endothelial cells, leading to inflammation and clot formation. Low-grade endotoxaemia has been described in patients at risk of or with overt cardiovascular disease, in whom low-grade endotoxaemia was associated with atherosclerotic burden and its clinical sequelae. In this Review, we describe the mechanisms favouring the development of low-grade endotoxaemia, focusing on gut dysbiosis and changes in gut permeability; the plausible biological mechanisms linking low-grade endotoxaemia and atherothrombosis; the clinical studies suggesting that low-grade endotoxaemia is a risk factor for cardiovascular events; and the potential therapeutic tools to improve gut permeability and eventually eliminate low-grade endotoxaemia.

For reliable and safe battery operations, accurate and robust State of Charge (SOC) and model parameters estimation is vital. However, the nonlinear dependency of the model parameters on battery states makes the problem challenging. We propose a Moving-Horizon Estimation (MHE)-based robust approach for joint state and parameters estimation. Dut to all the time scales involved in the model dynamics, a multi-rate MHE is designed to improve the estimation performance. Moreover, a parallelized structure for the observer is exploited to reduce the computational burden, combining both multi-rate and a reduced-order MHEs. Results show that the battery SOC and parameters can be effectively estimated. The proposed MHE observers are verified on a Simulink-based battery equivalent circuit model.

This paper addresses the problem of dynamic input allocation in the presence of plant uncertainties. The current state of the art shows how to design an Allocator as the cascade of an Optimizer and an Annihilator to achieve steady-state input optimality and output invisibility simultaneously. This work proposes a novel algorithm based on polynomial factorization to design a dynamic Annihilator. The critical aspect of this approach lies in the assumption of the perfect plant knowledge, making the Annihilator not robust to uncertainties. A robustification process is introduced by optimizing its design parameters. This approach is formulated as a model-matching problem aiming to reduce the output mismatch induced by the allocation scheme while maintaining steady-state optimality. As the numerical simulations highlight, this method applies to linear and nonlinear allocation problems.

Purpose: In North America, pediatric adenotonsillectomy (TA) is conducted as an ambulatory procedure, thus shifting the burden of postoperative care to parents. The purpose of this study was to describe this parental experience. Methods: We conducted a prospective single-centre qualitative study, recruiting the families of children (n= 317) undergoing elective TA in 2018. Parents were invited to submit written comments to two open-ended questions. We coded the comments from 144 parents in a grounded theory analysis and report representative exemplars. Themes and subthemes for the problems encountered, and strategies employed by parents, were developed. We then coded and classified factors that helped/hindered parents and developed models of the experience. Results: Some parents felt ill-prepared for the severity and duration of pain. Specific findings included a lack of strategies to manage pain at night, refusals, and night terrors. Parents identified the use of pain scales, pain diaries, and liaison with the research team as helpful supports at home. Inconsistent messaging was a barrier. The odynophagia associated with elixirs of acetaminophen and ibuprofen was a barrier to achieving analgesia. Conclusions: The findings from this qualitative analysis provide insight into the challenges faced by parents when caring for their children at home following TA; these challenges included difficulties managing physical needs and pain. The analysis suggests that educational content should be standardized and include the use of pain scales and diaries, and both pharmacologic and nonpharmacologic strategies. Development of support at home, including a practicable liaison with health care providers, seems to be warranted. Study registration: ClinicalTrials.gov (NCT03378830); registered 20 December 2017.

In this article, the problem of pollutant monitoring sensor allocation is formalized as a variant of the well-known set covering problem and solved by means of both a mixed-integer linear programming solver and genetic algorithms. The allocation of the sensors in the monitoring network is one of the most practical and challenging problems that regional authorities have to face, in particular due to the constraints that European Union Directives pose in terms of the number of sensors per area/subarea and in terms of representativeness capability (i.e., the ability that the data coming from the monitoring network have to represent the air quality levels in their surrounding areas). The methodology has been applied to the allocation of sensors for particulate matter (PM10) and nitrogen dioxides (NO$_2$) in Lombardy, Italy. The results are promising, showing that the two proposed approaches are able to strongly dominate the current solution.

Tumor-associated macrophages (TAMs), often adopting an immunosuppressive M2-like phenotype, correlate with unfavorable cancer outcomes. Our investigation unveiled elevated expression of the butyrophilin (BTN)2A1 in M2-like TAMs across diverse cancer types. We developed anti-BTN2A1 monoclonal antibodies (mAbs), and notably, one clone demonstrated a robust inhibitory effect on M2-like macrophage differentiation, inducing a shift toward an M1-like phenotype both in vitroand ex vivoin TAMs from patients with cancer. Macrophages treated with this anti-BTN2A1 mAb exhibited enhanced support for T cell proliferation and interferon-gamma (IFNγ) secretion. Mechanistically, BTN2A1 engagement induced spleen tyrosine kinase (SYK) recruitment, leading to sequential SYK and extracellular signal-regulated kinase (ERK) phosphorylation. Inhibition of SYK or ERK phosphorylation abolished M2 reprogramming upon BTN2A1 engagement. Our findings, derived from an analysis of macrophages from healthy donors and human tumors, underscore the pivotal role of BTN2A1 in immunosuppressive macrophage differentiation and function, offering potential applications in cancer immunotherapy.

Our city was significantly impacted by the initial COVID-19 outbreak in the United States. We describe how members of our Quality and Safety team were able to leverage skills in relational coordination and process improvement to respond to rapidly changing needs in a flexible and effective way.

While tactical performance in soccer is associated with the players’ and teams’ collective actions in the context of game stimuli, how tactical performance relates to players’ executive functions (EFs) and physical abilities should be examined. In this study, we examined these relationships among 81 Under-15 male soccer players who underwent tactical evaluation (FUT-SAT), EF tests (i.e.,(Stop-Signal Test and Design Fluency Test)), and physical tests (i.e.,(Maturity Offset, Yoyo Endurance Test II, Sargent Jump Test, and Sprint Test)). Multiple linear regression modeling with the stepwise method showed that approximately 48% of overall game tactical performance variance was explained by inhibitory control, biological maturation, and sprint capacity (p= .004; d= .54; r2= .479), whereas 35% of offensive tactical performance variance was explained by the same dimensions (p= .001; d= .91; r2= .353). In addition, approximately 28% of defensive tactical performance variance was explained by cognitive flexibility and aerobic resistance (p= .007; d= .39; r2= .280). These results reflect the combined importance of EFs and physical abilities for tactical performance in young soccer players, suggesting that these abilities may be targets for training when trying to improve young players’ performance.

The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints1,2. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function3–10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment.

The thermal degradation (pyrolysis) of renewable biomass (as crop residues or energy crops) into a carbon-rich byproduct has been proposed as a practice to fight soil degradation and to foster the mitigation of climate change. The pyrolysis conditions and the characteristics of the feedstock influence the quality of the biochar. The present study used a pilot updraft reactor to make a pyrogasification of the biomass of giant reed (Arundo donaxL.). The temperature varied in the range 300–400 °C and the process lasted 60–90 min, conditions specific to slow pyrolysis. The work aimed to compare three airflow rates (0.001 m3s−1, 0.0007 m3s−1, and natural ventilation) and the Arundobiomass collected in winter (February) or summer (June), on the base of known harvesting time. The biochar yield was comparable between February (19.8%) and June (21.8%) but the biochar composition in terms of CHNSO was depending on the airflow rate. The values of the molar ratios indicated that the biochar produced with Arundocollected in winter (February) in presence of the air (0.001 and 0.0007 m3s−1) may have the highest level of aromaticity (H/C ratio), hydrophilicity, and polarity. Germination test on lettuce seeds showed different results: the winter biochar produced at 0.0007 m3s−1gave germination comparable to the control up to a concentration in the substrate up to 2% in weight; the summer biochar reduced the growth of the seedlings already at 0.5% when produced under natural ventilation.

Background: Data on the interplay between sexual hormones balance, platelet function and clinical outcomes of adults with ischemic heart disease (IHD) are still lacking. Objective: To assess the association between the Testosterone (T)-to-Estradiol (E2) Ratio (T/E2) and platelet activation biomarkers in IHD and its predictive value on adverse outcomes. Methods: The EVA study is a prospective observational study of consecutive hospitalized adults with IHD undergoing coronary angiography and/or percutaneous coronary interventions. Serum T/E2 ratios E2, levels of thromboxane B2(TxB2) and nitrates (NO), were measured at admission and major adverse events, including all-cause mortality, were collected during a long-term follow-up. Results: Among 509 adults with IHD (mean age 67 ± 11 years, 30% females), males were older with a more adverse cluster of cardiovascular risk factors than females. Acute coronary syndrome and non-obstructive coronary artery disease were more prevalent in females versus males. The lower sex-specific T/E2 ratios identified adults with the highest level of serum TxB2and the lowest NO levels. During a median follow-up of 23.7 months, the lower sex-specific T/E2 was associated with higher all-cause mortality (HR 3.49; 95% CI 1.24–9.80; p= 0.018). In in vitro, platelets incubated with T/E2 ratios comparable to those measured in vivo in the lowest quartile showed increased platelet activation as indicated by higher levels of aggregation and TxB2production. Conclusion: Among adults with IHD, higher T/E2 ratio was associated with a lower long-term risk of fatal events. The effect of sex hormones on the platelet thromboxane release may partially explain such finding.

Cardiovascular diseases (CVDs) make a substantial contribution to the global burden of disease. Prevention strategies have succeeded in reducing the effect of acute CVD events and deaths, but the long-term consequences of cardiovascular risk factors still represent the major cause of disability and chronic illness, suggesting that some pathophysiological mechanisms might not be adequately targeted by current therapies. Many of the underlying causes of CVD have now been recognized to have immune and inflammatory components. However, inflammation and immune activation were mostly regarded as a consequence of target-organ damage. Only more recent findings have indicated that immune dysregulation can be pathogenic for CVD, identifying a need for novel immunomodulatory therapeutic strategies. The nervous system, through an array of afferent and efferent arms of the autonomic nervous system, profoundly affects cardiovascular function. Interestingly, the autonomic nervous system also innervates immune organs, and neuroimmune interactions that are biologically relevant to CVD have been discovered, providing the foundation to target neural reflexes as an immunomodulatory therapeutic strategy. This Review summarizes how the neural regulation of immunity and inflammation participates in the onset and progression of CVD and explores promising opportunities for future therapeutic strategies.