Guidelines for the development of a critical software under emergency.

Context: During the first wave of the COVID-19 pandemic, an international and heterogeneous team of scientists collaborated on a social project to produce a mechanical ventilator for intensive care units (MVM). MVM has been conceived to be produced and used also in poor countries: it is open-source, no patents, cheap, and can be produced with materials that are easy to retrieve. Objective: The objective of this work is to extract from the experience of the MVM development and software certification a set of lessons learned and then guidelines that can help developers to produce safety-critical devices in similar emergency situations. Method: We conducted a case study. We had full access to source code, comments on code, change requests, test reports, every deliverable (60 in total) produced for the software certification (safety concepts, requirements specifications, architecture and design, testing activities, etc.), notes, whiteboard sketches, emails, etc. We validated both lessons learned and guidelines with experts. Findings: We contribute a set of validated lessons learned and a set of validated guidelines, together with a discussion of benefits and risks of each guideline. Conclusion: In this work we share our experience in certifying software for healthcare devices produced under emergency, i.e. with strict and pressing time constraints and with the difficulty of establishing a heterogeneous development team made of volunteers. We believe that the guidelines will help engineers during the development of critical software under emergency.

Universal density of low-frequency states in silica glass at finite temperatures.

The theoretical understanding of the low-frequency modes in amorphous solids at finite temperature is still incomplete. The study of the relevant modes is obscured by the dressing of interparticle forces by collision-induced momentum transfer that is unavoidable at finite temperatures. Recently, it was proposed that low-frequency modes of vibrations around the thermally averaged configurations deserve special attention. In simple model glasses with bare binary interactions, these included quasilocalized modes whose density of states appears to be universal, depending on the frequencies as D(ω)∼ω^{4}, in agreement with the similar law that is obtained with bare forces at zero temperature. In this paper, we report investigations of a model of silica glass at finite temperature; here the bare forces include binary and ternary interactions. Nevertheless, we can establish the validity of the universal law of the density of quasilocalized modes also in this richer and more realistic model glass.

Predicting the failure of two-dimensional silica glasses.

Being able to predict the failure of materials based on structural information is a fundamental issue with enormous practical and industrial relevance for the monitoring of devices and components. Thanks to recent advances in deep learning, accurate failure predictions are becoming possible even for strongly disordered solids, but the sheer number of parameters used in the process renders a physical interpretation of the results impossible. Here we address this issue and use machine learning methods to predict the failure of simulated two dimensional silica glasses from their initial undeformed structure. We then exploit Gradient-weighted Class Activation Mapping (Grad-CAM) to build attention maps associated with the predictions, and we demonstrate that these maps are amenable to physical interpretation in terms of topological defects and local potential energies. We show that our predictions can be transferred to samples with different shape or size than those used in training, as well as to experimental images. Our strategy illustrates how artificial neural networks trained with numerical simulation results can provide interpretable predictions of the behavior of experimentally measured structures.

Evaluation of stereoacuity with a digital mobile application.

PURPOSE: Stereopsis is a fundamental skill in human vision and visual actions. There are many ways to test and quantify stereoacuity: traditional paper and new digital applications are both valid ways to test the stereoacuity. The aim of this study is to compare the results obtained using standard tests and the new Stereoacuity Test App developed by the University of Bergamo. METHODS: A group of 497 children (272 males), aged between 6 and 11 years old, were tested using different tests for the quantification of stereopsis at near. These tests were TNO, Weiss EKW, and the new developed Stereoacuity Test App. RESULTS: A one-way repeated measure ANOVA showed that the three tests give different thresholds of stereoacuity (p < 0.0001). Post hoc analyses with Bonferroni correction showed that all tests showed different thresholds (p < 0.0001). The lower threshold was obtained by Titmus Stereo Test followed by Stereoacuity App, Weiss MKW, and TNO. CONCLUSION: The stereoacuity based on global stereopsis showed that the better values were obtained in order by Stereoacuity Test App, TNO, and Weiss EKW. However, the clinical significance of their values is similar. The new digital test showed a greater compliance by the child, showing itself in tune with the digital characteristics of today's children.

How to communicate with families living in complete isolation.

IMPORTANCE: During the SARS-CoV-2 pandemic, a complete physical isolation has been worldwide introduced. The impossibility of visiting their loved ones during the hospital stay causes additional distress for families: in addition to the worries about clinical recovery, they may feel exclusion and powerlessness, anxiety, depression, mistrust in the care team and post-traumatic stress disorder. The impossibility of conducting the daily meetings with families poses a challenge for healthcare professionals. OBJECTIVE: This paper aims to delineate and share consensus statements in order to enable healthcare team to provide by telephone or video calls an optimal level of communication with patient's relatives under circumstances of complete isolation. EVIDENCE REVIEW: PubMed, Cochrane Database of Systematic Reviews, Database of Abstracts and Reviews of Effectiveness and the AHCPR Clinical Guidelines and Evidence Reports were explored from 1999 to 2019. Exclusion criteria were: poor or absent relevance regarding the aim of the consensus statements, studies prior to 1999, non-English language. Since the present pandemic context is completely new, unexpected and unexplored, there are not randomised controlled trials regarding clinical communication in a setting of complete isolation. Thus, a multiprofessional taskforce of physicians, nurses, psychologists and legal experts, together with some family members and former intensive care unit patients was established by four Italian national scientific societies. Using an e-Delphi methodology, general and specific questions were posed, relevant topics were argumented, until arriving to delineate position statements and practical checklist, which were set and evaluated through an evidence-based consensus procedure. FINDINGS: Ten statements and two practical checklists for phone or video calls were drafted and evaluated; they are related to who, when, why and how family members must be given clinical information under circumstances of complete isolation. CONCLUSIONS AND RELEVANCE: The statements and the checklists offer a structured methodology in order to ensure a good-quality communication between healthcare team and family members even in isolation, confirming that time dedicated to communication has to be intended as a time of care.

Universal Low-Frequency Vibrational Modes in Silica Glasses.

It was recently shown that different simple models of glass formers with binary interactions define a universality class in terms of the density of states of their quasilocalized low-frequency modes. Explicitly, once the hybridization with standard Debye (extended) modes is avoided, a number of such models exhibit a universal density of states, depending on the mode frequencies as D(ω)∼ω^{4}. It is unknown, however, how wide this universality class is, and whether it also pertains to more realistic models of glass formers. To address this issue we present analysis of the quasilocalized modes in silica, a network glass that has both binary and ternary interactions. We conclude that in three dimensions silica exhibits the very same frequency dependence at low frequencies, suggesting that this universal form is a generic consequence of amorphous glassiness.

Automatic design of mechanical metamaterial actuators.

Mechanical metamaterial actuators achieve pre-determined input-output operations exploiting architectural features encoded within a single 3D printed element, thus removing the need for assembling different structural components. Despite the rapid progress in the field, there is still a need for efficient strategies to optimize metamaterial design for a variety of functions. We present a computational method for the automatic design of mechanical metamaterial actuators that combines a reinforced Monte Carlo method with discrete element simulations. 3D printing of selected mechanical metamaterial actuators shows that the machine-generated structures can reach high efficiency, exceeding human-designed structures. We also show that it is possible to design efficient actuators by training a deep neural network which is then able to predict the efficiency from the image of a structure and to identify its functional regions. The elementary actuators devised here can be combined to produce metamaterial machines of arbitrary complexity for countless engineering applications.

Unjamming of active rotators.

Active particle assemblies can exhibit a wide range of interesting dynamical phases depending on internal parameters such as density, adhesion strength or self-propulsion. Active self-rotations are rarely studied in this context, although they can be relevant for active matter systems, as we illustrate by analyzing the motion of Chlamydomonas reinhardtii algae under different experimental conditions. Inspired by this example, we simulate the dynamics of a system of interacting active disks endowed with active torques and self-propulsive forces. At low packing fractions, adhesion causes the formation of small rotating clusters, resembling those observed when algae are stressed. At higher densities, the model shows a jamming to unjamming transition promoted by active torques and hindered by adhesion. We also study the interplay between self-propulsion and self-rotation and derive a phase diagram. Our results yield a comprehensive picture of the dynamics of active rotators, providing useful guidance to interpret experimental results in cellular systems where rotations might play a role.

Oscillatory instabilities in three-dimensional frictional granular matter.

The dynamics of amorphous granular matter with frictional interactions cannot be derived in general from a Hamiltonian and therefore displays oscillatory instabilities stemming from the onset of complex eigenvalues in the stability matrix. These instabilities were discovered in the context of one- and two-dimensional systems, while the three-dimensional case was never studied in detail. Here we fill this gap by deriving and demonstrating the presence of oscillatory instabilities in a three-dimensional granular packing. We study binary assemblies of spheres of two sizes interacting via classical Hertz and Mindlin force laws for the longitudinal and tangent interactions, respectively. We formulate analytically the stability matrix in three dimensions and observe that a couple of complex eigenvalues emerge at the onset of the instability as in the case of frictional disks in two dimensions. The dynamics then shows oscillatory exponential growth in the mean-square displacement, followed by a catastrophic event in which macroscopic portions of mechanical stress and energy are lost. The generality of these results for any choice of forces that break the symplectic Hamiltonian symmetry is discussed.

Chromatin and Cytoskeletal Tethering Determine Nuclear Morphology in Progerin-Expressing Cells.

The nuclear morphology of eukaryotic cells is determined by the interplay between the lamina forming the nuclear skeleton, the chromatin inside the nucleus, and the coupling with the cytoskeleton. Nuclear alterations are often associated with pathological conditions as in Hutchinson-Gilford progeria syndrome, in which a mutation in the lamin A gene yields an altered form of the protein, named progerin, and an aberrant nuclear shape. Here, we introduce an inducible cellular model of Hutchinson-Gilford progeria syndrome in HeLa cells in which increased progerin expression leads to alterations in the coupling of the lamin shell with cytoskeletal or chromatin tethers as well as with polycomb group proteins. Furthermore, our experiments show that progerin expression leads to enhanced nuclear shape fluctuations in response to cytoskeletal activity. To interpret the experimental results, we introduce a computational model of the cell nucleus that explicitly includes chromatin fibers, the nuclear shell, and coupling with the cytoskeleton. The model allows us to investigate how the geometrical organization of the chromatin-lamin tether affects nuclear morphology and shape fluctuations. In sum, our findings highlight the crucial role played by lamin-chromatin and lamin-cytoskeletal alterations in determining nuclear shape morphology and in affecting cellular functions and gene regulation.

Protein-driven lipid domain nucleation in biological membranes.

Lipid rafts are heterogeneous dynamic lipid domains of the cell membranes that are involved in several biological processes, such as protein and lipid specific transport and signaling. Our understanding of lipid raft formation is still limited due to the transient and elusive nature of these domains in vivo, in contrast with the stable phase-separated domains observed in artificial membranes. Inspired by experimental findings highlighting the relevance of transmembrane proteins for lipid rafts, we investigate lipid domain nucleation by coarse-grained molecular dynamics and Ising-model simulations. We find that the presence of a transmembrane protein can trigger lipid domain nucleation in a flat membrane from an otherwise mixed lipid phase. Furthermore, we study the role of the lipid domain in the diffusion of the protein showing that its mobility is hindered by the presence of the raft. The results of our coarse-grained molecular-dynamics and Ising-model simulations thus coherently support the important role played by transmembrane proteins in lipid domain formation and stability.

Metamaterial architecture from a self-shaping carnivorous plant.

As meticulously observed and recorded by Darwin, the leaves of the carnivorous plant Drosera capensis L. slowly fold around insects trapped on their sticky surface in order to ensure their digestion. While the biochemical signaling driving leaf closure has been associated with plant growth hormones, how mechanical forces actuate the process is still unknown. Here, we combine experimental tests of leaf mechanics with quantitative measurements of the leaf microstructure and biochemistry to demonstrate that the closure mechanism is programmed into the cellular architecture of D. capensis leaves, which converts a homogeneous biochemical signal into an asymmetric response. Inspired by the leaf closure mechanism, we devise and test a mechanical metamaterial, which curls under homogeneous mechanical stimuli. This kind of metamaterial could find possible applications as a component in soft robotics and provides an example of bio-inspired design.

Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins.

There is still no successful strategy to treat Huntington's disease, an inherited autosomal disorder associated with the aggregation of mutated forms of the huntingtin protein containing polyglutamine tracts with more than 36 repeats. Recent experimental evidence is challenging the conventional view of the disease by revealing transcellular transfer of mutated huntingtin proteins which are able to seed oligomers involving wild type forms of the protein. Here we decipher the molecular mechanism of this unconventional heterogeneous oligomerization by performing discrete molecular dynamics simulations. We identify the most probable oligomer conformations and the molecular regions that can be targeted to destabilize them. Our computational findings are complemented experimentally by fluorescence-lifetime imaging microscopy/fluorescence resonance energy transfer (FLIM-FRET) of cells co-transfected with huntingtin proteins containing short and large polyglutamine tracts. Our work clarifies the structural features responsible for heterogeneous huntingtin aggregation with possible implications to contrast the prion-like spreading of Huntington's disease.

Elementary plastic events in amorphous silica.

Plastic instabilities in amorphous materials are often studied using idealized models of binary mixtures that do not capture accurately molecular interactions and bonding present in real glasses. Here we study atomic-scale plastic instabilities in a three-dimensional molecular dynamics model of silica glass under quasistatic shear. We identify two distinct types of elementary plastic events, one is a standard quasilocalized atomic rearrangement while the second is a bond-breaking event that is absent in simplified models of fragile glass formers. Our results show that both plastic events can be predicted by a drop of the lowest nonzero eigenvalue of the Hessian matrix that vanishes at a critical strain. Remarkably, we find very high correlation between the associated eigenvectors and the nonaffine displacement fields accompanying the bond-breaking event, predicting the locus of structural failure. Both eigenvectors and nonaffine displacement fields display an Eshelby-like quadrupolar structure for both failure modes, rearrangement, and bond breaking. Our results thus clarify the nature of atomic-scale plastic instabilities in silica glasses, providing useful information for the development of mesoscale models of amorphous plasticity.

Damage Accumulation in Silica Glass Nanofibers.

The origin of the brittle-to-ductile transition, experimentally observed in amorphous silica nanofibers as the sample size is reduced, is still debated. Here we investigate the issue by extensive molecular dynamics simulations at low and room temperatures for a broad range of sample sizes, with open and periodic boundary conditions. Our results show that small sample-size enhanced ductility is primarily due to diffuse damage accumulation, that for larger samples leads to brittle catastrophic failure. Surface effects such as boundary fluidization contribute to ductility at room temperature by promoting necking, but are not the main driver of the transition. Our results suggest that the experimentally observed size-induced ductility of silica nanofibers is a manifestation of finite-size criticality, as expected in general for quasi-brittle disordered networks.

Methods to locate saddle points in complex landscapes.

We present a class of simple algorithms that allows us to find the reaction path in systems with a complex potential energy landscape. The approach does not need any knowledge on the product state and does not require the calculation of any second derivatives. The underlying idea is to use two nearby points in the configuration space to locate the path of the slowest ascent. By introducing a weak noise term, the algorithm is able to find even low-lying saddle points that are not directly reachable by means of the slowest ascent path. Since the algorithm only makes use of the value of the potential and its gradient, the computational effort to find saddle points is linear in the number of degrees of freedom if the potential is short-ranged. We test the performance of the algorithm for three potential energy landscapes. For the Müller-Brown surface, we find that the algorithm always finds the correct saddle point. For the modified Müller-Brown surface, which has a saddle point that is not reachable by means of the slowest ascent path, the algorithm is still able to find this saddle point with high probability. For the case of a three-dimensional Lennard-Jones cluster, the algorithm is able to find the lowest energy barrier with high probability, showing that the method is also efficient in landscapes with many dimensions.

Atomic-Scale Front Propagation at the Onset of Frictional Sliding.

Macroscopic frictional sliding emerges from atomic-scale interactions and processes at the contact interface, but bridging the gap between micro and macro scales still remains an unsolved challenge. Direct imaging of the contact surface and simultaneous measurement of stress fields during macroscopic frictional slip revealed the formation of crack precursors, questioning the traditional picture of frictional contacts described in terms of a single degree of freedom. Here we study the onset of frictional slip on the atomic scale by simulating the motion of an aluminum block pushed by a slider on a copper substrate. We show the formation of dynamic slip front propagation and precursory activity that resemble macroscopic observations. The analysis of stress patterns during slip, however, reveals subtle effects due to the lattice structures that hinder a direct application of linear elastic fracture mechanics. Our results illustrate that dynamic front propagation arises already on the atomic scales and shed light on the connections between atomic-scale and macroscopic friction.

[Sport-related concussion]. / La commotion cérébrale dans le sport.

Sport-related concussion is a frequent and complex pathology whose physiopathological mechanisms are not completely understood yet. A recent consensus statement has been published with the objective to provide practicioners with an overview of literature and give some guidelines based on the current state of knowledge. An 11R approach (Recognise, Remove, Re-evaluate, Rest, Rehabilitation, Refer, Recover, Return to sport, Reconsider, Residual effects and sequelae, Risk reduction) is proposed to evaluate and manage sport-related concussion. There is currently no available test predicting recovery, but the risk factors for a slow recovery are now known. Return to daily activities (as school) and to full sport participation should follow the graduated return-to-school or - sport strategy, and the ultimate decision is clinically based, and made by the physician.

La commotion dans le sport est une pathologie fréquente, complexe et dont les mécanismes physiopathologiques ne sont pas encore entièrement élucidés. Un consensus international vient récemment d'être publié avec une mise à jour des connaissances scientifiques, fournissant des conseils pour le médecin de terrain. L'évaluation et la prise en charge de la commotion se résument par les 11 R : Reconnaître, Retirer, Réévaluer, Repos, Réhabilitation, Référer, Récupérer, Retour au sport, Reconsidérer, séquelles et symptômes Résiduels, prévention du Risque. Il n'existe à ce jour aucun test pouvant prédire l'évolution de la commotion, mais certains facteurs sont reconnus comme responsables d'une récupération lente. Le retour à l'école et au sport est une décision médicale, après avoir suivi un protocole de réhabilitation progressive.

[Female athlete triad : what's new ?] / Triade de l'athlète féminine : quoi de neuf ?

The Relative Energy Deficiency in Sport has been suggested as the new and wider denomination of the Female athlete triad. This new terminology enables a wider approach to the different consequences of an insufficient energy intake amongst regular athletes. In fact, this energy dysbalance leads to a wider pathological phenomenon touching many systems (e.g. cardiovascular, psychological, hematological…). This designation is no longer restricted to the female gender, and now also includes men, whom are nowadays less affected or maybe only less assessed. This syndrome is still unknown to most primary care physicians and specialists, thereby its incidence and prevalence is probably greatly underestimated.

Le Relative Energy Deficiency in Sport (RED-S) a été proposé comme nouvelle dénomination plus large de la triade de l'athlète féminine. Ce nouveau terme introduit une vision plus globale des atteintes liées à une insuffisance d'apport calorique lors de la pratique régulière d'un sport. En effet, le RED-S amène d'autres implications physiologiques en lien avec un déséquilibre énergétique (atteintes cardiovasculaire, psychologique, hématologique…). De plus, cette appellation ne se restreint plus au sexe féminin, mais intègre également le genre masculin, toutefois encore relativement peu touché ou alors sous-évalué. Cette problématique reste encore méconnue de la plupart des médecins de premier recours et de certains spécialistes, ainsi son incidence et sa prévalence sont très probablement encore largement sous-estimées.