POSITION PAPER : Credibility of in silico trial technologies - a theoretical framing

Different research communities have developed various approaches to assess the credibility of predictive models. Each approach usually works well for a specific type of model, and under some epistemic conditions that are normally satisfied within that specific research domain. Some regulatory agencies recently started to consider evidences of safety and efficacy on new medical products obtained using computer modelling and simulation (which is referred to as In Silico Trials); this has raised the attention in the computational medicine research community on the regulatory science aspects of this emerging discipline. But this poses a foundational problem: in the domain of biomedical research the use of computer modelling is relatively recent, without a widely accepted epistemic framing for problem of model credibility. Also, because of the inherent complexity of living organisms, biomedical modellers tend to use a variety of modelling methods, sometimes mixing them in the solution of a single problem. In such context merely adopting credibility approaches developed within other research community might not be appropriate. In this position paper we propose a theoretical framing for the problem of assessing the credibility of a predictive models for In Silico Trials, which accounts for the epistemic specificity of this research field and is general enough to be used for different type of models

Experimental validation of a subject-specific finite element model of lumbar spine segment using digital image correlation

Pathologies such as cancer metastasis and osteoporosis strongly affect the mechanical properties of the vertebral bone and increase the risk of fragility fractures. The prediction of the fracture risk with a patient-specific model, directly generated from the diagnostic images of the patient, could help the clinician in the choice of the correct therapy to follow. But before such models can be used to support any clinical decision, their credibility must be demonstrated through verification, validation, and uncertainty quantification. In this study we describe a procedure for the generation of such patient-specific finite element models and present a first validation of the kinematics of the spine segment. Quantitative computed tomography images of a cadaveric lumbar spine segment presenting vertebral metastatic lesions were used to generate the model. The applied boundary conditions replicated a specific experimental test where the spine segment was loaded in compression-flexion. Model predictions in terms of vertebral surface displacements were compared against the full-field experimental displacements measured with Digital Image Correlation. A good agreement was obtained from the local comparison between experimental data and simulation results (R2 > 0.9 and RMSE% <8%). In conclusion, this work demonstrates the possibility to apply the developed modelling pipeline to predict the displacement field of human spine segment under physiological loading conditions, which is a first fundamental step in the credibility assessment of these clinical decision-support technology

Using musculoskeletal models to estimate in vivo total knee replacement kinematics and loads: effect of differences between models

Total knee replacement (TKR) is one of the most performed orthopedic surgeries to treat knee joint diseases in the elderly population. Although the survivorship of knee implants may extend beyond two decades, the poor outcome rate remains considerable. A recent computational approach used to better understand failure modes and improve TKR outcomes is based on the combination of musculoskeletal (MSK) and finite element models. This combined multiscale modeling approach is a promising strategy in the field of computational biomechanics; however, some critical aspects need to be investigated. In particular, the identification and quantification of the uncertainties related to the boundary conditions used as inputs to the finite element model due to a different definition of the MSK model are crucial. Therefore, the aim of this study is to investigate this problem, which is relevant for the model credibility assessment process. Three different generic MSK models available in the OpenSim platform were used to simulate gait, based on the experimental data from the fifth edition of the “Grand Challenge Competitions to Predict in vivo Knee Loads.” The outputs of the MSK analyses were compared in terms of relative kinematics of the knee implant components and joint reaction (JR) forces and moments acting on the tibial insert. Additionally, the estimated knee JRs were compared with those measured by the instrumented knee implant so that the “global goodness of fit” was quantified for each model. Our results indicated that the different kinematic definitions of the knee joint and the muscle model implemented in the different MSK models influenced both the motion and the load history of the artificial joint. This study demonstrates the importance of examining the influence of the model assumptions on the output results and represents the first step for future studies that will investigate how the uncertainties in the MSK models propagate on disease-specific finite element model results

Dual-acting stapled peptides target both HIV-1 entry and assembly

Background: Previously, we reported the conversion of the 12-mer linear and cell-impermeable peptide CAI to a cell-penetrating peptide NYAD-1 by using an i,i + 4 hydrocarbon stapling technique and confirmed its binding to the C-terminal domain (CTD) of the HIV-1 capsid (CA) protein with an improved affinity (Kd ~ 1 μM) compared to CAI (Kd ~ 15 μM). NYAD-1 disrupts the formation of both immature- and mature-like virus particles in in vitro and cell-based assembly assays. In addition, it displays potent anti-HIV-1 activity in cell culture against a range of laboratory-adapted and primary HIV-1 isolates.&lt;p&gt;&lt;/p&gt; Results: In this report, we expanded the study to i,i + 7 hydrocarbon-stapled peptides to delineate their mechanism of action and antiviral activity. We identified three potent inhibitors, NYAD-36, -66 and -67, which showed strong binding to CA in NMR and isothermal titration calorimetry (ITC) studies and disrupted the formation of mature-like particles. They showed typical α-helical structures and penetrated cells; however, the cell penetration was not as efficient as observed with the i,i + 4 peptides. Unlike NYAD-1, the i,i + 7 peptides did not have any effect on virus release; however, they impaired Gag precursor processing. HIV-1 particles produced in the presence of these peptides displayed impaired infectivity. Consistent with an effect on virus entry, selection for viral resistance led to the emergence of two mutations in the gp120 subunit of the viral envelope (Env) glycoprotein, V120Q and A327P, located in the conserved region 1 (C1) and the base of the V3 loop, respectively.&lt;p&gt;&lt;/p&gt; Conclusion: The i,i + 7 stapled peptides derived from CAI unexpectedly target both CA and the V3 loop of gp120. This dual-targeted activity is dependent on their ability to penetrate cells as well as their net charge. This mechanistic revelation will be useful in further modifying these peptides as potent anti-HIV-1 agents.&lt;p&gt;&lt;/p&gt

Widowhood and Mortality: A Meta-Analysis and Meta-Regression

The study of spousal bereavement and mortality has long been a major topic of interest for social scientists, but much remains unknown with respect to important moderating factors, such as age, follow-up duration, and geographic region. The present study examines these factors using meta-analysis. Keyword searches were conducted in multiple electronic databases, supplemented by extensive iterative hand searches. We extracted 1,377 mortality risk estimates from 123 publications, providing data on more than 500 million persons. Compared with married people, widowers had a mean hazard ratio (HR) of 1.23 (95% confidence interval (CI), 1.19–1.28) among HRs adjusted for age and additional covariates and a high subjective quality score. The mean HR was higher for men (HR, 1.27; 95% CI, 1.19–1.35) than for women (HR, 1.15; 95% CI, 1.08–1.22). A significant interaction effect was found between gender and mean age, with HRs decreasing more rapidly for men than for women as age increased. Other significant predictors of HR magnitude included sample size, geographic region, level of statistical adjustment, and study quality

Numerical Study of the Optical Response of ITO-In2O3 Core-Shell Nanocrystals for Multispectral Electromagnetic Shielding

Nowadays materials to protect equipment from unwanted multispectral electromagnetic waves are needed in a broad range of applications including electronics, medical, military and aerospace. However, the shielding materials currently in use are bulky and work effectively only in a limited frequency range. Therefore, nanostructured materials are under investigation by the relevant scientific community. In this framework, the design of multispectral shielding nanomaterials must be supplemented with proper numerical models that allow dealing with non-linearities and being effective in predicting their absorption spectra. In this study, the electromagnetic response of metal-oxide nanocrystals with multispectral electromagnetic shielding capability has been investigated. A numerical framework was developed to predict energy bands and electron density profiles of a core-shell nanocrystal and to evaluate its optical response at different wavelengths. To this aim, a finite element method software is used to solve a non-linear Poisson's equation. The numerical simulations allowed to model the optical response of ITO-In2O3 core-shell nanocrystals and can be effectively applied to different nanotopologies to support an enhanced design of nanomaterials with multispectral shielding capabilities

A Mathematical Model of a Solar Collector Augmented by a Flat Plate above Reflector: Optimum Inclination of Collector and Reflector

In this study a theoretical analysis of a collector augmented by a bottom booster reflector is presented. An analytical model has been developed and used to estimate the solar irradiation passing through the transparent cover of a flat collector, both with and without a bottom reflector. The analytical model is based on the anisotropic sky model and takes into account a finite length system with different angular configurations and reciprocal shading and reflections between reflector and collector. Computer simulations have been carried out in order to find the optimum angles of the reflector with respect to the plane of the collector. Optimal inclinations of the collector and reflector for each month at 39° N latitude have been identified

A Periodic Transmission Line Model for Body Channel Communication

Body channel communication (BCC) is a technique for data transmission exploiting the human body as communication channel. Even though it was pioneered about 25 years ago, the identification of a good electrical model behind its functioning is still an open research question. The proposed distributed model can then serve as a supporting tool for the design, allowing to enhance the performances of any BCC system. A novel finite periodic transmission line model was developed to describe the human body as transmission medium. According to this model, for the first time, the parasitic capacitance between the transmitter and the receiver is assumed to depend on their distance. The parameters related to the body and electrodes are acquired experimentally by fitting the bio-impedentiometric measurements, in the range of frequencies from 1 kHz to 1 MHz, obtaining a mean absolute error lower than 4° and 30 $Omega$ for the phase angle and impedance modulus, respectively. The proposed mathematical framework has been successfully validated by describing a ground-referred and low-complexity system called Live Wire, suitable as supporting tool for visually impaired people, and finding good agreement between the measured and the calculated data, marking a ±3% error for communication distances ranging from 20 to 150 cm. In this work we introduced a new circuital approach, for capacitive-coupling systems, based on finite periodic transmission line, capable to describe and model BCC systems allowing to optimize the performances of similar systems

Three-Body Dynamics and Self-Powering of an Electrodynamic Tether in a Plasmasphere

The dynamics of an electrodynamic tether in a three-body gravitational environment are investigated. In the classical two-body scenario the extraction of power is at the expense of orbital kinetic energy. As a result of power extraction, an electrodynamic tether satellite system loses altitude and deorbits. This concept has been proposed and well investigated in the past, for example for orbital debris mitigation and spent stages reentry. On the other hand, in the three-body scenario an electrodynamic tether can be placed in an equilibrium position fixed with respect to the two primary bodies without deorbiting, and at the same time generate power for onboard use. The appearance of new equilibrium positions in the perturbed three-body problem allow this to happen as the electrical power is extracted at the expenses of the plasma corotating with the primary body. Fundamental differences between the classical twobody dynamics and the new phenomena appearing in the circular restricted three-body problem perturbed by the electrodynamic force of the electrodynamic tether are shown in the paper. An interesting application of an electrodynamic tether placed in the Jupiter plasma torus is then considered, in which the electrodynamic tether generates useful electrical power of about 1 kW with a 20-km-long electrodynamic tether from the environmental plasma without losing orbital energy

Dynamic stabilization of L2 periodic orbits using attitude-orbit coupling effects

Numerical explorations show how the known periodic solutions of the Hill problem are modified in the case of the attitude-orbit coupling that may occur for large satellite structures. We focus on the case in which the elongation is the dominant satellite?s characteristic and find that a rotating structure may remain with its largest dimension in a plane parallel to the plane of the primaries. In this case, the effect produced by the non-negligible physical dimension is dynamically equivalent to the perturbation produced by an oblate central body on a masspoint satellite. Based on this, it is demonstrated that the attitude-orbital coupling of a long enough body may change the dynamical characteristics of a periodic orbit about the collinear Lagrangian points