Towards a 21st-century roadmap for biomedical research and drug discovery: consensus report and recommendations

Decades of costly failures in translating drug candidates from preclinical disease models to human therapeutic use warrant reconsideration of the priority placed on animal models in biomedical research. Following an international workshop attended by experts from academia, government institutions, research funding bodies, and the corporate and nongovernmental organisation (NGO) sectors, in this consensus report, we analyse, as case studies, five disease areas with major unmet needs for new treatments. In view of the scientifically driven transition towards a human pathway-based paradigm in toxicology, a similar paradigm shift appears to be justified in biomedical research. There is a pressing need for an approach that strategically implements advanced, human biology-based models and tools to understand disease pathways at multiple biological scales. We present recommendations to help achieve this.

Jointly event extraction and visualization on Twitter via probabilistic modelling

Event extraction from texts aims to detect structured information such as what has happened, to whom, where and when. Event extraction and visualization are typically considered as two different tasks. In this paper, we propose a novel approach based on probabilistic modelling to jointly extract and visualize events from tweets where both tasks benefit from each other. We model each event as a joint distribution over named entities, a date, a location and event-related keywords. Moreover, both tweets and event instances are associated with coordinates in the visualization space. The manifold assumption that the intrinsic geometry of tweets is a low-rank, non-linear manifold within the high-dimensional space is incorporated into the learning framework using a regularization. Experimental results show that the proposed approach can effectively deal with both event extraction and visualization and performs remarkably better than both the state-of-the-art event extraction method and a pipeline approach for event extraction and visualization.

Challenges in imaging and predictive modeling of rhizosphere processes

Background Plant-soil interaction is central to human food production and ecosystem function. Thus, it is essential to not only understand, but also to develop predictive mathematical models which can be used to assess how climate and soil management practices will affect these interactions. Scope In this paper we review the current developments in structural and chemical imaging of rhizosphere processes within the context of multiscale mathematical image based modeling. We outline areas that need more research and areas which would benefit from more detailed understanding. Conclusions We conclude that the combination of structural and chemical imaging with modeling is an incredibly powerful tool which is fundamental for understanding how plant roots interact with soil. We emphasize the need for more researchers to be attracted to this area that is so fertile for future discoveries. Finally, model building must go hand in hand with experiments. In particular, there is a real need to integrate rhizosphere structural and chemical imaging with modeling for better understanding of the rhizosphere processes leading to models which explicitly account for pore scale processes.

Myocardial edema after ischemia/reperfusion is not stable and follows a bimodal pattern: Imaging and histological tissue characterization

It is widely accepted that edema occurs early in the ischemic zone and persists in stable form for at least 1 week after myocardial ischemia/reperfusion. However, there are no longitudinal studies covering from very early (minutes) to late (1 week) reperfusion stages confirming this phenomenon. This study sought to perform a comprehensive longitudinal imaging and histological characterization of the edematous reaction after experimental myocardial ischemia/reperfusion. The study population consisted of 25 instrumented Large-White pigs (30 kg to 40 kg). Closed-chest 40-min ischemia/reperfusion was performed in 20 pigs, which were sacrificed at 120 min (n = 5), 24 h (n = 5), 4 days (n = 5), and 7 days (n = 5) after reperfusion and processed for histological quantification of myocardial water content. Cardiac magnetic resonance (CMR) scans with T2-weighted short-tau inversion recovery and T2-mapping sequences were performed at every follow-up stage until sacrifice. Five additional pigs sacrificed after baseline CMR served as controls. In all pigs, reperfusion was associated with a significant increase in T2 relaxation times in the ischemic region. On 24-h CMR, ischemic myocardium T2 times returned to normal values (similar to those seen pre-infarction). Thereafter, ischemic myocardium-T2 times in CMR performed on days 4 and 7 after reperfusion progressively and systematically increased. On day 7 CMR, T2 relaxation times were as high as those observed at reperfusion. Myocardial water content analysis in the ischemic region showed a parallel bimodal pattern: 2 high water content peaks at reperfusion and at day 7, and a significant decrease at 24 h. Contrary to the accepted view, myocardial edema during the first week after ischemia/reperfusion follows a bimodal pattern. The initial wave appears abruptly upon reperfusion and dissipates at 24 h. Conversely, the deferred wave of edema appears progressively days after ischemia/reperfusion and is maximal around day 7 after reperfusion.

PRISM (Polarized Radiation Imaging and Spectroscopy Mission): an extended white paper

PRISM (Polarized Radiation Imaging and Spectroscopy Mission) was proposed to ESA in May 2013 as a large-class mission for investigating within the framework of the ESA Cosmic Vision program a set of important scientific questions that require high res- olution, high sensitivity, full-sky observations of the sky emission at wavelengths ranging from millimeter-wave to the far-infrared. PRISM’s main objective is to explore the distant universe, probing cosmic history from very early times until now as well as the structures, distribution of matter, and velocity flows throughout our Hubble volume. PRISM will survey the full sky in a large number of frequency bands in both intensity and polarization and will measure the absolute spectrum of sky emission more than three orders of magnitude bet- ter than COBE FIRAS. The data obtained will allow us to precisely measure the absolute sky brightness and polarization of all the components of the sky emission in the observed frequency range, separating the primordial and extragalactic components cleanly from the galactic and zodiacal light emissions. The aim of this Extended White Paper is to provide a more detailed overview of the highlights of the new science that will be made possible by PRISM, which include: (1) the ultimate galaxy cluster survey using the Sunyaev-Zeldovich (SZ) e↵ect, detecting approximately 106 clusters extending to large redshift, including a char- acterization of the gas temperature of the brightest ones (through the relativistic corrections to the classic SZ template) as well as a peculiar velocity survey using the kinetic SZ e↵ect that comprises our entire Hubble volume; (2) a detailed characterization of the properties and evolution of dusty galaxies, where the most of the star formation in the universe took place, the faintest population of which constitute the di↵use CIB (Cosmic Infrared Background); (3) a characterization of the B modes from primordial gravity waves generated during inflation and from gravitational lensing, as well as the ultimate search for primordial non-Gaussianity using CMB polarization, which is less contaminated by foregrounds on small scales than thetemperature anisotropies; (4) a search for distortions from a perfect blackbody spectrum, which include some nearly certain signals and others that are more speculative but more informative; and (5) a study of the role of the magnetic field in star formation and its inter- action with other components of the interstellar medium of our Galaxy. These are but a few of the highlights presented here along with a description of the proposed instrument.

Development and optimization of techniques and design parameters for the engineering of atmospheric pressure plasma devices for biomedical applications and plasma medicine

In the last decades, the possibility to generate plasma at atmospheric pressure gave rise to a new emerging field called plasma medicine; it deals with the application of cold atmospheric pressure plasmas (CAPs) or plasma-activated solutions on or in the human body for therapeutic effects. Thanks to a blend of synergic biologically active agents and biocompatible temperatures, different CAP sources were successfully employed in many different biomedical applications such as dentistry, dermatology, wound healing, cancer treatment, blood coagulation, etc.… Despite their effectiveness has been verified in the above-mentioned biomedical applications, over the years, researchers throughout the world described numerous CAP sources which are still laboratory devices not optimized for the specific application. In this perspective, the aim of this dissertation was the development and the optimization of techniques and design parameters for the engineering of CAP sources for different biomedical applications and plasma medicine among which cancer treatment, dentistry and bioaerosol decontamination. In the first section, the discharge electrical parameters, the behavior of the plasma streamers and the liquid and the gas phase chemistry of a multiwire device for the treatment of liquids were performed. Moreover, two different plasma-activated liquids were used for the treatment of Epithelial Ovarian Cancer cells and fibroblasts to assess their selectivity. In the second section, in accordance with the most important standard regulations for medical devices, were reported the realization steps of a Plasma Gun device easy to handle and expected to be mounted on a tabletop device that could be used for dental clinical applications. In the third section, in relation to the current COVID-19 pandemic, were reported the first steps for the design, realization, and optimization of a dielectric barrier discharge source suitable for the treatment of different types of bioaerosol.

Hyperspectral imaging and other optical techniques for (in-field/in-lab) physico-chemical attributes estimation of agri-food vegetal products

In the agri-food sector, measurement and monitoring activities contribute to high quality end products. In particular, considering food of plant origin, several product quality attributes can be monitored. Among the non-destructive measurement techniques, a large variety of optical techniques are available, including hyperspectral imaging (HSI) in the visible/near-infrared (Vis/NIR) range, which, due to the capacity to integrate image analysis and spectroscopy, proved particularly useful in agronomy and food science. Many published studies regarding HSI systems were carried out under controlled laboratory conditions. In contrast, few studies describe the application of HSI technology directly in the field, in particular for high-resolution proximal measurements carried out on the ground. Based on this background, the activities of the present PhD project were aimed at exploring and deepening knowledge in the application of optical techniques for the estimation of quality attributes of agri-food plant products. First, research activities on laboratory trials carried out on apricots and kiwis for the estimation of soluble solids content (SSC) and flesh firmness (FF) through HSI were reported; subsequently, FF was estimated on kiwis using a NIR-sensitive device; finally, the procyanidin content of red wine was estimated through a device based on the pulsed spectral sensitive photometry technique. In the second part, trials were carried out directly in the field to assess the degree of ripeness of red wine grapes by estimating SSC through HSI, and finally a method for the automatic selection of regions of interest in hyperspectral images of the vineyard was developed. The activities described above have revealed the potential of the optical techniques for sorting-line application; moreover, the application of the HSI technique directly in the field has proved particularly interesting, suggesting further investigations to solve a variety of problems arising from the many environmental variables that may affect the results of the analyses.

Effective diagnosis of Alzheimer's disease by means of large margin-based methodology.

BACKGROUND Functional brain images such as Single-Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been widely used to guide the clinicians in the Alzheimer's Disease (AD) diagnosis. However, the subjectivity involved in their evaluation has favoured the development of Computer Aided Diagnosis (CAD) Systems. METHODS It is proposed a novel combination of feature extraction techniques to improve the diagnosis of AD. Firstly, Regions of Interest (ROIs) are selected by means of a t-test carried out on 3D Normalised Mean Square Error (NMSE) features restricted to be located within a predefined brain activation mask. In order to address the small sample-size problem, the dimension of the feature space was further reduced by: Large Margin Nearest Neighbours using a rectangular matrix (LMNN-RECT), Principal Component Analysis (PCA) or Partial Least Squares (PLS) (the two latter also analysed with a LMNN transformation). Regarding the classifiers, kernel Support Vector Machines (SVMs) and LMNN using Euclidean, Mahalanobis and Energy-based metrics were compared. RESULTS Several experiments were conducted in order to evaluate the proposed LMNN-based feature extraction algorithms and its benefits as: i) linear transformation of the PLS or PCA reduced data, ii) feature reduction technique, and iii) classifier (with Euclidean, Mahalanobis or Energy-based methodology). The system was evaluated by means of k-fold cross-validation yielding accuracy, sensitivity and specificity values of 92.78%, 91.07% and 95.12% (for SPECT) and 90.67%, 88% and 93.33% (for PET), respectively, when a NMSE-PLS-LMNN feature extraction method was used in combination with a SVM classifier, thus outperforming recently reported baseline methods. CONCLUSIONS All the proposed methods turned out to be a valid solution for the presented problem. One of the advances is the robustness of the LMNN algorithm that not only provides higher separation rate between the classes but it also makes (in combination with NMSE and PLS) this rate variation more stable. In addition, their generalization ability is another advance since several experiments were performed on two image modalities (SPECT and PET).

A direct D-bar reconstruction algorithm for recovering a complex conductivity in 2D

A direct reconstruction algorithm for complex conductivities in W-2,W-infinity(Omega), where Omega is a bounded, simply connected Lipschitz domain in R-2, is presented. The framework is based on the uniqueness proof by Francini (2000 Inverse Problems 6 107-19), but equations relating the Dirichlet-to-Neumann to the scattering transform and the exponentially growing solutions are not present in that work, and are derived here. The algorithm constitutes the first D-bar method for the reconstruction of conductivities and permittivities in two dimensions. Reconstructions of numerically simulated chest phantoms with discontinuities at the organ boundaries are included.

Femtosecond laser micro-inscription of optical coherence tomography resolution test artifacts

Optical coherence tomography (OCT) systems are becoming more commonly used in biomedical imaging and, to enable continued uptake, a reliable method of characterizing their performance and validating their operation is required. This paper outlines the use of femtosecond laser subsurface micro-inscription techniques to fabricate an OCT test artifact for validating the resolution performance of a commercial OCT system. The key advantage of this approach is that by utilizing the nonlinear absorption a three dimensional grid of highly localized point and line defects can be written in clear fused silica substrates.

A New Imaging Software To Evaluate The Centration Of Capsulorhexis And Intraocular Lens (IOL) After Cataract Surgery

Purpose: IOL centration and stability after cataract surgery is of high interest for cataract surgeons and IOL-producing companies. We present a new imaging software to evaluate the centration of the rhexis and the centration of the IOL after cataract surgery.Methods: We developed, in collaboration with the Biomedical Imaging Group (BIG), EPFL, Lausanne, a new working tool in order to assess precisely outcomes after IOL-implantation, such as ideal capsulorhexis and IOL-centration. The software is a plug-in of ImageJ, a general-purpose image processing and image-analysis package. The specifications of this software are: evaluation of the rhexis-centration and evaluation the position of the IOL in the posterior chamber. The end points are to analyze the quality of the centration of a rhexis after cataract surgery, the deformation of the rhexis with capsular bag retraction and the centration of the IOL after implantation.Results: This software delivers tools to interactively measure the distances between limbus, IOL and capsulorhexis and its changes over time. The user is invited to adjust nodes of three radial curves for the limbus, rhexis and the optic of the IOL. The radial distances of the curves are computed to evaluate the IOL implantation. The user is also able to define patterns for ideal capsulorhexis and optimal IOL-centration. We are going to present examples of calculations after cataract surgery.Conclusions: Evaluation of the centration of the rhexis and of the IOL after cataract surgery is an important end point for optimal IOL implantation after cataract surgery. Especially multifocal or accommodative lenses need a precise position in the bag with a good stability over time. This software is able to evaluate these parameters just after the surgery but also its changes over time. The results of these evaluations can lead to an optimizing of surgical procedures and materials.

MRI of coronary vessel walls using radial k-space sampling and steady-state free precession imaging.

OBJECTIVE: The objective of our study was to investigate the impact of radial k-space sampling and steady-state free precession (SSFP) imaging on image quality in MRI of coronary vessel walls. SUBJECTS AND METHODS: Eleven subjects were examined on a 1.5-T MR system using three high-resolution navigator-gated and cardiac-triggered 3D black blood sequences (cartesian gradient-echo [GRE], radial GRE, and radial SSFP) with identical spatial resolution (0.9 x 0.9 x 2.4 mm3). The signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), vessel wall sharpness, and motion artifacts were analyzed. RESULTS: The mean SNR and CNR of the coronary vessel wall were improved using radial imaging and were best using radial k-space sampling combined with SSFP imaging. Vessel border definition was similar for all three sequences. Radial k-space sampling was found to be less sensitive to motion. Consistently good image quality was seen with the radial GRE sequence. CONCLUSION: Radial k-space sampling in MRI of coronary vessel walls resulted in fewer motion artifacts and improved SNR and CNR. The use of SSFP imaging, however, did not result in improved coronary vessel wall visualization.

Visualization, manipulation and force spectroscopy of cylindrical polymer brushes

The Ph.D. thesis deals with the conformational study of individual cylindrical polymer brush molecules using atomic force microscopy (AFM). Imaging combined with single molecule manipulation has been used to unravel questions concerning conformational changes, desorption behavior and mechanical properties of individual macromolecules and supramolecular structures. In the first part of the thesis (chapter 5) molecular conformations of cylindrical polymer brushes with poly-(N-isopropylacrylamide) (PNIPAM) side chains were studied in various environmental conditions. Also micelle formation of cylindrical brush-coil blockcopolymers with polyacrylic acid side chains and polystyrene coil have been visualized. In chapter 6 the mechanical properties of single cylindrical polymer brushes with (PNIPAM) side chains were investigated. Assuming that the brushes adopt equilibrium conformation on the surface, an average persistence length of lp= (29 ± 3) nm was determined by the end-to-end distance vs. contour length analysis in terms of the wormlike chain (WLC) model. Stretching experiments suggest that an exact determination of the persistence length using force extension curves is impeded by the contribution of the side chains. Modeling the stretching of the bottle brush molecule as extension of a dual spring (side chain and main chain) explains the frequently observed very low persistence length arising from a dominant contribution of the side chain elasticity at small overall contour lengths. It has been shown that it is possible to estimate the “true” persistence length of the bottle brush molecule from the intercept of a linear extrapolation of the inverse square root of the apparent persistence length vs. the inverse contour length plot. By virtue of this procedure a “true” persistence length of 140 nm for the PNIPAM brush molecules is predicted. Chapter 7 and 8 deal with the force-extension behavior of PNIPAM cylindrical brushes studied in poor solvent conditions. The behavior is shown to be qualitatively different from that in a good solvent. Force induced globule-cylinder conformational changes are monitored using “molecule specific force spectroscopy” which is a combined AFM imaging and SMFS technique. An interesting behavior of the unfolding-folding transitions of single collapsed PNIPAM brush molecules has been observed by force spectroscopy using the so called “fly-fishing” mode. A plateau force is observed upon unfolding the collapsed molecule, which is attributed to a phase transition from a collapsed brush to a stretched conformation. Chapter 9 describes the desorption behavior of single cylindrical polyelectrolyte brushes with poly-L-lysine side chains deposited on a mica surface using the “molecule specific force spectroscopy” technique to resolve statistical discrepancies usually observed in SMFS experiments. Imaging of the brushes and inferring the persistence length from a end-to-end distance vs. contour length analysis results in an average persistence length of lp = (25 ± 5) nm assuming that the chains adopt their equilibrium conformation on the surface. Stretching experiments carried out on individual poly-L-lysine brush molecules by force spectroscopy using the “fly-fishing” mode provide a persistence length in the range of 7-23 nm in reasonable accordance with the imaging results. In chapter 10 the conformational behavior of cylindrical poly-L-lysine brush-sodium dodecyl sulfate complexes was studied using AFM imaging. Surfactant induced cylinder to helix like to globule conformational transitions were observed.

Format preferences of district attorneys for post-mortem medical imaging reports: understandability, cost effectiveness, and suitability for the courtroom: a questionnaire based study

The objective of this study was to explore the perception of the legal authorities regarding different report types and visualization techniques for post-mortem radiological findings.

Evaluation and quantification of spectral information in tissue by confocal microscopy

A confocal imaging and image processing scheme is introduced to visualize and evaluate the spatial distribution of spectral information in tissue. The image data are recorded using a confocal laser-scanning microscope equipped with a detection unit that provides high spectral resolution. The processing scheme is based on spectral data, is less error-prone than intensity-based visualization and evaluation methods, and provides quantitative information on the composition of the sample. The method is tested and validated in the context of the development of dermal drug delivery systems, introducing a quantitative uptake indicator to compare the performances of different delivery systems is introduced. A drug penetration study was performed in vitro. The results show that the method is able to detect, visualize and measure spectral information in tissue. In the penetration study, uptake efficiencies of different experiment setups could be discriminated and quantitatively described. The developed uptake indicator is a step towards a quantitative assessment and, in a more general view apart from pharmaceutical research, provides valuable information on tissue composition. It can potentially be used for clinical in vitro and in vivo applications.