Miracle-dz/UniFAR-FTUs huggingface dataset:
Critical Reflections on Reimbursement and Access of Advanced Therapies

Background: The health economic literature has questioned the cost-effectiveness and affordability of advanced therapies, proposed adjustments to value assessment frameworks, and discussed the use of outcome-based managed entry agreements and staggered payments in the last few years. The aim of this manuscript is to conduct a critical reflection on assessment criteria and access conditions for reimbursement of advanced therapies. Methods: A narrative review of the peer-reviewed literature and grey literature was conducted in April 2021 by searching PubMed; Google Scholar; policy and legislative documents; websites of health technology assessment agencies, advanced therapy organisations, governmental advanced therapy innovation programmes, consultancy agencies; ISPOR conference abstracts and presentations. Results: Based on the available evidence, this manuscript argues that: a) advanced therapies can be cost-effective at high prices set by manufacturers; b) the economic evaluation framework adopted by many payers under-values these products; c) advanced therapies can be affordable and may not require spread payments; d) outcome-based managed entry agreements are theoretically attractive, but challenging in practice; e) the cost-effectiveness of advanced therapies depends on the outcome-based managed entry agreement and payment approach; f) there is a role for multinational collaborations to manage reimbursement and access of advanced therapies. Conclusions: This manuscript shows that there is no single approach to reimbursement and access of advanced therapies. Instead, we support a more tailored assessment of health economic aspects of advanced therapies, which considers the heterogeneity of these products and their target populations.
Beyond Genetics: The Role of Metabolism in Photoreceptor Survival, Development and Repair

Vision commences in the retina with rod and cone photoreceptors that detect and convert light to electrical signals. The irreversible loss of photoreceptors due to neurodegenerative disease leads to visual impairment and blindness. Interventions now in development include transplanting photoreceptors, committed photoreceptor precursors, or retinal pigment epithelial (RPE) cells, with the latter protecting photoreceptors from dying. However, introducing exogenous human cells in a clinical setting faces both regulatory and supply chain hurdles. Recent work has shown that abnormalities in central cell metabolism pathways are an underlying feature of most neurodegenerative disorders, including those in the retina. Reversal of key metabolic alterations to drive retinal repair thus represents a novel strategy to treat vision loss based on cell regeneration. Here, we review the connection between photoreceptor degeneration and alterations in cell metabolism, along with new insights into how metabolic reprogramming drives both retinal development and repair following damage. The potential impact of metabolic reprogramming on retinal regeneration is also discussed, specifically in the context of how metabolic switches drive both retinal development and the activation of retinal glial cells known as Müller glia. Müller glia display latent regenerative properties in teleost fish, however, their capacity to regenerate new photoreceptors has been lost in mammals. Thus, re-activating the regenerative properties of Müller glia in mammals represents an exciting new area that integrates research into developmental cues, central metabolism, disease mechanisms, and glial cell biology. In addition, we discuss this work in relation to the latest insights gleaned from other tissues (brain, muscle) and regenerative species (zebrafish).
Comparative Metabolic Analysis Reveals a Metabolic Switch in Mature, Hydrated, and Germinated Pollen in Arabidopsis thaliana

Pollen germination is an essential process for pollen tube growth, pollination, and therefore seed production in flowering plants, and it requires energy either from remobilization of stored carbon sources, such as lipids and starches, or from secreted exudates from the stigma. Transcriptome analysis from in vitro pollen germination previously showed that 14 GO terms, including metabolism and energy, were overrepresented in Arabidopsis. However, little is understood about global changes in carbohydrate and energy-related metabolites during the transition from mature pollen grain to hydrated pollen, a prerequisite to pollen germination, in most plants, including Arabidopsis. In this study, we investigated differential metabolic pathway enrichment among mature, hydrated, and germinated pollen using an untargeted metabolomic approach. Integration of publicly available transcriptome data with metabolomic data generated as a part of this study revealed starch and sucrose metabolism increased significantly during pollen hydration and germination. We analyzed in detail alterations in central metabolism, focusing on soluble carbohydrates, non-esterified fatty acids, glycerophospholipids, and glycerolipids. We found that several metabolites, including palmitic acid, oleic acid, linolenic acid, quercetin, luteolin/kaempferol, and γ-aminobutyric acid (GABA), were elevated in hydrated pollen, suggesting a potential role in activating pollen tube emergence. The metabolite levels of mature, hydrated, and germinated pollen, presented in this work provide insights on the molecular basis of pollen germination.
Brain-Derived Neurotrophic Factor Is an Important Therapeutic Factor in Mesenchymal Stem Cell Secretions for Treatment of Traumatic Peripheral Pelvic Injuries

Traumatic neuromuscular injury to the pudendal nerve and urethra during childbirth does not regenerate well and contributes to stress urinary incontinence in women. Mesenchymal stem cells (MSCs) can improve neuroregeneration via their secretions, or secretome, which includes brain-derived neurotrophic factor (BDNF). In this study, we investigated whether BDNF is a key factor in the secretome of MSCs for the facilitation of functional recovery following a dual simulated childbirth injury. BDNF knockdown (KD) MSCs were created using an anti-BDNF shRNA lentivirus vector. A scrambled sequence was used as a transduction control (scrambled). Cells were cultured for 24 h before media was concentrated 50x to create concentrated conditioned media (CCM) containing MSC secretome. CCM of unmanipulated MSCs was screened for high BDNF expression (high BDNF CCM). Concentrated control media (CM) was created by concentrating media not conditioned by cells. Female Sprague-Dawley rats underwent bilateral pudendal nerve crush and vaginal distension (Injury) or sham injury. One hour and 1 week after injury, sham injured rats received CM, and injured rats received CM, high BDNF CCM, KD CCM, or scrambled CCM (300 μl intraperitoneally). Three weeks after injury, rats underwent leak point pressure (LPP) and pudendal nerve sensory branch potential (PNSBP) recordings. The urethra and pudendal nerve were harvested for anatomical assessment. ANOVA followed by the Student-Newman-Keuls test determined significant differences between groups (p < 0.05). BDNF KD CCM had significantly decreased BDNF concentration compared to scrambled CCM, while the concentration in high BDNF CCM was significantly increased. LPP was significantly decreased in CM and KD CCM treated animals compared to sham injury, but not with scrambled or high BDNF CCM. PNSBP firing rate showed a significant decrease with CM treatment compared to sham injury. Neuromuscular junctions in the urethral sphincter in KD CCM, scrambled CCM, and high BDNF CCM were healthier than CM treated rats. While anatomical and nerve function tests demonstrate regeneration of the pudendal nerve with any CCM treatment, LPP results suggest it takes longer to recover continence with reduced BDNF in CCM. BDNF in MSC CCM is an important factor for the acceleration of recovery from a dual nerve and muscle injury.
The Role of Plasma Membrane Sodium/Hydrogen Exchangers in Gastrointestinal Functions: Proliferation and Differentiation, Fluid/Electrolyte Transport and Barrier Integrity

The five plasma membrane Na+/H+ exchanger (NHE) isoforms in the gastrointestinal tract are characterized by distinct cellular localization, tissue distribution, inhibitor sensitivities, and physiological regulation. NHE1 (Slc9a1) is ubiquitously expressed along the gastrointestinal tract in the basolateral membrane of enterocytes, but so far, an exclusive role for NHE1 in enterocyte physiology has remained elusive. NHE2 (Slc9a2) and NHE8 (Slc9a8) are apically expressed isoforms with ubiquitous distribution along the colonic crypt axis. They are involved in pHi regulation of intestinal epithelial cells. Combined use of a knockout mouse model, intestinal organoid technology, and specific inhibitors revealed previously unrecognized actions of NHE2 and NHE8 in enterocyte proliferation and differentiation. NHE3 (Slc9a3), expressed in the apical membrane of differentiated intestinal epithelial cells, functions as the predominant nutrient-independent Na+ absorptive mechanism in the gut. The new selective NHE3 inhibitor (Tenapanor) allowed discovery of novel pathophysiological and drug-targetable NHE3 functions in cystic-fibrosis associated intestinal obstructions. NHE4, expressed in the basolateral membrane of parietal cells, is essential for parietal cell integrity and acid secretory function, through its role in cell volume regulation. This review focuses on the expression, regulation and activity of the five plasma membrane Na+/H+ exchangers in the gastrointestinal tract, emphasizing their role in maintaining intestinal homeostasis, or their impact on disease pathogenesis. We point to major open questions in identifying NHE interacting partners in central cellular pathways and processes and the necessity of determining their physiological role in a system where their endogenous expression/activity is maintained, such as organoids derived from different parts of the gastrointestinal tract.
Inner Nuclear Membrane Protein, SUN1, is Required for Cytoskeletal Force Generation and Focal Adhesion Maturation

The linker of nucleoskeleton and cytoskeleton (LINC) complex is composed of the inner nuclear membrane-spanning SUN proteins and the outer nuclear membrane-spanning nesprin proteins. The LINC complex physically connects the nucleus and plasma membrane via the actin cytoskeleton to perform diverse functions including mechanotransduction from the extracellular environment to the nucleus. Mammalian somatic cells express two principal SUN proteins, namely SUN1 and SUN2. We have previously reported that SUN1, but not SUN2, is essential for directional cell migration; however, the underlying mechanism remains elusive. Because the balance between adhesive force and traction force is critical for cell migration, in the present study, we focused on focal adhesions (FAs) and the actin cytoskeleton. We observed that siRNA-mediated SUN1 depletion did not affect the recruitment of integrin β1, one of the ubiquitously expressed focal adhesion molecules, to the plasma membrane. Consistently, SUN1-depleted cells normally adhered to extracellular matrix proteins, including collagen, fibronectin, laminin, and vitronectin. In contrast, SUN1 depletion reduced the activation of integrin β1. Strikingly, the depletion of SUN1 interfered with the incorporation of vinculin into the focal adhesions, whereas no significant differences in the expression of vinculin were observed between wild-type and SUN1-depleted cells. In addition, SUN1 depletion suppressed the recruitment of zyxin to nascent focal adhesions. These data indicate that SUN1 is involved in the maturation of focal adhesions. Moreover, disruption of the SUN1-containing LINC complex abrogates the actin cytoskeleton and generation of intracellular traction force, despite the presence of SUN2. Thus, a physical link between the nucleus and cytoskeleton through SUN1 is required for the proper organization of actin, thereby suppressing the incorporation of vinculin and zyxin into focal adhesions and the activation of integrin β1, both of which are dependent on traction force. This study provides insights into a previously unappreciated signaling pathway from the nucleus to the cytoskeleton, which is in the opposite direction to the well-known mechanotransduction pathways from the extracellular matrix to the nucleus.
Combining SBFL with Mutation Testing: Challenges of a Practical Approach

: Research on fault localization techniques focuses on their efficiency and cost reduction. Spectra-Based Fault Localization (SBFL) counts to the mostly used methods. Hybrid approaches have been shown to be beneficial. We discuss the challenges of a revised approach combining SBFL with mutation testing. Certain unconvinced issues of mutation testing have been identified, and a practical framework has been prepared to evaluate different variants of the approach. Building a new repository with faulty programs has been launched in order to study the approach not only on the commonly used legacy programs, but also on faulty programs of more contemporary versions of the Java language and unit tests.
Concepts for Conceptual Modelling of an IoT Application

: The design of IoT applications has been considered as a specification of devices and their inter-connection. In terms of the Systems Development Life Cycle, this addresses the stage of implementation design. Without explicitly modelling the application problem, this could lead to ill-fitting devices, missing processing of data and inappropriate communication choices. To obviate this, the upstream stage of conceptual modelling is explored in this paper. By, analogy with Information Systems, IoT applications are looked upon as Information Systems of Things, ISoT and the conceptual model for an ISoT is referred to as the Conceptual Model of Things, CMoT. It is shown that agent-orientation is more appropriate to ISoT than object-orientation. Agents have aspects that are its measurable properties. The proposals are illustrated with an example.
Process Mining to Discover the Global Process from its Fragments' Executions

: Process analysis to improve performance and detect anomalies is important for process management. However, such an analysis requires a global process model that is sometimes hard to get, especially for complex processes involving various teams. This is also an obstacle for BAPE (Bottom-up Artifact-centric Process Environment) , an artifact-centric process management environment that allows splitting a process into several fragments which are separately modeled and enacted by different actors. Thus, the knowledge about the whole process is distributed over the involved teams and an overview on the complete process is missing. This paper presents the integration of process mining into BAPE in order to construct the overall process model from the execution data of process fragments.
Thermal assembly of polysilicon microstructures

Thermal microassembly techniques are demonstrated which extend the capabilities of surface micromachining technology. Bridges are cleanly severed by application of a single 30 mA, 100 mu s pulse. Delicately suspended microstructures are supported by tee bridges during wet etching of phosphosilicate glass, in order to reduce yield loss due to breakage and stiction to the substrate during rinsing and drying. The supports are subsequently severed to release the structure. Mechanical contacts are welded together with 30 mA of current, with a microprobe used to force together the contacts. Qualitative destructive tests indicate that the welded contact is robust. Electrostatic force applied by interdigitated electrodes is insufficient to initiate welding of polysilicon, possibly because the native oxide film must be penetrated to allow current to pass through the contact. Current vs. voltage measurements of polysilicon microbridges agree well with a first-order model, in which heat conduction and convection in air are neglected. Values of the voltage needed to melt the bridge are found to vary with bridge dimensions, because the bridge anchors are not perfect heat sinks. <<ETX>>
Improvement Metaheuristic for the Time Dependent Vehicle Routing Problem Based on Simulated Annealing

The time dependent vehicle routing problem (TDVRP) is defined as a vehicle fleet of fixed capacities serves customers of fixed demands from a central depot with consideration of road networks conditions. The travel time between two customers or between customer and the depot depends on the distance of the two points and time of a day. A mathematical model is formulated for the TDVRP problem and a simulated annealing (SA) based improvement method is proposed for solving it. The main objective is to minimize the number of vehicles and the second objective is to minimize the total travel distance of the vehicles. The proposed approach was tested on the 56 test problems with 100 customers from Figliozzi’s benchmark, and results show that the improvement metaheuristic could get better solutions than Figliozzi’s algorithm in the different time dependent speeds function within an accepted computational time.
Reflection properties of mushroom-type surfaces wi th loaded vias

In this paper we study the reflection phase characteristics of mushroom-type surfaces with impedance loadings (as lumped loads) at the junction of vias and metallic elements (patches and ground plane). The analysis is carried out using the nonlocal homogenization model for the mushroom structure with a generalized additional boundary condition for loaded vias. It is observed that the reflection characteristics obtained with the homogenization model strongly depend on the type of the load (inductive or capacitive), and are in a good agreement with the full-wave simulation results.
Poster: PhishLex: A Proactive Zero-Day Phishing Defence Mechanism using URL Lexical Features

—Google reports that 68% of all Phishing URLs that are blocked by them are zero-day phishing attacks that remain undetected using traditional blacklist-based approaches. Machine learning-based (ML) techniques can improve the accuracy of detecting zero-day attacks. However, a key limitation of current ML-based approaches is the lack of quality datasets to train the ML models. Existing publicly available phishing datasets are outdated, limited in size and often depend on third-party services. The latency in third-party look-ups and delay in registering potential phishing URLs in blacklist databases are prohibitive for anti-phishing solutions to be used in standalone or real-time detection scenarios. To address these issues, we have designed new lexical features, created a new dataset using the latest Phishing URLs, and trained a predictive model (PhishLex). Experimental evaluation demonstrates that PhishLex outperforms the state-of-the-art techniques by achieving higher accuracy (97%) and lower false negative rate (0.27%). Furthermore, we have tested PhishLex on zero-day phishing attacks with rolling validations against Google Safe Browsing. Our experiments show 95% phishing detection rate can be achieved for zero-day phishing. We have published the PhishLexURL phishing dataset with 114 lexical URL features on Github which will help researchers to train their model without relying on third-party look-ups.
Developments in New Fluid Rotational Seismometers: Instrument Performance and Future Directions

In this article we describe prototype designs and tests for low‐cost rotational medium‐ and strong‐motion seismometers using three types of proof mass (two liquid and one solid) and a number of transducer configurations. This article describes the third set of designs and tests in our development program. The details of our results for most of these are in the Ⓔ electronic supplement to this article, whereas here we concentrate on three of the most promising and representative design combinations. Most of our results pertain to sensors with water or silicon oil as the proof mass, though we also tested a torsion‐bar design with a solid proof mass. We find that most mass–transducer combinations lead to output proportional to rotational acceleration, with varying degrees of fidelity. Most combinations we tested can be dismissed from further development for reasons of performance or inconvenience during analysis of acceleration response (compare with Ⓔ electronic supplement). In this article, we describe three of the more promising combinations, one each for the three types of response functions we measured. Of these three, one mass–transducer combination in particular (a hinged sensing element and capacitive transduction) has output voltage closely proportional to rotational displacement (angle) over a wide frequency range; such displacement proportionality obviates two of the integration steps normally required to solve for continuum single‐point motions or correct for tilt‐induced errors in horizontal translational sensors. Thus, although we illustrate two other designs of some promise, we propose a new design that follows this displacement‐proportional path while increasing the device’s sensitivity to on‐axis rotations, improving its manufacturing ease and lowering its sensitivity to translational motions. Online Material: Results and related material for mass–transceiver combinations, drawings and photographs of liquid proof masses, amplitude and phase transfer functions, clip and linearity tests, and noise plots.
Volume parametrization quantization for hexahedral meshing

Developments in the field of parametrization-based quad mesh generation on surfaces have been impactful over the past decade. In this context, an important advance has been the replacement of error-prone rounding in the generation of integer-grid maps, by robust quantization methods. In parallel, parametrization-based hex mesh generation for volumes has been advanced. In this volumetric context, however, the state-of-the-art still relies on fragile rounding, not rarely producing defective meshes, especially when targeting a coarse mesh resolution. We present a method to robustly quantize volume parametrizations, i.e., to determine guaranteed valid choices of integers for 3D integer-grid maps. Inspired by the 2D case, we base our construction on a non-conforming cell decomposition of the volume, a 3D analogue of a T-mesh. In particular, we leverage the motorcycle complex, a recent generalization of the motorcycle graph, for this purpose. Integer values are expressed in a differential manner on the edges of this complex, enabling the efficient formulation of the conditions required to strictly prevent forcing the map into degeneration. Applying our method in the context of hexahedral meshing, we demonstrate that hexahedral meshes can be generated with significantly improved flexibility.