Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this ...STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US.
STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes vg/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed).
From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 67% of 33), upper respiratory infection (11 33%), and increased alanine aminotransferase (nine 27%). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study.
STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline.
Novartis Gene Therapies.
Fuel cell durability being one of the technical bolts regarding the technology industrialization in the automotive sector, durability improvement methods are particularly relevant. Fault tolerant ...control process enables to increase fuel cell durability by detecting and correcting fuel cell faults in real time. Fuel cells are prone to faults because they are very sensitive to operating conditions. In vehicle application, fault risk is exacerbated as dynamic conditions are often encountered. Dynamic conditions make the fuel cell control harder because it impacts reactants supply, thermal management, water management… If not corrected, those faults degrade the fuel cell and reduce its remaining useful lifetime.
Fault tolerant control consists in diagnosing faults, then taking corrective actions to resolve those faults. This article treats the diagnosis part, which consists in detecting and identifying faults, in vehicle application. Vehicle applications engender several constraints as the reduced cost, the hydrogen usage and computation limitations or the safety regulations for algorithms implementation. Three steps are necessary for diagnosis: real time measurements, useful information extraction, and classification. In this article, a state-of-the-art of methods for each of these steps independently is presented. In the last section, useful explanations to convert offline diagnosis algorithm into an embedded diagnosis tool are provided.
•Review about diagnosis tools for vehicle applications.•The combination of fuel cell diagnosis and control can improve fuel cell durability.•Model based and non-model-based diagnosis methods are presented.•The embeddability of diagnosis tools with vehicle constraints are specified.
Background and purpose
Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in ...tertiary‐care centers or enrolled in any disease registry.
Methods
We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type.
Results
The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb’s angle >50° (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p > 0.05).
Conclusions
Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes.
Percentages of regularly followed patients and newcomers.
The proton exchange membrane fuel cell (PEMFC) is an emission-free alternative to the internal combustion engine. Post-assembly, a PEMFC must be “activated’, to elevate and stabilize its performance ...to a reproducible threshold value. This procedure is costly, time-consuming, and not suited for mass-production. This paper provides a detailed review of the break-in physical principles, activation procedures and characterization methods. First, all sparse knowledge from the literature is translated into a set of activation mechanisms. Activating a cell mainly alters the membrane electrode assembly morphology (e.g. catalyst layer porosity, catalyst size, shape and activity, polymer chain orientation). Second, an in-depth analysis off all break-in methods is provided. Cell components can be pre-activated using steam, acid, plasma or through compression. Dynamic, high temperature/pressure and supersaturated operation promote break-in kinetics. Generating oxidizing and reducing conditions is essential, and is achievable by short circuit, Cyclic Voltammetry, cathode starvation or reactant switch. Uniform activation over the cell surface is obtained with gas flow direction reversal or hydrogen pumping. Compression cycles minimize PEMFC contact resistances. Finally, deficiencies of conventional break-in characterization methods (to measure cell performance and impact on durability) are highlighted. Better reproducibility is achievable using advanced electrochemical characterization, post-mortem and cell output species analysis.
•Each morphological change associated to PEM fuel cell break-in is detailed.•All ex-situ and in-situ activation methodologies are reviewed.•Break-in characterization methods are studied, and advanced solutions are proposed.•A critical analysis of the current “end-of-break-in” criteria is provided.
This paper presents the results of a sensibility analysis applied to a Reservoir Computing method. The method ANOVA has been chosen in order to analyse the influence of the different parameters of a ...new kind of Neural Network paradigm: the Echo State Network. The three sets of parameters used correspond to the more influential parameters in the case of the fuel cell voltage ageing forecasting. The simulations are then compared with experimental data obtained after a 1700 h long duration test. The results obtained, with a Mean Average Percentage Error of less than 5%, prove that Echo State Network is an interesting and promising tool.
In this paper a dynamic membrane electrode assembly water transport model, based on the Finite Volume Method, is presented. The purpose of this paper is to provide an accessible and reproductible ...model capable of real time simulation. To this aim, a detailed explanation is provided regarding the equations and methods used to compute the physical-based fuel cell model. Additionally, the model is purposely developed using basic code (on Matlab™), to not be limited to a single programming language. Two phase water transport through multi-gaseous porous media (electrodes), interfacial transport, as well as diffusion, convection, and electro-osmosis within the polymer are considered. The main novelty relies in the restructuring of all equations into a single implicit system, which can iteratively be resolved through LU decomposition. This computationally efficient method allows the model to be capable of real-time simulation, by displaying the membrane water content profile evolution on a 3D figure. For nominal PEMFC operating conditions, a dry membrane reaches 35% of its final water concentration value after 2 s, and fully converges after 20 s. The final water content profile displays an 18% gradient (9 and 11 molecules per sulfonic acid sites on the anode and cathode sides, respectively). To calibrate and validate this model, mass transfer (flowmeter) and electrical (ohmmeter) methods have been applied.
•Dynamic membrane electrode assembly water transport model, based on finite difference method.•Water transport equations and resolution process detailed, to aim for model reproducibility.•Restructuring of water transport equations into implicit equation system.•Iterative equation system resolution through LU decomposition, allowing for real time simulation.•3-dimensional figures of Nafion™ hydration profile, to study its behavior.
Fuel Cells prognostics using echo state network Morando, S.; Jemei, S.; Gouriveau, R. ...
IECON 2013 - 39th Annual Conference of the IEEE Industrial Electronics Society,
2013-Nov.
Conference Proceeding
Odprti dostop
One remaining technological bottleneck to develop industrial Fuel Cell (FC) applications resides in the system limited useful lifetime. Consequently, it is important to develop failure diagnostic and ...prognostic tools enabling the optimization of the FC. Among all the existing prognostics approaches, datamining methods such as artificial neural networks aim at estimating the process' behavior without huge knowledge about the underlying physical phenomena. Nevertheless, this kind of approach needs huge learning dataset. Also, the deployment of such an approach can be long (trial and error method), which represents a real problem for industrial applications where real-time complying algorithms must be developed. According to this, the aim of this paper is to study the application of a reservoir computing tool (the Echo State Network) as a prognostics system enabling the estimation of the Remaining Useful Life of a Proton Exchange Membrane Fuel Cell. Developments emphasize on the prediction of the mean voltage cells of a degrading FC. Accuracy and time consumption of the approach are studied, as well as sensitivity of several parameters of the ESN. Results appear to be very promising.
Proton exchange membrane fuel cells (PEMFC) are extremely promising devices. Nevertheless some technological constraints concerning system durability and reliability costs, still limit their ...large-scale production. In this framework, lifetime prediction and durability enhancement studies are mainly concerned. To solve this issue, methods based on Prognostic and Health Management (PHM) are developed. It is worth noting that these methods usually require to establish a consistent database concerning the system ageing referring to specific mission profiles. To this purpose, long-term tests are commonly performed. Among different applications, this paper will focus on two micro-cogeneration (μ-CHP) durability tests, based on the same load demand. The first test is realized in 1000 h while the second one is reduced to 500 h resulting in a compressed profile. We observed that the respective global voltage degradation rates are similar. Consequently a reflection is proposed to support accelerated tests protocol development.
•The ageing effects induced by a real load profile are taking into account by making experimental tests.•The influence of the steady state conditions durations, OCV and sudden load variations are analyzed.•The effects of the long-term test duration reduction on voltage decay are analyzed too.•New methods can be proposed to reduce long duration tests by increasing the real load cycle frequency.•Results with experimental data verify the effectiveness of the method.
Background: While bone marrow derived mesenchymal stem cells (MSC) have been proposed for brain repair due to their multipotentiality, recent experimental data challenged their transdifferentiation ...capacity and suggested that they could modulate pathogenic immune responses. Objective: The aim of this study was to address the in vivo effects of MSC on neural cells inside the inflamed central nervous system (CNS) as well as on key T cell subsets infiltrating both in the lymphoid organs and in the CNS. Methods: We evaluated the MSC-mediated effects in MOG-induced experimental autoimmune encephalomyelitis (EAE) by immunological, histological and molecular analysis of CNS specimens. Results: We showed that irrespective of the lack of MSC neural differentiation, MSC decreased axonal sufferance through the inhibition of astrogliosis and microglia activation and the upregulation of genes involved in the BMP and Notch pathways. In addition, upon isolation of T cells from the brain of EAE-affected mice we detected an increase of CD4+ FoxP3 + T regulatory cells and a decrease of IL-17 producing T cells compared with control EAE mice. Conclusions: Thus MSC may represent a valuable approach for the treatment of autoimmune diseases such as multiple sclerosis where tissue degeneration is associated with inflammation.
The Hydrogen energy vector is one of the possible solutions to overcome future energy crisis announced by the International Energy Agency. However, various bottleneck, whether technological or ...societal, slow the industrial interest for this technology and therefore the mass production of fuel cells. Among these locks that may be mentioned one relating to the still limited useful lifetime of the fuel cells. To improve this lifetime, one of the existing approaches is to use the discipline of PHM (for Prognostics and Health Management). This discipline aims to improve the efficiency of control and maintenance operations on the system by using diagnostic or prognostics algorithms. This article covers the prognostics aspect of PHM applied to a PEMFC using an algorithm based on a tool from the reservoir computing discipline to predict the Remaining Useful Lifetime.
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