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.
In daily practice as well as in clinical trials, patients with spinal muscular atrophy (SMA) treated by a disease-modifying therapy (DMT) are classified as responders (R) or non-responders (NR) ...according to the fact that they reach or do not reach a specific level of improvement on validated functional scales. However, small functional improvements or even stabilization not captured by current outcome measures may appear inexistant or non-significant, although they can have a significant impact on a patient's daily life. The aim of this international multicenter study is to investigate the treatment benefit after 15 months of Spinraza in post-symptomatically treated patients measured by current functional scales compared with individualised aspects of patients’ perception that are not measured in the functional scales. We included patients with SMA type I, II and III and established an order of priority for the functional scales according to each SMA type and age at treatment initiation based on the literature (i.e., patients with SMA II from 24 months: HFMSE-MFM-RULM). Patients were divided into three groups whether they did show clinically significant improvement (i.e., > 4 points on the CHOP Intend), non-clinically significant improvement (i.e., < 4 points on the CHOP Intend) or no improvement (i.e., 0 points or loss on the CHOP Intend) 15 months after treatment initiation. Finally, we designed and conducted a scoring system based on the Clinical Global Impression-Improvement scale, which uses 7 ratings scored from very much improved to very much worse on 22 questions targeting important aspects and tasks in daily life of patients with SMA (i.e., balance, fatigability, swallowing) and which allows the patient to estimate whether a change is perceived after 12 months of stable treatment. This quantification of approximately 100 patients’ impressions across the different groups collected from 7 sites based in Europe and USA will be presented.
This work deals with the influence of biaxial orientation on the mechanical behavior of Polylactide (PLA) films. Comparisons between a crystallizable grade and a non-crystallizable one have been made ...in order to separate the effect of macromolecular orientation from the potential influence of the crystalline phase induced during the thermomechanical treatment. While unstretched PLAs exhibited brittle behavior at room temperature, it was observed for both types of PLA the strains at break for biaxially drawn films were remarkably enhanced to values over 100%. This study highlights for the first time, in the case of PLA, that a critical molecular chain orientation of the amorphous phase is the necessary condition to induce a ductile behavior. In-situ small-angle X-ray scattering (SAXS) experiments and post-mortem microscopic observations have revealed that it is a change of elementary plastic deformation mechanisms that is at the origin of this Brittle-to-Ductile (B-D) transition.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
One of the most drastic diseases causing economic losses in sunflower crops is fusarium root rot caused by Fusarium solani. Plant extracts and ionizing radiation provide alternative environmentally ...safe control agents that have a significant role in controlling and overcoming this fungal plant pathogen.
In the present study, the effect of different concentrations of aqueous Chenopodium album extract (2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 and 6.0%) and gamma radiation at a dose of 6 Gy were examined for their efficacy in inducing resistance of sunflower plants against fusarium root rot caused by F. solani MG‐3 by evaluation of some physiological and biochemical parameters of infected and healthy plants under greenhouse conditions.
The pre‐treatment of sunflower seeds with 6% C. album extract and 6 Gy gamma radiation reduced fusarium incidence from 47.49% to 28.25%. Also, nucleic acid content, ascorbic acid, α‐tocopherol, anthocyanin, total flavonoids, proline, glycine betaine and lipid components significantly increased in irradiated infected plants treated with C. album extract, while H2O2 content and lipid peroxidation markedly decreased as compared with healthy control plants. Moreover, treatment with gamma radiation reduced the amount of unsaturated fatty acids through accumulation of saturated fatty acids compared with non‐irradiated plants; treatment with C. album extract also enhanced the content of unsaturated fatty acids, with a noticeable decrease in saturated fatty acid content.
Hence, C. album extract and gamma radiation can be used to enhance biological control of fusarium root rot of sunflower plants.
Application of ecofriendly dual treatment of Chenopodium album extract (6.0 %) and gamma rays (6 Gy) could alert sunflower plant's resistance to root rot disease caused by Fusarium solani under greenhouse conditions.
The mechanical behavior of Poly(ethylene 2,5-furandicarboxylate) upon biaxial stretching and the associated strain-induced structural evolution is studied in the light of its molecular weight. ...Besides it is shown that the increase of molecular weight favors strain-induced crystallization (SIC) and that SIC in PEF occurs when a critical molecular orientation ratio is achieved. The earlier occurrence of SIC in the case of the higher macromolecular weight is explained by the faster macromolecular orientation due to a more robust entanglement network.
Regarding the mechanical behavior, it appears that a strain-hardening stage is observed whatever the molecular weight, this stage originates from both macromolecular orientation and formation of crystals upon stretching. Finally, it is shown that biaxial orientation (BO) has a positive effect on both oxygen barrier properties and mechanical properties. Particularly it was highlighted that, while as-cast PEF is brittle, BO PEF films are ductile when a critical biaxial draw ratio is achieved.
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•Molecular weight influence the mechanical behavior of PEF upon biaxial stretching.•The increase of the molecular weight favors strain-induced crystallization.•The mechanical behavior is driven by macromolecular orientation.•Biaxial stretching induced a brittle to ductile transition.•Macromolecular orientation and crystallinity improves water vapor barrier properties.
Summary
Reasons for performing study: Endoscopic scoring of airway mucus quantity and quality has not been critically assessed.
Objectives: To evaluate mucus scores for 1) observer‐ and horse‐related ...variance and 2) association with inflammation, mucus viscoelasticity and measured volume.
Methods: Variance of scoring within and between observers and over time within horses were determined for airway mucus accumulation, apparent viscosity, localisation and colour, and correlations of mucus accumulation scores with neutrophil ratios in secretions. The relationship of accumulation score to measured volumes of ‘artificial mucus’ was investigated. Correlations of mucus accumulation, apparent viscosity and colour scores with measured viscoelasticity were tested. Viscoelasticity was compared between tracheal secretion samples collected ventrally and dorsally.
Results: Mucus accumulation scoring showed excellent interobserver agreement and moderate horse‐related variance, was related to measured volumes of ‘artificial mucus’, and correlated well with neutrophilic airway inflammation. Scores of mucus viscosity, colour and localisation showed high observer‐related variance. Mucus accumulation, apparent viscosity and colour scores did not correlate with measured tracheal mucus viscoelasticity, but dorsally‐localised mucus showed 2‐fold higher measured viscoelasticity than ventrally‐localised samples.
Conclusions: Mucus accumulation scores are a reproducible measure of mucus volumes in the trachea.
Potential relevance: Endoscopic scoring of mucus accumulation is a reliable clinical and research tool. In contrast, apparent viscosity, localisation and colour scores should be interpreted with caution.
Recurrent airway obstruction (RAO) is a common condition in stabled horses characterised by small airway inflammation, airway neutrophilia and obstruction following exposure of susceptible horses to ...mouldy hay and straw and is thus regarded as a hypersensitivity reaction to mould spores. However, the role of IgE-mediated reactions in RAO remains unclear.
The aim of the study was to investigate with a serological IgE ELISA test (Allercept™), an
in vitro sulfidoleukotriene (sLT) release assay (CAST
®) and with intradermal testing (IDT) whether serum IgE and IgE-mediated reactions against various mould, mite and pollen extracts are associated with RAO. IDT reactions were evaluated at different times in order to detect IgE-mediated immediate type reactions (type I hypersensitivity reactions, 0.5–1
h), immune complex-mediated late type reactions (type III reactions, 4–10
h) and cell-mediated delayed type reactions (type IV hypersensitivity reactions 24–48
h).
In the serological test, overall the control horses displayed more positive reactions than the RAO-affected horses but the difference was not significant. Comparison of the measured IgE levels showed that the RAO-affected horses had slightly higher IgE levels against
Aspergillus fumigatus than controls (35 and 16
AU, respectively,
p
<
0.05), but all values were below the cut off (150
AU) of the test. In the sLT release assay, seven positive reactions were observed in the RAO-affected horses and four in the controls but this difference was not significant.
A significantly higher proportion of late type IDT reactions was observed in RAO-affected horses compared to controls (25 of 238 possible reactions versus 12 of 238 possible reactions, respectively,
p
<
0.05). Interestingly, four RAO-affected but none of the control horses reacted with the recombinant mould allergen
A. fumigatus 8 (rAsp f 8,
p
<
0.05), but only late phase and delayed type reactions were observed.
In all three tests the majority of the positive reactions was observed with the mite extracts (64%, 74% and 88% of all positive reactions, respectively) but none of the tests showed a significant difference between RAO-affected and control animals. Our findings do not support that IgE-mediated reactions are important in the pathogenesis of RAO. Further studies are needed to investigate whether sensitisation to mite allergens is of clinical relevance in the horse and to understand the role of immune reactions against rAsp f 8.
ObjectiveTo assess the impact of changes in use of care and implementation of hospital reorganisations spurred by the COVID-19 pandemic (first wave) on the acute management times of patients who had ...a stroke and ST-segment elevation myocardial infarction (STEMI).DesignTwo cohorts of patients who had an STEMI and stroke in the Aquitaine Cardio-Neuro-Vascular (CNV) registry.Setting6 emergency medical services, 30 emergency units (EUs), 14 hospitalisation units and 11 cathlabs in the Aquitaine region.ParticipantsThis study involved 9218 patients (6436 patients who had a stroke and 2782 patients who had an STEMI) in the CNV Registry from January 2019 to August 2020.MethodHospital reorganisations, retrieved in a scoping review, were collected from heads of hospital departments. Other data were from the CNV Registry. Associations between reorganisations, use of care and care management times were analysed using multivariate linear regression mixed models. Interaction terms between use-of-care variables and period (pre-wave, per-wave and post-wave) were introduced.Main outcome measuresSTEMI cohort, first medical contact-to-procedure time; stroke cohort, EU admission-to-imaging time.ResultsPer-wave period management times deteriorated for stroke but were maintained for STEMI. Per-wave changes in use of care did not affect STEMI management. No association was found between reorganisations and stroke management times. In the STEMI cohort, the implementation of systematic testing at admission was associated with a 41% increase in care management time (exp=1.409, 95% CI 1.075 to 1.848, p=0.013). Implementation of plan blanc, which concentrated resources in emergency activities, was associated with a 19% decrease in management time (exp=0.801, 95% CI 0.639 to 1.023, p=0.077).ConclusionsThe pandemic did not markedly alter the functioning of the emergency network. Although stroke patient management deteriorated, the resilience of the STEMI pathway was linked to its stronger structuring. Transversal reorganisations, aiming at concentrating resources on emergency care, contributed to maintenance of the quality of care.Trial registration numberNCT04979208.
Objectifs Evaluer les performances de l’IRM hypophysaire pour la détection des microadénomes corticotropes, en précisant l’impact de l’expertise neuroradiologique et des progrès technologiques. ...Matériel & Méthodes Les IRM hypophysaires préopératoires de 128 patients, opérés pour maladie de Cushing dans notre institution entre 1983 et 2010, ont été confrontées à la localisation réelle des microadénomes corticotropes. Quatre-vingts IRM ont bénéficié d’une deuxième lecture en aveugle par 2 neuroradiologues experts. Les performances des IRM réalisées avant 2000 étaient comparées à celles des IRM réalisées après 2000. Une étude des propriétés intrinsèques et l’analyse de concordance entre la localisation IRM et réelle ont été réalisées en considérant les IRM douteuses soit comme négatives (d - ), soit comme positives (d + ). Résultats La sensibilité de l’IRM en lecture experte est 66.1 % (d - ) et 83.9 % (d + ), contre 53.2 % (d - ) et 67.7 % (d + ) en lecture initiale. La spécificité en lecture experte 66.7 % (d - ) et 38.9 %(d + ), contre 61,1 % (d - ) et 33.3 % (d + ) en lecture initiale. La concordance anatomoradiochirurgicale est à 66,3 %, coefficient kappa de Cohen 0,53 en lecture experte, contre 52.5 %, kappa à 0,34 en lecture initiale. La localisation de l’adénome est latérale dans 85 % des cas, le signe indirect le plus fréquent est la déviation de la tige pituitaire (28 %). Il n’existe pas de différence de concordance entre les IRM réalisées avant ou après 2000 (kappa 0,59 vs 0,53). Conclusion L’expertise neuroradiologique permet un gain de sensibilité de l’IRM sans perte de spécificité, alors qu’il n’est pas possible de démontrer un gain diagnostique lié au progrès technologique.
Abstract
BACKGROUND: Understanding the pathophysiologic mechanism of intracranial aneurysm (IA) formation is a prerequisite to assess the potential risk of rupture. Nowadays, there are neither ...reliable biomarkers nor diagnostic tools to predict the formation or the evolution of IA. Increasing evidence suggests a genetic component of IA but genetics studies have failed to identify genetic variation causally related to IA.
OBJECTIVE: To develop diagnostic and predictive tools for the risk of IA formation and rupture.
METHODS: The French ICAN project is a noninterventional nationwide and multicentric research program. Each typical IA of bifurcation will be included. For familial forms, further IA screening will be applied among first-degree relatives. By accurate phenotype description with high-throughput genetic screening, we aim to identify new genes involved in IA. These potential genetic markers will be tested in large groups of patients. Any relevant pathway identified will be further explored in a large cohort of sporadic carriers of IA, which will be well documented with clinical, biological, and imaging data.
EXPECTED OUTCOMES: Discovering genetic risk factors, better understanding the pathophysiology, and identifying molecular mechanisms responsible for IA formation will be essential bases for the development of biomarkers and identification of therapeutic targets.
DISCUSSION: Our protocol has many assets. A nationwide recruitment allows for the inclusion of large pedigrees with familial forms of IA. It will combine accurate phenotyping and comprehensive imaging with high-throughput genetic screening. Last, it will enable exploiting metadata to explore new pathophysiological pathways of interest by crossing clinical, genetic, biological, and imaging information.
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