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| 3. |
- Heard, J. M., et al.
(författare)
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Availability, accessibility and delivery to patients of the 28 orphan medicines approved by the European Medicine Agency for hereditary metabolic diseases in the MetabERN network
- 2020
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The European Medicine Agency granted marketing approval to 164 orphan medicinal products for rare diseases, among which 28 products intended for the treatment of hereditary metabolic diseases. Taking advantage of its privileged connection with 69 healthcare centres of excellence in this field, MetabERN, the European Reference Network for hereditary metabolic diseases, performed a survey asking health care providers from 18 European countries whether these products are available on the market, reimbursed and therefore accessible for prescription, and actually delivered in their centre. Results Responses received from 52 centres (75%) concerned the design of treatment plans, the access to marketed products, and the barriers to delivery. Treatment options are always discussed with patients, who are often involved in their treatment plan. Most products (26/28) are available in most countries (15/18). Among the 15 broadly accessible products (88.5% of the centres), 9 are delivered to most patients (mean 70.1%), and the others to only few (16.5%). Among the 10 less accessible products (40.2% of the centres), 6 are delivered to many patients (66.7%), and 4 are rarely used (6.3%). Information was missing for 3 products. Delay between prescription and delivery is on average one month. Beside the lack of availability or accessibility, the most frequent reasons for not prescribing a treatment are patients' clinical status, characteristic, and personal choice. Conclusions Data collected from health care providers in the MetabERN network indicate that two-third of the orphan medicines approved by EMA for the treatment of hereditary metabolic diseases are accessible to treating patients, although often less than one-half of the patients with the relevant conditions actually received the approved product to treat their disease. Thus, in spite of the remarkable achievement of many products, patients concerned by EMA-approved orphan medicinal products have persistent unmet needs, which deserve consideration. The enormous investments made by the companies to develop products, and the high financial burden for the Member States to purchase these products emphasize the importance of a scrupulous appreciation of treatment value involving all stakeholders at early stage of development, before marketing authorization, and during follow up.
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| 4. |
- Maas, R. R., et al.
(författare)
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Progressive deafness–dystonia due to SERAC1 mutations: A study of 67 cases
- 2017
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 82:6, s. 1004-1015
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Tidskriftsartikel (refereegranskat)abstract
- Objective: 3-Methylglutaconic aciduria, dystonia–deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. Methods: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. Results: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days–33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic “putaminal eye” was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. Interpretation: MEGDHEL syndrome is a progressive deafness–dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004–1015. © 2017 American Neurological Association
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| 5. |
- van Houten, C. B., et al.
(författare)
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Antibiotic misuse in respiratory tract infections in children and adultsa prospective, multicentre study (TAILORED Treatment)
- 2019
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Ingår i: European Journal of Clinical Microbiology & Infectious Diseases. - : Springer Science and Business Media LLC. - 0934-9723 .- 1435-4373. ; 38:3, s. 505-514
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Tidskriftsartikel (refereegranskat)abstract
- Respiratory tract infections (RTI) are more commonly caused by viral pathogens in children than in adults. Surprisingly, little is known about antibiotic use in children as compared to adults with RTI. This prospective study aimed to determine antibiotic misuse in children and adults with RTI, using an expert panel reference standard, in order to prioritise the target age population for antibiotic stewardship interventions. We recruited children and adults who presented at the emergency department or were hospitalised with clinical presentation of RTI in The Netherlands and Israel. A panel of three experienced physicians adjudicated a reference standard diagnosis (i.e. bacterial or viral infection) for all the patients using all available clinical and laboratory information, including a 28-day follow-up assessment. The cohort included 284 children and 232 adults with RTI (median age, 1.3years and 64.5years, respectively). The proportion of viral infections was larger in children than in adults (209(74%) versus 89(38%), p<0.001). In case of viral RTI, antibiotics were prescribed (i.e. overuse) less frequently in children than in adults (77/209 (37%) versus 74/89 (83%), p<0.001). One (1%) child and three (2%) adults with bacterial infection were not treated with antibiotics (i.e. underuse); all were mild cases. This international, prospective study confirms major antibiotic overuse in patients with RTI. Viral infection is more common in children, but antibiotic overuse is more frequent in adults with viral RTI. Together, these findings support the need for effective interventions to decrease antibiotic overuse in RTI patients of all ages.
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| 8. |
- Geoerger, B., et al.
(författare)
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Enasidenib treatment in two individuals with D-2-hydroxyglutaric aciduria carrying a germline IDH2 mutation
- 2023
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Ingår i: Nature Medicine. - 1078-8956. ; 29:6
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Tidskriftsartikel (refereegranskat)abstract
- D-2-hydroxyglutaric aciduria type II (D2HGA2) is a severe inborn disorder of metabolism caused by heterozygous R140 mutations in the IDH2 (isocitrate dehydrogenase 2) gene. Here we report the results of treatment of two children with D2HGA2, one of whom exhibited severe dilated cardiomyopathy, with the selective mutant IDH2 enzyme inhibitor enasidenib. In both children, enasidenib treatment led to normalization of D-2-hydroxyglutarate (D-2-HG) concentrations in body fluids. At doses of 50 mg and 60 mg per day, no side effects were observed, except for asymptomatic hyperbilirubinemia. For the child with cardiomyopathy, chronic D-2-HG inhibition was associated with improved cardiac function, and for both children, therapy was associated with improved daily functioning, global motility and social interactions. Treatment of the child with cardiomyopathy led to therapy-coordinated changes in serum phospholipid levels, which were partly recapitulated in cultured fibroblasts, associated with complex effects on lipid and redox-related gene pathways. These findings indicate that targeted inhibition of a mutant enzyme can partly reverse the pathology of a chronic neurometabolic genetic disorder. In a study of two children with the metabolic condition D-2-hydroxyglutaric aciduria type II, the drug enasidenib, developed as a selective mutant IDH2 inhibitor for treatment of acute myeloid leukemia, had beneficial effects on cardiac and neurodevelopmental abnormalities, indicating the potential for the repurposing of this drug for this hereditary condition.
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- Wortmann, Saskia B, et al.
(författare)
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Eyes on MEGDEL: Distinctive Basal Ganglia Involvement in Dystonia Deafness Syndrome.
- 2015
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Ingår i: Neuropediatrics. - : Georg Thieme Verlag KG. - 1439-1899 .- 0174-304X. ; 46:2, s. 098-103
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Tidskriftsartikel (refereegranskat)abstract
- Pediatric movement disorders are still a diagnostic challenge, as many patients remain without a (genetic) diagnosis. Magnetic resonance imaging (MRI) pattern recognition can lead to the diagnosis. MEGDEL syndrome (3-MethylGlutaconic aciduria, Deafness, Encephalopathy, Leigh-like syndrome MIM #614739) is a clinically and biochemically highly distinctive dystonia deafness syndrome accompanied by 3-methylglutaconic aciduria, severe developmental delay, and progressive spasticity. Mutations are found in SERAC1, encoding a phosphatidylglycerol remodeling enzyme essential for both mitochondrial function and intracellular cholesterol trafficking. Based on the homogenous phenotype, we hypothesized an accordingly characteristic MRI pattern. A total of 43 complete MRI studies of 30 patients were systematically reevaluated. All patients presented a distinctive brain MRI pattern with five characteristic disease stages affecting the basal ganglia, especially the putamen. In stage 1, T2 signal changes of the pallidum are present. In stage 2, swelling of the putamen and caudate nucleus is seen. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease. It later increases, reflecting progressive putaminal involvement. This "eye" was found in all patients with MEGDEL syndrome during a specific age range, and has not been reported in other disorders, making it pathognomonic for MEDGEL and allowing diagnosis based on MRI findings.
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| 11. |
- Canini, M., et al.
(författare)
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A Self-Organizing Distributed and In-Band SDN Control Plane
- 2017
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Ingår i: Proceedings - International Conference on Distributed Computing Systems. - 9781538617915 ; , s. 2656-2657
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Konferensbidrag (refereegranskat)abstract
- Adopting distributed control planes is critical towards ensuring high availability and fault-tolerance of dependable Software-Defined Networks (SDNs). However, designing and bootstrapping a distributed SDN control plane is a challenging task, especially if to be done in-band, without a dedicated control network, and without relying on legacy networking protocols. One of the most appealing and powerful notions of fault-tolerance is self-organization and this paper discusses the possibility of selforganizing algorithms for in-band control planes.
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| 12. |
- Canini, M., et al.
(författare)
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Renaissance: A self-stabilizing distributed SDN control plane
- 2018
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Ingår i: Proceedings - International Conference on Distributed Computing Systems. ; 2018-July, s. 233-243
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Konferensbidrag (refereegranskat)abstract
- By introducing programmability, automated verification, and innovative debugging tools, Software-Defined Networks (SDNs) are poised to meet the increasingly stringent dependability requirements of today's communication networks. However, the design of fault-tolerant SDNs remains an open challenge. This paper considers the design of dependable SDNs through the lenses of self-stabilization - a very strong notion of fault-tolerance. In particular, we develop algorithms for an in-band and distributed control plane for SDNs, called Renaissance, which tolerates a wide range of (concurrent) controller, link, and communication failures. Our self-stabilizing algorithms ensure that after the occurrence of an arbitrary combination of failures, (i) every non-faulty SDN controller can eventually reach any switch in the network within a bounded communication delay (in the presence of a bounded number of concurrent failures) and (ii) every switch is managed by at least one non-faulty controller. We evaluate Renaissance through a rigorous worst-case analysis as well as a prototype implementation (based on OVS and Floodlight), and we report on our experiments using Mininet.
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| 13. |
- Canini, M., et al.
(författare)
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Renaissance: A self-stabilizing distributed SDN control plane using in-band communications
- 2022
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Ingår i: Journal of Computer and System Sciences. - : Elsevier BV. - 1090-2724 .- 0022-0000. ; 127, s. 91-121
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Tidskriftsartikel (refereegranskat)abstract
- By introducing programmability, automated verification, and innovative debugging tools, Software-Defined Networks (SDNs) are poised to meet the increasingly stringent dependability requirements of today's communication networks. However, the design of fault-tolerant SDNs remains an open challenge. This paper considers the design of dependable SDNs through the lenses of self-stabilization—a very strong notion of fault-tolerance. In particular, we develop algorithms for an in-band and distributed control plane for SDNs, called Renaissance, which tolerate a wide range of failures. Our self-stabilizing algorithms ensure that after the occurrence of arbitrary failures, (i) every non-faulty SDN controller can reach any switch (or another controller) within a bounded communication delay (in the presence of a bounded number of failures) and (ii) every switch is managed by a controller. We evaluate Renaissance through a rigorous worst-case analysis as well as a prototype implementation (based on OVS and Floodlight, and Mininet).
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| 14. |
- Fadanelli, S., et al.
(författare)
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Four-Spacecraft Measurements of the Shape and Dimensionality of Magnetic Structures in the Near-Earth Plasma Environment
- 2019
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Ingår i: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 124:8, s. 6850-6868
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Tidskriftsartikel (refereegranskat)abstract
- We present a new method for determining the main relevant features of the local magnetic field configuration, based entirely on the knowledge of the magnetic field gradient four‐spacecraft measurements. The method, named “magnetic configuration analysis” (MCA), estimates the spatial scales on which the magnetic field varies locally. While it directly derives from the well‐known magnetic directional derivative and magnetic rotational analysis procedures (Shi et al., 2005, htpps://doi.org/10.1029/2005GL022454; Shen et al., 2007, https://doi.org/10.1029/2005JA011584), MCA was specifically designed to address the actual magnetic field geometry. By applying MCA to multispacecraft data from the Magnetospheric Multiscale (MMS) satellites, we perform both case and statistical analyses of local magnetic field shape and dimensionality at very high cadence and small scales. We apply this technique to different near‐Earth environments and define a classification scheme for the type of configuration observed. While our case studies allow us to benchmark the method with those used in past works, our statistical analysis unveils the typical shape of magnetic configurations and their statistical distributions. We show that small‐scale magnetic configurations are generally elongated, displaying forms of cigar and blade shapes, but occasionally being planar in shape like thin pancakes (mostly inside current sheets). Magnetic configurations, however, rarely show isotropy in their magnetic variance. The planar nature of magnetic configurations and, most importantly, their scale lengths strongly depend on the plasma β parameter. Finally, the most invariant direction is statistically aligned with the electric current, reminiscent of the importance of electromagnetic forces in shaping the local magnetic configuration.
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- Rudà, Roberta, et al.
(författare)
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Eano-Euracan-Sno Guidelines on Circumscribed Astrocytic GLIOMAS, Glioneuronal and Neuronaltumors.
- 2022
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Ingår i: Neuro-oncology. - : Oxford University Press (OUP). - 1523-5866 .- 1522-8517. ; 24:12, s. 2015-2034
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Forskningsöversikt (refereegranskat)abstract
- In the new WHO 2021 Classification of CNS Tumors the chapter "Circumscribed astrocytic gliomas, glioneuronal and neuronal tumors" encompasses several different rare tumor entities, which occur more frequently in children, adolescents and young adults. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is low particularly for adult patients, and draw recommendations accordingly. Tumor diagnosis, based on WHO 2021, is primarily performed using conventional histological techniques; however, molecular workup is important for differential diagnosis, in particular DNA methylation profiling for the definitive classification of histologically unresolved cases. Molecular factors are increasingly of prognostic and predictive importance. MRI finding are non specific, but for some tumors are characteristic and suggestive. Gross total resection, when feasible, is the most important treatment in terms of prolonging survival and achieving long-term seizure control. Conformal radiotherapy should be considered in grade 3 and incompletely resected grade 2 tumors. In recurrent tumors reoperation and radiotherapy, including stereotactic radiotherapy, can be useful. Targeted therapies may be used in selected patients: BRAF and MEK inhibitors in pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas when BRAF altered, and mTOR inhibitor everolimus in subependymal giant cells astrocytomas .Sequencing to identify molecular targets is advocated for diagnostic clarification and to direct potential targeted therapies.
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- Sorrentino, S, et al.
(författare)
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Presenting features of neuroblastoma with spinal canal invasion. A prospective study of the International Society of Pediatric Oncology Europe - Neuroblastoma (SIOPEN)
- 2022
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Ingår i: Frontiers in pediatrics. - : Frontiers Media SA. - 2296-2360. ; 10, s. 1023498-
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Tidskriftsartikel (refereegranskat)abstract
- Between 5 and 15% of children with neuroblastoma (NB) present with or develop spinal canal invasion (SCI). The majority of these children have symptoms of epidural compression of spinal cord and/or spinal nerves. Treatment of NB-SCI is considered an emergency but its modalities are not yet well-established. Independently of treatment, NB-SCI may result in significant long-term disabilities. We report on the first prospective study of NB-SCI focused on presenting characteristics of both symptomatic and asymptomatic patients and correlation between SCI-related symptoms and imaging features.Materials and methodsThis SIOPEN prospective NB-SCI study opened in June 2014. Patient data including SCI symptoms evaluated by standardized measures and spinal cord imaging studies were collected for each patient. For the purpose of this study data entry was locked on July 2021.ResultsOf the 208 NB-SCI patients registered, 196 were evaluable for this analysis of whom 67% were symptomatic and 33% asymptomatic. Median age was 11 months. The thorax was the commonest primary tumor site. The median intervals between initial symptoms and diagnosis and between first medical visit and diagnosis were 14 and 3 days, respectively. The was no statistical difference in frequency of presenting characteristics between symptomatic and asymptomatic patients. Presenting features of NB-SCI patients differed from other NBs for older median age, prevalence of thoracic vs. abdominal primary site, prevalence of localized vs. metastatic disease and lower incidence of MYCN gene amplification. The most common SCI features were motor deficit in the younger and pain in the older patients that correlated on imaging with both transverse and longitudinal extent but not with the level of intraspinal tumor. Spinal cord T2-hyperintensity was more frequently detected in symptomatic patients (not significant).ConclusionThis prospective study confirms that children with NB-SCI differ from NBs without SCI. Compared to previous studies, it provides more detailed information regarding presenting symptoms, time intervals between SCI symptoms, medical visit and diagnosis, and correlations between symptoms and imaging features.
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| 23. |
- Strand, V, et al.
(författare)
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Certolizumab pegol plus methotrexate provides broad relief from the burden of rheumatoid arthritis: analysis of patient-reported outcomes from the RAPID 2 trial
- 2011
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 70:6, s. 996-1002
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Tidskriftsartikel (refereegranskat)abstract
- To assess the impact of certolizumab pegol (CZP) on patient-reported outcomes (PROs) in rheumatoid arthritis (RA), and to interpret these results using number needed to treat (NNT), and associations between PRO responses and longer term outcomes.MethodsA total of 619 patients with active RA were randomised to CZP 200 or 400 mg, or placebo plus methotrexate (MTX). PROs assessed included pain, patient's global assessment of disease activity (PtGA), physical function, fatigue and health-related quality of life. Treatment impact on PROs, NNT to achieve simultaneous improvements in multiple PROs and correlations between PROs were calculated. Times to onset of improvements greater than or equal to minimum clinically important differences (MCIDs) in pain as a determinant of clinical outcomes at week 24 were compared between week 6 and 12 responders, and in patients with improvements in pain ≥MCID at week 12 (week 12 responders/non-responders).ResultsCZP 200 and 400 mg plus MTX were associated with rapid, clinically meaningful improvements in all PROs. The NNT for subjects to report changes ≥MCID in up to five PROs was two to three, and five for all six PROs (pain, PtGA, physical function, fatigue and short-form 36-item Physical and Mental Component Summary Scores). More patients with improvements ≥MCID in pain at week 6 than those at week 12 had lower disease activity at week 24. Week 12 pain responders had better clinical outcomes at week 24 than non-responders.ConclusionsThe data demonstrate that CZP provides broad relief from the burden of RA.Trial registration numberNCT00160602.
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| 26. |
- Zhang, Y. C., et al.
(författare)
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Quantitative analysis of a Hall system in the exhaust of asymmetric magnetic reconnection
- 2017
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Ingår i: Journal of Geophysical Research - Space Physics. - : Blackwell Publishing Ltd. - 2169-9380 .- 2169-9402. ; 122:5, s. 5277-5289
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Tidskriftsartikel (refereegranskat)abstract
- Taking advantage of high-resolution measurements from the MMS mission, we find evidence for a complete Hall system in the exhaust of asymmetric magnetic reconnection 40 Di downstream of the X line. The investigation of the fine structure of the Hall system reveals that it displays features in the exhaust similar to those reported previously in the ion diffusion region by simulations and observations. This finding confirms the importance of particle-scale processes in the reconnection exhaust as well. On the magnetospheric side of the exhaust, electrons are strongly accelerated by parallel electric fields. This process significantly contributes to feed the Hall current system, resulting in a nonnegligible Hall magnetic field signature on this side despite an otherwise lower density. Calculation of the induced out-of-plane magnetic field by in-plane currents (based on Biot-Savart law) provides direct quantitative evidence for the process of Hall magnetic field generation by the Hall current system. A strong normal Hall electric field is present only on the magnetospheric side of the exhaust region, consistent with previous works. Multipoint data analysis shows that the ion pressure gradient in the ion momentum equation produces this Hall electric field. This global pattern of the Hall system can be explained by kinetic Alfvén wave theory.
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