| 1. |
- Mercuri, E., et al.
(författare)
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Safety and effectiveness of ataluren: comparison of results from the STRIDE Registry and CINRG DMD Natural History Study
- 2020
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Ingår i: Journal of Comparative Effectiveness Research. - : Becaris Publishing Limited. - 2042-6305 .- 2042-6313. ; 9:5, s. 341-360
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). We examined the effectiveness of ataluren + standard of care (SoC) in the registry versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), DMD genotype-phenotype/-ataluren benefit correlations and ataluren safety. Patients & methods: Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established disease progression predictors (registry cut-off date, 9 July 2018). Results & conclusion: Kaplan-Meier analyses demonstrated that ataluren + SoC significantly delayed age at loss of ambulation and age at worsening performance in timed function tests versus SoC alone (p <= 0.05). There were no DMD genotype-phenotype/ataluren benefit correlations. Ataluren was well tolerated. These results indicate that ataluren + SoC delays functional milestones of DMD progression in patients with nmDMD in routine clinical practice. ClinicalTrials.gov identifier: NCT02369731. ClinicalTrials.gov identifier: NCT02369731.
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| 2. |
- Finkel, R. S., et al.
(författare)
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Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy
- 2017
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 377:18, s. 1723-1732
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & para;& para;Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein.& para;& para;METHODS & para;& para;We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included over all survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis.& para;& para;RESULTS & para;& para;In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41 %] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.& para;& para;CONCLUSIONS & para;& para;Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug.
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| 3. |
- Mercuri, E., et al.
(författare)
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Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy
- 2018
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 378:7, s. 625-635
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). METHODS We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2: 1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (>= 3 points), an outcome that indicates improvement in at least two motor skills. RESULTS In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P< 0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P< 0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively). CONCLUSIONS Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials. gov number, NCT02292537.)
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| 7. |
- Campbell, C., et al.
(författare)
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Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy
- 2020
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Ingår i: Journal of Comparative Effectiveness Research. - : Becaris Publishing Limited. - 2042-6305 .- 2042-6313. ; 9:14
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Tidskriftsartikel (refereegranskat)abstract
- Aim:Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD).Materials & methods:Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] >= 300-<400 or <400 m). Meta-analyses examined 6MWD change from baseline to week 48.Results:Statistically significant differences in 6MWD change with ataluren versus placebo were observed across all three meta-analyses. Least-squares mean difference (95% CI): ITT (n = 342), +17.2 (0.2-34.1) m, p = 0.0473; >= 300-<400 m (n = 143), +43.9 (18.2-69.6) m, p = 0.0008; <400 m (n = 216), +27.7 (6.4-49.0) m, p = 0.0109.Conclusion:These meta-analyses support previous evidence for ataluren in slowing disease progression versus placebo in patients with nmDMD over 48 weeks. Treatment benefit was most evident in patients with a baseline 6MWD >= 300-<400 m (the ambulatory transition phase), thereby informing future trial design.
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| 10. |
- Izdebski, A., et al.
(författare)
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Palaeoecological data indicates land-use changes across Europe linked to spatial heterogeneity in mortality during the Black Death pandemic
- 2022
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Ingår i: Nature Ecology & Evolution. - : Springer Science and Business Media LLC. - 2397-334X. ; :6, s. 297-306
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Tidskriftsartikel (refereegranskat)abstract
- The Black Death (1347–1352 CE) is the most renowned pandemic in human history, believed by many to have killed half of Europe’s population. However, despite advances in ancient DNA research that conclusively identified the pandemic’s causative agent (bacterium Yersinia pestis), our knowledge of the Black Death remains limited, based primarily on qualitative remarks in medieval written sources available for some areas of Western Europe. Here, we remedy this situation by applying a pioneering new approach, ‘big data palaeoecology’, which, starting from palynological data, evaluates the scale of the Black Death’s mortality on a regional scale across Europe. We collected pollen data on landscape change from 261 radiocarbon-dated coring sites (lakes and wetlands) located across 19 modern-day European countries. We used two independent methods of analysis to evaluate whether the changes we see in the landscape at the time of the Black Death agree with the hypothesis that a large portion of the population, upwards of half, died within a few years in the 21 historical regions we studied. While we can confirm that the Black Death had a devastating impact in some regions, we found that it had negligible or no impact in others. These inter-regional differences in the Black Death’s mortality across Europe demonstrate the significance of cultural, ecological, economic, societal and climatic factors that mediated the dissemination and impact of the disease. The complex interplay of these factors, along with the historical ecology of plague, should be a focus of future research on historical pandemics.
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| 11. |
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| 12. |
- Mercuri, E., et al.
(författare)
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Safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE Registry compared with the CINRG Duchenne Natural History Study (2015-2022): 2022 interim analysis
- 2023
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Ingår i: Journal of Neurology. - 0340-5354. ; 270, s. 3896-3913
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveStrategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, international, multicenter registry of real-world ataluren use in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in clinical practice. This updated interim report (data cut-off: January 31, 2022), describes STRIDE patient characteristics and ataluren safety data, as well as the effectiveness of ataluren plus standard of care (SoC) in STRIDE versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS).MethodsPatients are followed up from enrollment for at least 5 years or until study withdrawal. Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established predictors of disease progression.ResultsAs of January 31, 2022, 307 patients were enrolled from 14 countries. Mean (standard deviation [SD]) ages at first symptoms and at genetic diagnosis were 2.9 (1.7) years and 4.5 (3.7) years, respectively. Mean (SD) duration of ataluren exposure was 1671 (56.8) days. Ataluren had a favorable safety profile; most treatment-emergent adverse events were mild or moderate and unrelated to ataluren. Kaplan-Meier analyses demonstrated that ataluren plus SoC significantly delayed age at loss of ambulation by 4 years (p < 0.0001) and age at decline to %-predicted forced vital capacity of < 60% and < 50% by 1.8 years (p = 0.0021) and 2.3 years (p = 0.0207), respectively, compared with SoC alone.ConclusionLong-term, real-world treatment with ataluren plus SoC delays several disease progression milestones in individuals with nmDMD. NCT02369731; registration date: February 24, 2015.
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| 13. |
- Ferrari, S., et al.
(författare)
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Nonmetastatic Ewing family tumors: high-dose chemotherapy with stem cell rescue in poor responder patients. Results of the Italian Sarcoma Group/Scandinavian Sarcoma Group III protocol
- 2011
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Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 22:5, s. 1221-1227
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Tidskriftsartikel (refereegranskat)abstract
- Background: High-dose chemotherapy (HDT) was added to conventional chemotherapy in Ewing sarcoma family tumor (EFT) patients, poor responders (PRs) to induction chemotherapy in order to improve their survival. Patients and methods: Patients aged <= 40 years with nonmetastatic Ewing sarcoma (ES) received vincristine (V), doxorubicin (A), cyclofosfamide (C), actinomycin (Ac), ifosfamide (I) and etoposide (E) (VACAc-IE regimen) as induction chemotherapy. As maintenance treatment, good responders (GR) received nine cycles of VACAc-IE regimen. PRs received three cycles of VAC-IE, mobilizing cycle with CE and HDT with Busulfan and Melphalan with stem cell support. Results: Three hundred patients [median age 15 years (3-40 years)] entered the study. One patient refused local treatment, 242 (81%) underwent surgery [with radiotherapy (RT) in 80] and 57 (19%) RT alone. No toxic deaths were recorded. Overall GR were 146 (49%). Twenty-eight PR did not receive HDT. At a median follow-up of 64 months (21-116 months), 5-year overall and event-free survival (EFS) were 75% and 69%, respectively. Five-year EFS was 75% for GR, 72% for PR treated with HDT and 33% for PR who did not receive HDT. Conclusions: High-dose therapy added to the VACA-IE regimen in PR patients is feasible and effective. Selected groups of patients with ES can benefit from HDT.
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| 19. |
- Muntoni, F., et al.
(författare)
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Ataluren use in patients with nonsense mutation Duchenne muscular dystrophy: patient demographics and characteristics from the STRIDE Registry
- 2019
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Ingår i: Journal of Comparative Effectiveness Research. - : Becaris Publishing Limited. - 2042-6305 .- 2042-6313. ; 8:14, s. 1187-1200
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (DMD) in clinical practice (NCT02369731). Here, we describe the initial demographic characteristics of the registry population. Patients & methods: Patients will be followed up from enrollment for >= 5 years or until study withdrawal. Results & conclusion: As of 9 July 2018, 213 DMD boys were enrolled from 11 countries. Mean (standard deviation) ages at first symptoms and at study treatment start were 2.7 (1.7) years and 9.8 (3.7) years, respectively. Corticosteroids were used by 190 patients (89.2%) before data cut-off. Mean (standard deviation) ataluren exposure was 639.0 (362.9) days. Six patients withdrew. STRIDE is the first drug registry for patients with DMD and represents the largest real-world registry of patients with nmDMD to date.
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| 20. |
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| 21. |
- Neff, A, et al.
(författare)
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The ESTMJS (European Society of Temporomandibular Joint Surgeons) Consensus and Evidence-Based Recommendations on Management of Condylar Dislocation
- 2021
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Ingår i: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 10:21
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Tidskriftsartikel (refereegranskat)abstract
- Although condylar dislocation is not uncommon, terminology, diagnostics, and treatment concepts vary considerably worldwide. This study aims to present a consensus recommendation based on systematically reviewed literature and approved by the European Society of TMJ Surgeons (ESTMJS). Based on the template of the evidence-based German guideline (register # 007-063) the ESTMJS members voted on 30 draft recommendations regarding terminology, diagnostics, and treatment initially via a blinded modified Delphi procedure. After unblinding, a discussion and voting followed, using a structured consensus process in 2019. An independent moderator documented and evaluated voting results and alterations from the original draft. Although the results of the preliminary voting were very heterogenous and differed significantly from the German S3 guideline (p < 0.0005), a strong consensus was achieved in the final voting on terminology, diagnostics, and treatment. In this voting, multiple alterations, including adding and discarding recommendations, led to 24 final recommendations on assessment and management of TMJ dislocation. To our knowledge, the ESTMJS condylar dislocation recommendations are the first both evidence and consensus-based international recommendations in the field of TMJ surgery. We recommend they form the basis for clinical practice guidelines for the management of dislocations of the mandibular condyle.
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| 22. |
- Onofri, E, et al.
(författare)
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Dysgraphia in Relation to Cognitive Performance in Patients with Alzheimer’s Disease
- 2013
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Ingår i: Journal of Intellectual Disability - Diagnosis and Treatment. - : Lifescience Global. - 2292-2598. ; 1:2, s. 113-124
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Tidskriftsartikel (refereegranskat)abstract
- Dysgraphia has been observed in patients presenting mild to moderate levels of Alzheimer’s disease (AD) in several studies. In the present study, 30 AD patients and 30 matched healthy controls, originating from the Lazio region, Rome, Italy, were examined on tests of letter-writing ability and cognitive performance over a series of 10 test days that extended over 19 days (Test days: 1, 3, 5, 7, 9 11, 13, 15, 17, and 19). Consistent deficits by the AD patients over the initial cognition test (PQ1), 2nd cognition test (PQ2) and the difference between them (D∆), expressing deterioration, and writing-time compared the group of healthy control subjects were obtained. Furthermore, the performances of the AD patients on the PQ1, D∆ and writing-time, but not the PQ2, tests deteriorated from the 1st five days of testing (Days 1-9) to the 2nd five days (11-19). Both AD patients’ and healthy controls’ MMSE scores were markedly and significantly correlated with performance of PQ1, writing-time and PQ2. The extent of dysgraphia and progressive deficits in the AD patients implicate multiple brain regions in the loss of functional integrity.
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| 23. |
- Onofri, E., et al.
(författare)
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Effect of cognitive fluctuation on handwriting in Alzheimer's patient: A case study
- 2015
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Ingår i: Acta Medica Mediterranea. - 0393-6384. ; 31:3, s. 751-755
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The older population is rapidly growing in the European states and across the globe; and in aging we notice a cognitive declines, a decrease in memory and decision-making abilities. Characteristics of the cognitive fluctuations occur infrequently in the elderly, but they are present in patients with dementia. Fluctuating cognition and abilities have been described as periods of behavioral and thought confusion, inattention, and incoherent speech alternating with episodes of lucidity. It is common in Dementia with Lewy bodies (DLB), however, the role of fluctuations in Alzheimer 's disease (AD) has not been much considered. Case presentation: The present study examines the relationship between cognitive status and handwritten scripts, presented as 'letter-writing' in AD patient, as oscillations of the symptoms phase. Discussion: We present evidence that the deficits of attention and its fluctuations and the cognitive impairment are related with the handwritten expression.
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| 24. |
- Onofri, E., et al.
(författare)
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Legal medical consideration of Alzheimer's disease patients' dysgraphia and cognitive dysfunction: a 6 month follow up
- 2016
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Ingår i: Clinical Interventions in Aging. - : Informa UK Limited. - 1178-1998. ; 11, s. 279-284
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Tidskriftsartikel (refereegranskat)abstract
- Background: The purpose of this study was to investigate the ability of Alzheimer's disease (AD) patients to express intentions and desires, and their decision-making capacity. This study examines the findings from a 6-month follow-up of our previous results in which 30 patients participated. Materials and methods: The patient's cognition was examined by conducting the tests of 14 questions and letter-writing ability over a period of 19 days, and it was repeated after 6 months. The difference between these two cognitive measures (PQ1 before-PQ2 before), tested previously and later the writing test, was designated D Delta before. The test was repeated after 6 months, and PQ1 after-PQ2 after was designated D Delta after. Results: Several markedly strong relationships between dysgraphia and other measures of cognitive performance in AD patients were observed. The most aged patients (over 86 years), despite less frequency, maintain the cognitive capacity manifested in the graphic expressions. A document, written by an AD patient presents an honest expression of the patient's intention if that document is legible, clear, and comprehensive. Conclusion: The identification of impairment/ deficits in writing and cognition during different phases of AD may facilitate the understanding of disease progression and identify the occasions during which the patient may be considered sufficiently lucid to make decisions.
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