| 1. |
- Coley, Nicola, et al.
(författare)
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Plasma p-tau181 as an outcome and predictor of multidomain intervention effects: a secondary analysis of a randomised, controlled, dementia prevention trial
- 2024
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Ingår i: The Lancet Healthy Longevity. - 2666-7568. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is unknown whether multidomain interventions, which might preserve late-life cognition, affect Alzheimer's disease pathology. Previous studies measured cerebrospinal fluid and imaging Alzheimer's disease biomarkers in small subsamples of multidomain trial participants. Newly developed assays enable the measurement of blood-based Alzheimer's disease biomarkers in larger samples. We aimed to assess whether plasma tau phosphorylated at threonine 181 (p-tau181) was able to detect or predict 3-year multidomain intervention effects. Methods: This is a secondary analysis of the randomised, controlled, Multidomain Alzheimer Prevention Trial (MAPT) testing a 3-year multidomain intervention, omega-3 fatty acid supplementation, or both versus placebo, in individuals aged 70 years and older in 13 memory centres in France and Monaco. Plasma p-tau181 was measured in stored blood samples in a subsample of 527 participants on an intention-to-treat basis. Changes in cognitive score were calculated as a composite measure using the average of Z scores for the following tests: Mini Mental State Examination orientation items, Free and Cued Selective Reminding Test (sum of free and total recall scores), category fluency, and Digit Symbol Substitution Test. Intervention effects on 3-year change in p-tau181 concentration were estimated by use of a linear mixed model with centre-specific random intercepts. Findings: Recruitment took place between May 30, 2008, and Feb 24, 2011. Median baseline plasma p-tau181 was 8·8 pg/mL (IQR 6·7–11·9) in the total sample, and significantly higher in older individuals, men, APOE ε4 carriers, and participants with renal dysfunction or a positive PET amyloid scan. During 3-year follow-up, individuals with raised baseline p-tau181 underwent greater cognitive decline (eg, mean difference in 3-year change on the composite cognitive score between control group participants with normal and abnormal baseline levels of p-tau was −0·34 [effect size −0·52; 95% CI −0·61 to 0·07] in the fully adjusted model using a 12·4 pg/mL cutoff for abnormal baseline p-tau181), but there were no intervention effects on change in p-tau181 either in this subgroup or the total population, and no effect on cognitive change in individuals with raised baseline p-tau181 (eg, in the fully adjusted model using the 12·4 pg/mL cutoff for p-tau181 abnormality, the mean difference [95% CI] in this subgroup in 3-year decline on the composite cognitive score between the control group and the multidomain + omega-3 group, the omega-3 group, and the multidomain intervention group, was, respectively: 0·13 [−0·21 to 0·47], 0·03 [−0·30 to 0·36], and 0·10 [−0·26 to 0·46]). Surprisingly, individuals with raised baseline p-tau181 showed a decrease in p-tau181 during follow-up (eg, unadjusted mean [95% CI] 3-year change was −3·01 pg/mL (−4·45 to −1·56) in control group subjects with abnormal baseline p-tau181 [using the 12·4 pg/mL abnormal p-tau cutoff]). Interpretation: Our results support the utility of p-tau181 as a prognostic biomarker, but it did not predict or detect intervention effects in this study. Further investigation of its usefulness as a prevention trial outcome measure is required.
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| 2. |
- Manry, Jérémy, et al.
(författare)
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The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:21
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Tidskriftsartikel (refereegranskat)abstract
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
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| 3. |
- Matuozzo, Daniela, et al.
(författare)
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Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.
- 2023
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Ingår i: Genome medicine. - 1756-994X. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in~80% of cases.We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1×10-4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1×10-4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4×10-3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7×10-8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68×10-5).Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60years old.
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| 4. |
- Bastard, Paul, et al.
(författare)
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Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.
- 2021
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Ingår i: The Journal of experimental medicine. - 1540-9538. ; 218:7
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Tidskriftsartikel (refereegranskat)abstract
- Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
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| 5. |
- Khelladi, Djamel Eddine, et al.
(författare)
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A semi-automatic maintenance and co-evolution of OCL constraints with (meta)model evolution
- 2017
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Ingår i: Journal of Systems and Software. - : Elsevier BV. - 0164-1212. ; 134, s. 242-260
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 Elsevier Inc. Metamodels are core components of modeling languages to define structural aspects of a business domain. As a complement, OCL constraints are used to specify detailed aspects of the business domain, e.g. more than 750 constraints come with the UML metamodel. As the metamodel evolves, its OCL constraints may need to be co-evolved too. Our systematic analysis shows that semantically different resolutions can be applied depending not only on the metamodel changes, but also on the user intent and on the structure of the impacted constraints. In this paper, we first investigate the syntactical reasons that lead to apply different resolutions. We then propose a co-evolution approach that offers alternative resolutions while allowing the user to choose the best applicable one. We evaluated our approach on six case studies of metamodel evolution and their OCL constraints co-evolution. The results show the usefulness of alternative resolutions along with user decision to cope with real co-evolution scenarios. Within our six case studies our approach led to an average of 92% (syntactically) and 93% (semantically) matching co-evolution w.r.t. the user intent.
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| 6. |
- Khelladi, Djamel Eddine, et al.
(författare)
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Coadapting multidimension process properties
- 2017
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Ingår i: Journal of Software: Evolution and Process, 29 (11). - : Wiley. - 2047-7481 .- 2047-7473.
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Konferensbidrag (refereegranskat)abstract
- © 2017 John Wiley & Sons, Ltd. In the last decades, process verification has been intensively addressed and has become an essential activity to correct and to remove errors before process execution. Typical process verification ecosystems propose to express properties to be verified on the process. A property expresses a desired behavior that must hold or not in the process execution. Processes during their lifespan are continuously adapted for several purposes: enriching, correcting, and refactoring the process. When a process is adapted, the existing properties must naturally be rechecked to ensure that no errors have been introduced, ie, the properties still hold. However, the properties may become outdated and must be coadapted w.r.t. the adapted process before to be rechecked. Otherwise, the verification may raise false alarms or may not detect newly introduced errors. In this paper, we propose a coadaptation approach of properties while considering process adaptation for the different dimensions, namely, control flow, object flow, resources, and timing. We systematically studied process changes in the multiple dimensions to identify those that do impact properties and for which we propose resolution strategies. Our preliminary evaluation shows that our resolutions strategies allow to support users in correctly coadapting impacted properties.
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| 7. |
- Khelladi, Djamel Eddine, et al.
(författare)
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Detecting complex changes and refactorings during (Meta)model evolution
- 2016
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Ingår i: Elsevier - Information Systems. - : Elsevier BV. - 0306-4379. ; 62, s. 220-241
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Tidskriftsartikel (refereegranskat)abstract
- Evolution of metamodels can be represented at the finest grain by the trace of atomic changes such as add, delete, and update of elements. For many applications, like automatic correction of models when the metamodel evolves, a higher grained trace must be inferred, composed of complex changes, each one aggregating several atomic changes. Complex change detection is a challenging task since multiple sequences of atomic changes may define a single user intention and complex changes may overlap over the atomic change trace. In this paper, we propose a detection engine of complex changes that simultaneously addresses these two challenges of variability and overlap. We introduce three ranking heuristics to help users to decide which overlapping complex changes are likely to be correct. In our approach, we record the trace of atomic changes rather than computing them with the difference between the original and evolved metamodel. Thus, we have a complete and an ordered sequence of atomic changes without hidden changes. Furthermore, we consider the issue of undo operations (i.e. change canceling actions) while recording the sequence of atomic changes, and we illustrate how we cope with it. We validate our approach on 8 real case studies demonstrating its feasibility and its applicability. We observe that a full recall is always reached in all case studies and an average precision of 70.75%. The precision is improved by the heuristics up to 91% and 100% in some cases.
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| 8. |
- Khelladi, Djamel Eddine, et al.
(författare)
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Metamodel and constraints co-evolution: A semi automatic maintenance of ocl constraints
- 2016
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Ingår i: International Conference on Software Reuse. - Cham : Springer International Publishing. - 0302-9743 .- 1611-3349. - 9783319351216 ; 9679, s. 333-349
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Konferensbidrag (refereegranskat)abstract
- Metamodels are core components of modeling languages to define structural aspects of a business domain. As a complement, OCL constraints are used to specify detailed aspects of the business domain, e.g. more than 750 constraints come with the UML metamodel. As the metamodel evolves, its OCL constraints may need to be co-evolved too. Our systematic analysis shows that semantically different resolutions can be applied depending not only on the metamodel changes, but also on the user intent and on the structure of the impacted constraints. In this paper, we investigate the reasons that lead to apply different resolutions. We then propose a co-evolution approach that offers alternative resolutions while allowing the user to choose the best applicable one. We evaluated our approach on the evolution of the UML case study. The results confirm the need of alternative resolutions along with user decision to cope with real co-evolution scenarios. The results show that our approach reaches 80 % of semantically correct co-evolution
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| 9. |
- Khelladi, Djamel Eddine, et al.
(författare)
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Supporting the Co-adaption of Process Properties
- 2016
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Ingår i: Proceedings of the International Conference on Software and Systems Process (ICSSP). - New York, NY, USA : Association for Computing Machinery (ACM). - 9781450341882
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Konferensbidrag (refereegranskat)abstract
- Process verification has become an essential activity to correct and to remove errors before process execution. Typical process verification ecosystems propose to express properties to be verified on the process. When a process is adapted, the existing properties must naturally be re-checked to ensure that no errors have been introduced. However, the properties may become outdated and must be co-adapted w.r.t. the adapted process before to be re-checked. Otherwise, the verification may raise false alarms or may not detect newly introduced errors. In this paper, we propose a co-adaptation approach for control-flow process properties. We systematically studied control-flow process changes to identify those that do impact properties, and for which we propose resolution strategies. Our preliminary evaluation shows that our resolutions strategies allow to support users in correctly co-adapting impacted properties.
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| 10. |
- López-Fauqued, M., et al.
(författare)
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Safety profile of the adjuvanted recombinant zoster vaccine : Pooled analysis of two large randomised phase 3 trials
- 2019
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Ingår i: Vaccine. - : Elsevier Ltd. - 0264-410X .- 1873-2518. ; 37:18, s. 2482-2493
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Tidskriftsartikel (refereegranskat)abstract
- Background: The ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) phase 3 clinical trials showed that the adjuvanted recombinant zoster vaccine (RZV) was ≥90% efficacious in preventing herpes zoster in adults. Here we present a comprehensive overview of the safety data from these studies. Methods: Adults aged ≥50 (ZOE-50) and ≥70 (ZOE-70) years were randomly vaccinated with RZV or placebo. Safety analyses were performed on the pooled total vaccinated cohort, consisting of participants receiving at least one dose of RZV or placebo. Solicited and unsolicited adverse events (AEs) were collected for 7 and 30 days after each vaccination, respectively. Serious AEs (SAEs) were collected from the first vaccination until 12 months post-last dose. Fatal AEs, vaccination-related SAEs, and potential immune-mediated diseases (pIMDs) were collected during the entire study period. Results: Safety was evaluated in 14,645 RZV and 14,660 placebo recipients. More RZV than placebo recipients reported unsolicited AEs (50.5% versus 32.0%); the difference was driven by transient injection site and solicited systemic reactions that were generally seen in the first week post-vaccination. The occurrence of overall SAEs (RZV: 10.1%; Placebo: 10.4%), fatal AEs (RZV: 4.3%; Placebo: 4.6%), and pIMDs (RZV: 1.2%; Placebo: 1.4%) was balanced between groups. The occurrence of possible exacerbations of pIMDs was rare and similar between groups. Overall, except for the expected local and systemic symptoms, the safety results were comparable between the RZV and Placebo groups irrespective of participant age, gender, or race. Conclusions: No safety concerns arose, supporting the favorable benefit-risk profile of RZV. © 2019 GlaxoSmithKline Biologicals SA
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