| 11. |
- Kliest, Tessa, et al.
(författare)
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Clinical trials in pediatric ALS: a TRICALS feasibility study
- 2022
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis Group. - 2167-8421 .- 2167-9223. ; 23:7-8, s. 481-488
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.
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| 12. |
- Walker, Tom W. N., et al.
(författare)
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Lowland plant arrival in alpine ecosystems facilitates a decrease in soil carbon content under experimental climate warming
- 2022
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Ingår i: eLIFE. - : eLife Sciences Publications, Ltd. - 2050-084X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Climate warming is releasing carbon from soils around the world1–3, constituting a positive climate feedback. Warming is also causing species to expand their ranges into new ecosystems4–9. Yet, in most ecosystems, whether range expanding species will amplify or buffer expected soil carbon loss is unknown10. Here we used two whole-community transplant experiments and a follow-up glasshouse experiment to determine whether the establishment of herbaceous lowland plants in alpine ecosystems influences soil carbon content under warming. We found that warming (transplantation to low elevation) led to a negligible decrease in alpine soil carbon content, but its effects became significant and 52% ± 31% (mean ± 95% CIs) larger after lowland plants were introduced at low density into the ecosystem. We present evidence that decreases in soil carbon content likely occurred via lowland plants increasing rates of root exudation, soil microbial respiration and CO2 release under warming. Our findings suggest that warming-induced range expansions of herbaceous plants have the potential to alter climate feedbacks from this system, and that plant range expansions among herbaceous communities may be an overlooked mediator of warming effects on carbon dynamics.
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| 13. |
- Bellenguez, C, et al.
(författare)
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New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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| 14. |
- Brovkin, Victor, et al.
(författare)
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Past abrupt changes, tipping points and cascading impacts in the Earth system
- 2021
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Ingår i: Nature Geoscience. - : Springer Science and Business Media LLC. - 1752-0894 .- 1752-0908. ; 14:8, s. 550-558
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Forskningsöversikt (refereegranskat)abstract
- A synthesis of intervals of rapid climatic change evident in the geological record reveals some of the Earth system processes and tipping points that could lead to similar events in the future. The geological record shows that abrupt changes in the Earth system can occur on timescales short enough to challenge the capacity of human societies to adapt to environmental pressures. In many cases, abrupt changes arise from slow changes in one component of the Earth system that eventually pass a critical threshold, or tipping point, after which impacts cascade through coupled climate-ecological-social systems. The chance of detecting abrupt changes and tipping points increases with the length of observations. The geological record provides the only long-term information we have on the conditions and processes that can drive physical, ecological and social systems into new states or organizational structures that may be irreversible within human time frames. Here, we use well-documented abrupt changes of the past 30 kyr to illustrate how their impacts cascade through the Earth system. We review useful indicators of upcoming abrupt changes, or early warning signals, and provide a perspective on the contributions of palaeoclimate science to the understanding of abrupt changes in the Earth system.
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| 15. |
- Garcia-Hernandez, D. A., et al.
(författare)
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The Carbon Star DY Persei May Be a Cool R Coronae Borealis Variable
- 2023
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Ingår i: Astrophysical Journal. - : Institute of Physics Publishing (IOPP). - 0004-637X .- 1538-4357. ; 948:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical and near-IR photometry suggests that the carbon star DY Persei exhibits fadings similar to those of R Coronae Borealis (RCB) variables. Photometric surveys of the Galaxy and Magellanic Clouds uncovered new DY Per variables with infrared photometry identifying them with cool carbon stars, perhaps, with an unusual tendency to shed mass. In an attempt to resolve DY Per's identity crisis-a cool carbon giant or a cool RCB variable?-we analyze a high-resolution IGRINS H&K-band spectrum of DY Per. The CO first-overtone bands in the K band of DY Per show a high abundance of O-18 such that O-16/O-18 = 4 +/- 1, a ratio sharply at odds with published results for regular cool carbon giants with O-16/O-18 similar to 1000 but this exceptionally low ratio is characteristic of RCB variables and HdC stars. This similarity suggests that DY Per indeed may be a cool RCB variable. Current opinion considers RCB variables to result from the merger of a He onto a CO white dwarf; observed abundances of these H-deficient stars including the exceptionally low O-16/O-18 ratios are in fair accord with predicted compositions for white dwarf merger products. An H-deficiency for DY Per is not directly observable but is suggested from the strength of an HF line and an assumption that F may be overabundant, as observed and predicted for RCB stars.
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| 16. |
- Gonzalez-Robles, Cristina, et al.
(författare)
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Outcome Measures for Disease-Modifying Trials in Parkinson's Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative
- 2023
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Ingår i: JOURNAL OF PARKINSONS DISEASE. - 1877-7171 .- 1877-718X. ; 13:6, s. 1013-1035
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. Objective: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. Methods: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. Results: An extensive inventory ofOMwas created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. Conclusion: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges.
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| 17. |
- Gould, Rebecca L., et al.
(författare)
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Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND) : a multicentre, parallel, randomised controlled trial in the UK
- 2024
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 403:10442, s. 2381-2394
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Tidskriftsartikel (refereegranskat)abstract
- Background: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease.Methods: We conducted a parallel, multicentre, two -arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory -supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web -based system, stratified by site. Participants were followed up at 6 months and 9 months post -randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire -Revised (MQOL-R) at 6 months post -randomisation. Primary analyses were multi -level modelling and modified intention to treat among participants with available data. This trial was pre -registered with the ISRCTN Registry (ISRCTN12655391).Findings: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63⋅1 years (SD 11⋅0). 155 (81%) participants had primary outcome data at 6 months post -randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0⋅66 [95% CI 0⋅22-1⋅10]; d=0⋅46 [0⋅16-0⋅77]; p=0⋅0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention.Interpretation: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services.
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| 18. |
- Khatri, C, et al.
(författare)
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Outcomes after perioperative SARS-CoV-2 infection in patients with proximal femoral fractures: an international cohort study
- 2021
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 11:11, s. e050830-
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Tidskriftsartikel (refereegranskat)abstract
- Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.SettingProspective, international, multicentre, observational cohort study.ParticipantsPatients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.ResultsThis study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p<0.001), age >80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).ConclusionsPatients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration numberNCT04323644
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| 19. |
- Le Guen, Yann, et al.
(författare)
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Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
- 2023
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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 (PNAS). - 1091-6490 .- 0027-8424. ; 120:36
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Tidskriftsartikel (refereegranskat)abstract
- Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
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| 20. |
- Long, Maeve, et al.
(författare)
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DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion
- 2022
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Ingår i: EMBO Journal. - : John Wiley & Sons. - 0261-4189 .- 1460-2075. ; 41
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Tidskriftsartikel (refereegranskat)abstract
- Mitophagy removes defective mitochondria via lysosomal elimination. Increased mitophagy coincides with metabolic reprogramming, yet it remains unknown whether mitophagy is a cause or consequence of such state changes. The signalling pathways that integrate with mitophagy to sustain cell and tissue integrity also remain poorly defined. We performed temporal metabolomics on mammalian cells treated with deferiprone, a therapeutic iron chelator that stimulates PINK1/PARKIN-independent mitophagy. Iron depletion profoundly rewired the metabolome, hallmarked by remodelling of lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurred several hours before mitochondrial clearance, with lipid droplets bordering mitochondria upon iron chelation. We demonstrate that DGAT1 inhibition restricts mitophagy in vitro, with impaired lysosomal homeostasis and cell viability. Importantly, genetic depletion of DGAT1 in vivo significantly impaired neuronal mitophagy and locomotor function in Drosophila. Our data define iron depletion as a potent signal that rapidly reshapes metabolism and establishes an unexpected synergy between lipid homeostasis and mitophagy that safeguards cell and tissue integrity.
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