SwePub - sökning: WFRF:(Lambert Thomas)

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1.	2021 swepub:Mat__t
2.	Menkveld, Albert J., et al. (författare) Nonstandard Errors 2024 Ingår i: JOURNAL OF FINANCE. - : Wiley-Blackwell. - 0022-1082 .- 1540-6261. ; 79:3, s. 2339-2390 Tidskriftsartikel (refereegranskat)abstract In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants.
3.	2021 swepub:Mat__t
4.	Amare, Azmeraw, et al. (författare) Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder. 2023 Ingår i: Research square. - : Research Square Platform LLC. Tidskriftsartikel (refereegranskat)abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<��.
5.	Amare, Azmeraw T, et al. (författare) Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder. 2023 Ingår i: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261 Tidskriftsartikel (refereegranskat)abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
6.	Glasbey, JC, et al. (författare) 2021 swepub:Mat__t
7.	Bravo, L, et al. (författare) 2021 swepub:Mat__t
8.	Tabiri, S, et al. (författare) 2021 swepub:Mat__t
9.	Bellenguez, C, et al. (författare) New insights into the genetic etiology of Alzheimer's disease and related dementias 2022 Ingår i: Nature genetics. - : NATURE PORTFOLIO. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436 Tidskriftsartikel (refereegranskat)
10.	Campbell, PJ, et al. (författare) Pan-cancer analysis of whole genomes 2020 Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82- Tidskriftsartikel (refereegranskat)abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
11.	Kliest, Tessa, et al. (författare) Clinical trials in pediatric ALS: a TRICALS feasibility study 2022 Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis Group. - 2167-8421 .- 2167-9223. ; 23:7-8, s. 481-488 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.
12.	Walker, Tom W. N., et al. (författare) Lowland plant arrival in alpine ecosystems facilitates a decrease in soil carbon content under experimental climate warming 2022 Ingår i: eLIFE. - : eLife Sciences Publications, Ltd. - 2050-084X. ; 11 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.
13.	Bellenguez, C, et al. (författare) New insights into the genetic etiology of Alzheimer's disease and related dementias 2022 Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436 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.
14.	Brovkin, Victor, et al. (författare) Past abrupt changes, tipping points and cascading impacts in the Earth system 2021 Ingår i: Nature Geoscience. - : Springer Science and Business Media LLC. - 1752-0894 .- 1752-0908. ; 14:8, s. 550-558 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.
15.	Garcia-Hernandez, D. A., et al. (författare) The Carbon Star DY Persei May Be a Cool R Coronae Borealis Variable 2023 Ingår i: Astrophysical Journal. - : Institute of Physics Publishing (IOPP). - 0004-637X .- 1538-4357. ; 948:1 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.
16.	Gonzalez-Robles, Cristina, et al. (författare) Outcome Measures for Disease-Modifying Trials in Parkinson's Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative 2023 Ingår i: JOURNAL OF PARKINSONS DISEASE. - 1877-7171 .- 1877-718X. ; 13:6, s. 1013-1035 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.
17.	Gould, Rebecca L., et al. (författare) 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 Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 403:10442, s. 2381-2394 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.
18.	Khatri, C, et al. (författare) Outcomes after perioperative SARS-CoV-2 infection in patients with proximal femoral fractures: an international cohort study 2021 Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 11:11, s. e050830- 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
19.	Le Guen, Yann, et al. (författare) Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB104 subtypes. 2023 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 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-DRB104 subtypes best accounted for the association, strongest with HLA-DRB104:04 and HLA-DRB104:07, and intermediary with HLA-DRB104:01 and HLA-DRB104:03. 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-DRB104 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.
20.	Long, Maeve, et al. (författare) DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion 2022 Ingår i: EMBO Journal. - : John Wiley & Sons. - 0261-4189 .- 1460-2075. ; 41 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.
21.	Luo, Jiao, et al. (författare) Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease 2023 Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 6:5 Tidskriftsartikel (refereegranskat)abstract IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022.EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors.RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]).CONCLUSIONS AND RELEVANCE This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.
22.	Miller, Rachael, et al. (författare) Socio-ecological correlates of neophobia in corvids 2022 Ingår i: Current Biology. - : Elsevier BV. - 0960-9822. ; 32:1, s. 4-85 Tidskriftsartikel (refereegranskat)abstract Behavioral responses to novelty, including fear and subsequent avoidance of novel stimuli, i.e., neophobia, determine how animals interact with their environment. Neophobia aids in navigating risk and impacts on adaptability and survival. There is variation within and between individuals and species; however, lack of large-scale, comparative studies critically limits investigation of the socio-ecological drivers of neophobia. In this study, we tested responses to novel objects and food (alongside familiar food) versus a baseline (familiar food alone) in 10 corvid species (241 subjects) across 10 labs worldwide. There were species differences in the latency to touch familiar food in the novel object and novel food conditions relative to the baseline. Four of seven socio-ecological factors influenced object neophobia: (1) use of urban habitat (versus not), (2) territorial pair versus family group sociality, (3) large versus small maximum flock size, and (4) moderate versus specialized caching (whereas range, hunting live animals, and genus did not), while only maximum flock size influenced food neophobia. We found that, overall, individuals were temporally and contextually repeatable (i.e., consistent) in their novelty responses in all conditions, indicating neophobia is a stable behavioral trait. With this study, we have established a network of corvid researchers, demonstrating potential for further collaboration to explore the evolution of cognition in corvids and other bird species. These novel findings enable us, for the first time in corvids, to identify the socio-ecological correlates of neophobia and grant insight into specific elements that drive higher neophobic responses in this avian family group. Video abstract: [Figure presented]
23.	Morales, Daniel R, et al. (författare) Renin-angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis. 2021 Ingår i: The Lancet Digital health. - 2589-7500. ; 3:2 Tidskriftsartikel (refereegranskat)abstract Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been postulated to affect susceptibility to COVID-19. Observational studies so far have lacked rigorous ascertainment adjustment and international generalisability. We aimed to determine whether use of ACEIs or ARBs is associated with an increased susceptibility to COVID-19 in patients with hypertension.In this international, open science, cohort analysis, we used electronic health records from Spain (Information Systems for Research in Primary Care [SIDIAP]) and the USA (Columbia University Irving Medical Center data warehouse [CUIMC] and Department of Veterans Affairs Observational Medical Outcomes Partnership [VA-OMOP]) to identify patients aged 18 years or older with at least one prescription for ACEIs and ARBs (target cohort) or calcium channel blockers (CCBs) and thiazide or thiazide-like diuretics (THZs; comparator cohort) between Nov 1, 2019, and Jan 31, 2020. Users were defined separately as receiving either monotherapy with these four drug classes, or monotherapy or combination therapy (combination use) with other antihypertensive medications. We assessed four outcomes: COVID-19 diagnosis; hospital admission with COVID-19; hospital admission with pneumonia; and hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis. We built large-scale propensity score methods derived through a data-driven approach and negative control experiments across ten pairwise comparisons, with results meta-analysed to generate 1280 study effects. For each study effect, we did negative control outcome experiments using a possible 123 controls identified through a data-rich algorithm. This process used a set of predefined baseline patient characteristics to provide the most accurate prediction of treatment and balance among patient cohorts across characteristics. The study is registered with the EU Post-Authorisation Studies register, EUPAS35296.Among 1355349 antihypertensive users (363785 ACEI or ARB monotherapy users, 248915 CCB or THZ monotherapy users, 711799 ACEI or ARB combination users, and 473076 CCB or THZ combination users) included in analyses, no association was observed between COVID-19 diagnosis and exposure to ACEI or ARB monotherapy versus CCB or THZ monotherapy (calibrated hazard ratio [HR] 0·98, 95% CI 0·84-1·14) or combination use exposure (1·01, 0·90-1·15). ACEIs alone similarly showed no relative risk difference when compared with CCB or THZ monotherapy (HR 0·91, 95% CI 0·68-1·21; with heterogeneity of >40%) or combination use (0·95, 0·83-1·07). Directly comparing ACEIs with ARBs demonstrated a moderately lower risk with ACEIs, which was significant with combination use (HR 0·88, 95% CI 0·79-0·99) and non-significant for monotherapy (0·85, 0·69-1·05). We observed no significant difference between drug classes for risk of hospital admission with COVID-19, hospital admission with pneumonia, or hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis across all comparisons.No clinically significant increased risk of COVID-19 diagnosis or hospital admission-related outcomes associated with ACEI or ARB use was observed, suggesting users should not discontinue or change their treatment to decrease their risk of COVID-19.Wellcome Trust, UK National Institute for Health Research, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research & Development, IQVIA, South Korean Ministry of Health and Welfare Republic, Australian National Health and Medical Research Council, and European Health Data and Evidence Network.
24.	Neal, DE, et al. (författare) Ten-year Mortality, Disease Progression, and Treatment-related Side Effects in Men with Localised Prostate Cancer from the ProtecT Randomised Controlled Trial According to Treatment Received 2020 Ingår i: European urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 77:3, s. 320-330 Tidskriftsartikel (refereegranskat)
25.	Reinke, Beth A, et al. (författare) Diverse aging rates in ectothermic tetrapods provide insights for the evolution of aging and longevity 2022 Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 376:6600, s. 1459-1466 Tidskriftsartikel (refereegranskat)abstract Comparative studies of mortality in the wild are necessary to understand the evolution of aging; yet, ectothermic tetrapods are underrepresented in this comparative landscape, despite their suitability for testing evolutionary hypotheses. We present a study of aging rates and longevity across wild tetrapod ectotherms, using data from 107 populations (77 species) of nonavian reptiles and amphibians. We test hypotheses of how thermoregulatory mode, environmental temperature, protective phenotypes, and pace of life history contribute to demographic aging. Controlling for phylogeny and body size, ectotherms display a higher diversity of aging rates compared with endotherms and include phylogenetically widespread evidence of negligible aging. Protective phenotypes and life-history strategies further explain macroevolutionary patterns of aging. Analyzing ectothermic tetrapods in a comparative context enhances our understanding of the evolution of aging.
26.	Sergeev, Denis E., et al. (författare) The TRAPPIST-1 Habitable Atmosphere Intercomparison (THAI). II. Moist Cases-The Two Waterworlds 2022 Ingår i: The Planetary Science Journal. - : IOP Publishing Ltd. - 2632-3338. ; 3:9 Tidskriftsartikel (refereegranskat)abstract To identify promising exoplanets for atmospheric characterization and to make the best use of observational data, a thorough understanding of their atmospheres is needed. Three-dimensional general circulation models (GCMs) are one of the most comprehensive tools available for this task and will be used to interpret observations of temperate rocky exoplanets. Due to parameterization choices made in GCMs, they can produce different results, even for the same planet. Employing four widely used exoplanetary GCMs-ExoCAM, LMD-G, ROCKE-3D, and the UM-we continue the TRAPPIST-1 Habitable Atmosphere Intercomparison by modeling aquaplanet climates of TRAPPIST-1e with a moist atmosphere dominated by either nitrogen or carbon dioxide. Although the GCMs disagree on the details of the simulated regimes, they all predict a temperate climate with neither of the two cases pushed out of the habitable state. Nevertheless, the intermodel spread in the global mean surface temperature is nonnegligible: 14 K and 24 K in the nitrogen- and carbon dioxide-dominated case, respectively. We find substantial intermodel differences in moist variables, with the smallest amount of clouds in LMD-Generic and the largest in ROCKE-3D. ExoCAM predicts the warmest climate for both cases and thus has the highest water vapor content and the largest amount and variability of cloud condensate. The UM tends to produce colder conditions, especially in the nitrogen-dominated case due to a strong negative cloud radiative effect on the day side of TRAPPIST-1e. Our study highlights various biases of GCMs and emphasizes the importance of not relying solely on one model to understand exoplanet climates.
27.	Tancin Lambert, Anna, et al. (författare) Biomarkers Predictive of Atrial Fibrillation in Patients with Cryptogenic Stroke. Insights from The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study 2023 Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 30:5, s. 1352-1363 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: There are currently no biomarkers used to select cryptogenic stroke (CS) patients for monitoring with insertable cardiac monitors (ICMs), the most effective tool for diagnosing atrial fibrillation (AF) in CS. The purpose of this study was to assess clinically available biomarkers as predictors of AF.METHODS: Eligible CS and cryptogenic transient ischemic attack (TIA) patients underwent 12-month monitoring with ICMs, clinical follow-up, and biomarker sampling. Levels of cardiac and thromboembolic biomarkers, taken within 14 days from symptom onset, were compared between patients diagnosed with AF (n=74) during monitoring and those without AF (n=185). Receiver operating characteristic (ROC) curves were created. Biomarkers reaching area under ROC curve (AUC) ≥ 0.7 were dichotomized by finding optimal cut-off values and used in logistic regression establishing their predictive value for increased risk of AF in unadjusted and adjusted models.RESULTS: B-type natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP), creatine kinase, D-dimer, high-sensitivity cardiac Troponin I and T were significantly higher in the AF than non-AF group. BNP and NT-proBNP reached predefined AUC level, 0.755 and 0.725 respectively. Optimal cut-off values were 33.5 ng/L for BNP, and 87 ng/L for NT-proBNP. Regression analysis showed that NT-proBNP was a predictor of AF in both unadjusted, odds ratio (OR) 7.72 (95% confidence interval [CI] 3.16-18.87), and age and sex adjusted models, OR 4.82 (95% CI 1.79-12.96).CONCLUSION: Several clinically established biomarkers were associated with AF. NT-proBNP performed best as AF predictor and could be used for selecting patients for long-term monitoring with ICMs.
28.	Turbet, Martin, et al. (författare) The TRAPPIST-1 Habitable Atmosphere Intercomparison (THAI). I. Dry Cases-The Fellowship of the GCMs 2022 Ingår i: The Planetary Science Journal. - : IOP Publishing Ltd. - 2632-3338. ; 3:9 Tidskriftsartikel (refereegranskat)abstract With the commissioning of powerful, new-generation telescopes such as the James Webb Space Telescope (JWST) and the ground-based Extremely Large Telescopes, the first characterization of a high molecular weight atmosphere around a temperate rocky exoplanet is imminent. Atmospheric simulations and synthetic observables of target exoplanets are essential to prepare and interpret these observations. Here we report the results of the first part of the TRAPPIST-1 Habitable Atmosphere Intercomparison (THAI) project, which compares 3D numerical simulations performed with four state-of-the-art global climate models (ExoCAM, LMD-Generic, ROCKE-3D, Unified Model) for the potentially habitable target TRAPPIST-1e. In this first part, we present the results of dry atmospheric simulations. These simulations serve as a benchmark to test how radiative transfer, subgrid-scale mixing (dry turbulence and convection), and large-scale dynamics impact the climate of TRAPPIST-1e and consequently the transit spectroscopy signature as seen by JWST. To first order, the four models give results in good agreement. The intermodel spread in the global mean surface temperature amounts to 7 K (6 K) for the N-2-dominated (CO2-dominated) atmosphere. The radiative fluxes are also remarkably similar (intermodel variations less than 5%), from the surface (1 bar) up to atmospheric pressures similar to 5 mbar. Moderate differences between the models appear in the atmospheric circulation pattern (winds) and the (stratospheric) thermal structure. These differences arise between the models from (1) large-scale dynamics, because TRAPPIST-1e lies at the tipping point between two different circulation regimes (fast and Rhines rotators) in which the models can be alternatively trapped, and (2) parameterizations used in the upper atmosphere such as numerical damping.
29.	Wagner, Jessica, et al. (författare) Medin co-aggregates with vascular amyloid-beta in Alzheimers disease 2022 Ingår i: Nature. - : Nature Portfolio. - 0028-0836 .- 1476-4687. ; 612, s. 123-131 Tidskriftsartikel (refereegranskat)abstract Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age(1,)(2), making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction(3). Here we demonstrate in amyloid-beta precursor protein (APP) transgenic mice and in patients with Alzheimers disease that medin co-localizes with vascular amyloid-beta deposits, and that in mice, medin deficiency reduces vascular amyloid-beta deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-beta burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimers disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-beta to promote its aggregation, as medin forms heterologous fibrils with amyloid-beta, affects amyloid-beta fibril structure, and cross-seeds amyloid-beta aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-beta deposition in the blood vessels of the brain.

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