| 1. |
- Christesen, Henrik Thybo, et al.
(author)
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Tissue variations of mosaic genome-wide paternal uniparental disomy and phenotype of multi-syndromal congenital hyperinsulinism
- 2020
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In: European Journal of Medical Genetics. - : Elsevier BV. - 1769-7212 .- 1878-0849. ; 63:1
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Journal article (peer-reviewed)abstract
- Mosaic genome-wide paternal uniparental disomy (GW-pUPD) is a rarely recognised disorder. The phenotypic manifestations of multilocus imprinting defects (MLIDs) remain unclear. We report of an apparently non-syndromic infant with severe congenital hyperinsulinism (CHI) and diffuse pancreatic labelling by 18F*-DOPA-PET/CT leading to near-total pancreatectomy. The histology was atypical with pronounced proliferation of endocrine cells comprising >70% of the pancreatic tissue and a small pancreatoblastoma. Routine genetic analysis for CHI was normal in the blood and resected pancreatic tissue. At two years’ age, Beckwith-Wiedemann Syndrome (BWS) stigmata emerged, and at five years a liver tumour with focal nodular hyperplasia and an adrenal tumour were resected. pUPD was detected in 11p15 and next in the entire chromosome 11 with microsatellite markers. Quantitative fluorescent PCR with amplification of chromosome-specific DNA sequences for chromosomes 13, 18, 21 and X indicated GW-pUPD. A next generation sequencing panel with 303 SNPs on 21 chromosomes showed pUPD in both blood and pancreatic tissue. The mosaic distribution of GW-pUPD ranged from 31 to 35% in blood and buccal swap to 74% in the resected pancreas, 80% in a non-tumour liver biopsy, and 100% in the liver focal nodular hyperplasia and adrenal tumour. MLID features included transient conjugated hyperbilirubinaemia and lack of macrosomia from BWS (pUPD6); and behavioural and psychomotor manifestations of Angelman Syndrome (pUPD15) on follow-up. In conclusion, atypical pancreatic histology in apparently non-syndromic severe CHI patients may be the first clue to BWS and multi-syndromal CHI from GW-pUPD. Variations in the degree of mosaicism between tissues explained the phenotype.
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| 2. |
- Jensen, Lars Henrik, et al.
(author)
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Phase III randomized clinical trial comparing the efficacy of neoadjuvant chemotherapy and standard treatment in patients with locally advanced colon cancer: The NeoCol trial.
- 2023
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In: JOURNAL OF CLINICAL ONCOLOGY. - 0732-183X .- 1527-7755. ; 41:17_SUPPL
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Journal article (peer-reviewed)abstract
- LBA3503Background: Locally advanced colon cancer presents a therapeutic challenge regarding improving survival and minimizing side effects by optimizing the timing of surgical and systemic treatments. Neoadjuvant chemotherapy is a widely accepted approach in numerous cancers as it aims to eliminate micrometastases and reduce tumor size. Our study aimed to assess the impact of neoadjuvant chemotherapy on locally advanced colon cancer compared to standard initial surgery. Methods: This was a randomized, controlled, phase III clinical trial. Patients aged 18 years or older with biopsy-proven colon cancer were eligible for inclusion if staged as T4 or T3 with invasion depth >= 5 mm, N0-2, and M0 according to CT scan evaluation. Patients were randomly assigned to either standard upfront surgery or surgery after neoadjuvant chemotherapy with either 3 cycles of CAPOX (oxaliplatin, capecitabine every 3 weeks) or 4 cycles of FOLFOX (oxaliplatin, 5FU every 2 weeks). Adjuvant chemotherapy was chosen based on the pathological stage of the cancer according to guidelines. The primary endpoint, disease-free survival (DFS), was analyzed on an intent-to-treat basis. The sample size was set at 125 patients per arm, based on a projected increase in two-year disease-free survival from 80% to 90%, with a two-sided significance level of 5%, power of 80%, 3 years of inclusion, 2 years of follow-up, and a 10% drop-out rate. Results: Nine centers in 3 countries included 122 patients in the standard group and 126 patients in the neoadjuvant group from 10/2013 to 11/2021. Forty-four % were female, the median age was 66 years, and 91% had a performance status (PS) of 0, while 9% had a PS of 1. Seventy-three % of the tumors were classified as T3, with a median outgrowth of 11 mm, while 26% were classified as T4 on the baseline CT scan. There were no significant differences in baseline characteristics. The median number of chemotherapy cycles was lower in the neoadjuvant group, 3 (IQR 1-7) vs. 4 (0-8). There were slightly more postoperative complications in the standard group regarding ileus, anastomotic leakage, and length of stay. Postoperatively, more patients in the standard arm had an indication of adjuvant chemotherapy, 88 vs. 72 (p = 0.02). DFS at 2 years was similar in the two arms (p = 0.95, logrank), as was overall survival (OS) (p = 0.95, logrank). Conclusions: Neoadjuvant chemotherapy and standard upfront surgery showed no significant difference in DFS and OS in patients with colon cancer. However, neoadjuvant chemotherapy seemed to have more favorable outcomes in terms of chemotherapy cycles, postoperative complications, and downstaging. CT scan alone may not be sufficient in identifying high-risk patients preoperatively. These findings suggest that neoadjuvant chemotherapy could be considered a viable treatment option for patients with locally advanced colon cancer. Clinical trial information: NCT01918527.
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| 3. |
- Kloske, C. M., et al.
(author)
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APOE and immunity: Research highlights
- 2023
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In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:6, s. 2677-2696
-
Research review (peer-reviewed)abstract
- INTRODUCTIONAt the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODSThe meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTSDuring the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor alpha [TNF alpha]). DISCUSSIONThis manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.
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| 4. |
- Allen-Perkins, Alfonso, et al.
(author)
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CropPol : a dynamic, open and global database on crop pollination
- 2022
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In: Ecology. - : Wiley. - 0012-9658 .- 1939-9170. ; 103:3
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Journal article (peer-reviewed)abstract
- Seventy five percent of the world's food crops benefit from insect pollination. Hence, there has been increased interest in how global change drivers impact this critical ecosystem service. Because standardized data on crop pollination are rarely available, we are limited in our capacity to understand the variation in pollination benefits to crop yield, as well as to anticipate changes in this service, develop predictions, and inform management actions. Here, we present CropPol, a dynamic, open and global database on crop pollination. It contains measurements recorded from 202 crop studies, covering 3,394 field observations, 2,552 yield measurements (i.e. berry weight, number of fruits and kg per hectare, among others), and 47,752 insect records from 48 commercial crops distributed around the globe. CropPol comprises 32 of the 87 leading global crops and commodities that are pollinator dependent. Malus domestica is the most represented crop (32 studies), followed by Brassica napus (22 studies), Vaccinium corymbosum (13 studies), and Citrullus lanatus (12 studies). The most abundant pollinator guilds recorded are honey bees (34.22% counts), bumblebees (19.19%), flies other than Syrphidae and Bombyliidae (13.18%), other wild bees (13.13%), beetles (10.97%), Syrphidae (4.87%), and Bombyliidae (0.05%). Locations comprise 34 countries distributed among Europe (76 studies), Northern America (60), Latin America and the Caribbean (29), Asia (20), Oceania (10), and Africa (7). Sampling spans three decades and is concentrated on 2001-05 (21 studies), 2006-10 (40), 2011-15 (88), and 2016-20 (50). This is the most comprehensive open global data set on measurements of crop flower visitors, crop pollinators and pollination to date, and we encourage researchers to add more datasets to this database in the future. This data set is released for non-commercial use only. Credits should be given to this paper (i.e., proper citation), and the products generated with this database should be shared under the same license terms (CC BY-NC-SA). This article is protected by copyright. All rights reserved.
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| 5. |
- Andersen, Mikkel Rathsach, et al.
(author)
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Tibial Component Undersizing Is Related to High Degrees of Implant Migration Following Cementless Total Knee Arthroplasty : A Study of Radiostereometric Analysis Data for 111 Patients with 2-Year Follow-up
- 2023
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In: JBJS Open Access. - 2472-7245. ; 8:3
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Journal article (peer-reviewed)abstract
- Background: Radiostereometric analysis (RSA) studies have shown that the continuous migration of tibial components is predictive of aseptic loosening following total knee arthroplasty (TKA). In the present study, we investigated whether accurate sizing and placement of tibial components are related to the degree of implant migration as measured with use of RSA.Methods:A total of 111 patients who underwent TKA surgery with a cementless tibial component were followed for a period of 2 years postoperatively, during which implant migration was assessed with use of RSA. RSA was performed within 7 days postoperatively and after 3, 6, 12, and 24 months. Postoperative radiographs were evaluated for component size and placement in the tibia. The evaluations were performed by experienced knee surgeons who were blinded to the migration data and clinical outcomes. A multivariable linear regression analysis was conducted.Results:Continuous implant migration (i.e., migration occurring between 12 and 24 months postoperatively) had a negative association with tibial component size (coefficient [B], -0.2; 95% confidence interval [CI], -0.33 to -0.08). Subsidence was associated with the absence of posterior cortical bone support (B, -0.7; 95% CI, -1.09 to -0.28), the absence of lateral cortical bone support (B, 0.8; 95% CI, 0.29 to 1.37), frontal-plane varus malalignment (B, 0.6; 95% CI, 0.12 to 1.16), and component undersizing (B, -0.4; 95% CI, -0.06 to -0.68). Posterior tilt was associated only with undersizing (B, 0.6; 95% CI, 0.27 to 1.11).Conclusions:Undersized cementless tibial components are at a higher risk for poor fixation with continuous migration following TKA. Therefore, a higher risk of aseptic loosening should be expected.Level of Evidence:Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
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| 6. |
- Bonde, Jens Peter Ellekilde, et al.
(author)
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Occupational risk of COVID-19 related hospital admission in Denmark 2020–2021 : a follow-up study
- 2023
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In: Scandinavian Journal of Work, Environment and Health. - : Scandinavian Journal of Work, Environment and Health. - 0355-3140 .- 1795-990X. ; 49:1, s. 84-94
-
Journal article (peer-reviewed)abstract
- Objective: Mounting evidence indicates increased risk of COVID-19 among healthcare personnel, but the evidence on risks in other occupations is limited. In this study, we quantify the occupational risk of COVID-19-related hospital admission in Denmark during 2020-2021.Methods: The source population included 2.4 million employees age 20-69 years. All information was retrieved from public registers. The risk of COVID-19 related hospital admission was examined in 155 occupations with at least 2000 employees (at-risk, N=1 620 231) referenced to a group of mainly office workers defined by a COVID-19 job exposure matrix (N=369 341). Incidence rate ratios (IRR) were computed by Poisson regression.Results: During 186 million person-weeks of follow-up, we observed 2944 COVID-19 related hospital admissions in at-risk occupations and 559 in referents. Adjusted risk of such admission was elevated in several occupations within healthcare (including health care assistants, nurses, medical practitioners and laboratory technicians but not physiotherapists or midwives), social care (daycare assistants for children aged 4-7, and nursing aides in institutions and private homes, but not family daycare workers) and transportation (bus drivers, but not lorry drivers). Most IRR in these at-risk occupations were in the range of 1.5-3. Employees in education, retail sales and various service occupations seemed not to be at risk.Conclusion: Employees in several occupations within and outside healthcare are at substantially increased risk of COVID-19. There is a need to revisit safety measures and precautions to mitigate viral transmission in the workplace during the current and forthcoming pandemics.
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| 7. |
- Christiansen, Jacob Stordal, et al.
(author)
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Filled Julia Sets of Chebyshev Polynomials
- 2021
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In: Journal of Geometric Analysis. - : Springer Science and Business Media LLC. - 1050-6926 .- 1559-002X. ; 31:12, s. 12250-12263
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Journal article (peer-reviewed)abstract
- We study the possible Hausdorff limits of the Julia sets and filled Julia sets of subsequences of the sequence of dual Chebyshev polynomials of a non-polar compact set K⊂ C and compare such limits to K. Moreover, we prove that the measures of maximal entropy for the sequence of dual Chebyshev polynomials of K converges weak* to the equilibrium measure on K.
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| 8. |
- Feng, Shaohong, et al.
(author)
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Dense sampling of bird diversity increases power of comparative genomics
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 587:7833
-
Journal article (peer-reviewed)abstract
- Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity(1-4). Sparse taxon sampling has previously been proposed to confound phylogenetic inference(5), and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families-including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species. A dataset of the genomes of 363 species from the Bird 10,000 Genomes Project shows increased power to detect shared and lineage-specific variation, demonstrating the importance of phylogenetically diverse taxon sampling in whole-genome sequencing.
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| 9. |
- Ghouse, Jonas, et al.
(author)
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Association of Variants Near the Bradykinin Receptor B2 Gene With Angioedema in Patients Taking ACE Inhibitors
- 2021
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In: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 78:7, s. 696-709
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Journal article (peer-reviewed)abstract
- BACKGROUND Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensinconverting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. OBJECTIVES The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema. METHODS A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors #180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model. RESULTS The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 x 10-8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 x 10-9). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 x 10-3). We found that carriers of the risk allele had significantly lower systolic (-0.46 mm Hg per T allele; 95% CI:-0.83 to-0.10; P = 0.013) and diastolic (-0.26 mm Hg per T allele; 95% CI:-0.46 to-0.05; P = 0.013) blood pressure. CONCLUSIONS In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with increased risk for ACE inhibitor-related angioedema.
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| 10. |
- Heegård Petersen, Jan, et al.
(author)
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Narrative structures in languages of the Hindu Kush : A preliminary corpus-based study
- 2022
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Conference paper (peer-reviewed)abstract
- There is a growing body of areal-typological as well as descriptive studies on languages of the linguistically rich and diverse Hindu Kush region of High Asia (Bashir 2016; Liljegren 2020b), but comparatively little attention has been given to properties related to discourse structures and the characteristics of e.g. storytelling and other primarily oral genres (Heegård Petersen 2015: 75–82; Obrtelová 2019; Schmidt 2003). In the present study, documentation corpora, consisting primarily of narratives with single speakers, have been analysed, with the explicit goal of establishing an areal typology of narrative structures. While the analytical focus is on well-annotated corpora of two selected Indo-Aryan languages spoken in the region that have been subject to modern documentation efforts, additional comparisons are made with – more or less thoroughly – annotated text data from past or ongoing documentation efforts in neighbouring languages.Some of the characteristics of Hindu Kush narratives – while far from forming a complete orstructured list – are: a) a high frequency of discourse markers signalling e.g. new developments, topic-shifting or contrast; b) the occurrence of tail-head-linkage and cosubordination (Haspelmath 1995: 20–27); c) the occurrence of “dramatizing” or “intensifying” features, e.g. by means of reduplication or prosodic features such as lengthening, laryngealization or creaky voice; d) feedback prompting, gestural or explicitly expressed as ‘did you understand?’; e) a frequent – although not necessarily a fully grammaticalized - use of evidentiality markers/contrasts, signalling e.g. hearsay, reported speech or reported perception (Bashir 2010; Liljegren 2020a: 147–150); f) formulaic expressions, occurring primarily in the opening or closing phases of a narrative; and g) contents referring to otherwise rarely mentioned mythical creatures or former (particularly pre-Islamic) religious practices (Schmidt 2006).While this investigation is largely descriptive by nature, we aim at addressing to what extent the structures that have been identified can be defined as truly area-specific or culture specific, or whether these properties in fact largely line up with more general observations made about narratives.
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| 11. |
- Jensen, Elisabeth Kjær, et al.
(author)
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Somatosensory Outcomes Following Re-Surgery in Persistent Severe Pain After Groin Hernia Repair : A Prospective Observational Study
- 2023
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In: Journal of Pain Research. - 1178-7090. ; 16, s. 943-959
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Journal article (peer-reviewed)abstract
- Purpose: After groin hernia repair (globally more than 20 million/year) 2–4% will develop persistent severe pain (PSPG). Pain management is challenging and may require multimodal interventions, including re-surgery. Quantitative somatosensory testing (QST) is an investigational psychophysiological tool with the potential to uncover the pathophysiological mechanisms behind the pain, ie, revealing neuropathic or inflammatory components. The primary objective was to examine and describe the underlying pathophysiological changes in the groin areas by QST before and after re-surgery with mesh removal and selective neurectomy. Patients and Methods: Sixty patients with PSPG scheduled for re-surgery and with an inflammatory “component” indicated by blunt pressure algometry were examined in median (95% CI) 7.9 (5.8–11.5) months before and 4.0 (3.5–4.6) months after re-surgery. The QST-analyses included standardized assessments of cutaneous mechanical/thermal detection and pain thresholds. Suprathreshold heat stimuli were applied. Deep tissue sensitivity was tested by pressure algometry. Testing sites were the groin areas and the lower arm. Before/after QST data were z-transformed. Results: Re-surgery resulted in median changes in rest, average, and maximal pain intensity scores of −2.0, −2.5, and −2.0 NRS (0/ 10) units, respectively (P = 0.0001), and proportional increases in various standardized functional scores (P = 0.0001). Compared with the control sites, the cutaneous somatosensory detection thresholds of the painful groin were increased before re-surgery and increased further after re-surgery (median difference: 1.28 z-values; P = 0.001), indicating a successive post-surgical loss of nerve fiber function (“deafferentation”). Pressure algometry thresholds increased after re-surgery (median difference: 0.30 z-values; P = 0.001). Conclusion: In this subset of patients with PSPG who underwent re-surgery, the procedure was associated with improved pain and functional outcomes. While the increase in somatosensory detection thresholds mirrors the surgery-induced cutaneous deafferentation, the increase in pressure algometry thresholds mirrors the removal of the deep “pain generator”. The QST-analyses are useful adjuncts in mechanism-based somatosensory research.
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| 12. |
- Kanoni, Stavroula, et al.
(author)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Journal article (peer-reviewed)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 13. |
- Mielke, M. M., et al.
(author)
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Comparison of CSF neurofilament light chain, neurogranin, and tau to MRI markers
- 2021
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In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:5, s. 801-812
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Journal article (peer-reviewed)abstract
- Introduction We determined whether cerebrospinal fluid (CSF) neurofilament light (NfL), neurogranin (Ng), and total-tau (t-tau) differentially mapped to magnetic resonance imaging (MRI) measures of cortical thickness, microstructural integrity (corpus callosum and cingulum fractional anisotropy [FA]), and white matter hyperintensities (WMH). Methods Analyses included 536 non-demented Mayo Clinic Study of Aging participants with CSF NfL, Ng, t-tau, amyloid beta (A beta)42 and longitudinal MRI scans. Linear mixed models assessed longitudinal associations between CSF markers and MRI changes. Results Higher CSF NfL was associated with decreasing microstructural integrity and WMH. Higher t-tau was associated with decreasing temporal lobe and Alzheimer's disease (AD) meta region of interest (ROI) cortical thickness. There was no association between Ng and any MRI measure. CSF A beta 42 interacted with Ng for declines in temporal lobe and AD meta ROI cortical thickness and cingulum FA. Discussion CSF NfL predicts changes in white matter integrity, t-tau reflects non-specific changes in cortical thickness, and Ng reflects AD-specific synaptic and neuronal degeneration.
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| 14. |
- Mielke, M. M., et al.
(author)
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Comparison of Plasma Phosphorylated Tau Species With Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes
- 2021
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In: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:9, s. 1108-1117
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Journal article (peer-reviewed)abstract
- IMPORTANCE Cerebrospinal fluid phosphorylated tau (p-tau) 181, p-tau217, and p-tau231 are associated with neuropathological outcomes, but a comparison of these p-tau isoforms in blood samples is needed. OBJECTIVE To conduct a head-to-head comparison of plasma p-tau181 and p-tau231 measured on the single-molecule array (Simoa) platform and p-tau181 and p-tau217 measured on the Meso Scale Discovery (MSD) platform on amyloid and tau positron emission tomography (PET) measures, neurodegeneration, vascular pathology, and cognitive outcomes. DESIGN, SETTING, AND PARTICIPANTS This study included data from the Mayo Clinic Study on Aging collected from March 1, 2015, to September 30, 2017, and analyzed between December 15, 2020, and May 17, 2021. Associations between the 4 plasma p-tau measures and dichotomous amyloid PET, metaregion of interest tau PET, and entorhinal cortex tau PET were analyzed using logistic regression models; the predictive accuracy was summarized using area under the receiver operating characteristic curve (AUROC) statistic. Of 1329 participants without dementia and with p-tau181 and p-tau217 on MSD, 200 participants with plasma p-tau181 and p-tau231 on Simoa and magnetic resonance imaging and amyloid and tau PET data at the same study visit were eligible. MAIN OUTCOMES AND MEASURES Primary outcomes included amyloid (greater than 1.48 standardized uptake value ratio) and tau PET, white matter hyperintensities, white matter microstructural integrity (fractional anisotropy genu of corpus callosum and hippocampal cingulum bundle), and cognition. RESULTS Of 200 included participants, 101 (50.5%) were male, and the median (interquartile range [IQR]) age was 79.5 (71.1-84.1) years. A total of 177 were cognitively unimpaired (CU) and 23 had mild cognitive impairment. Compared with amyloid-negative CU participants, among amyloid-positive CU participants, the median (IQR) Simoa p-tau181 measure was 49% higher (2.58 [2.00-3.72] vs 1.73 [1.45-2.13] pg/mL), MSD p-tau181 measure was 53% higher (1.22 [0.91-1.56] vs 0.80 [0.66-0.97] pg/mL), MSD p-tau217 measure was 77% higher (0.23 [0.17-0.34] vs 0.13 [0.09-0.18] pg/mL), and Simoa p-tau231 measure was 49% higher (20.21 [15.60-25.41] vs 14.27 [11.27-18.10] pg/mL). There were no differences between the p-tau species for amyloid PET and tau PET metaregions of interest. However, among CU participants, both MSD p-tau181 and MSD p-tau217 more accurately predicted abnormal entorhinal cortex tau PET than Simoa p-tau181 (MSD p-tau181: AUROC, 0.80 vs 0.70; P=.046; MSD p-tau217: AUROC, 0.81 vs 0.70; P=.04). MSD p-tau181 and p-tau217 and Simoa p-tau181, but not p-tau231, were associated with greater white matter hyperintensity volume and lower white matter microstructural integrity. CONCLUSIONS AND RELEVANCE In this largely presymptomatic population, these results suggest subtle differences across plasma p-tau species and platforms for the prediction of amyloid and tau PET and magnetic resonance imaging measures of cerebrovascular and Alzheimer-related pathology.
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| 15. |
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| 16. |
- Orme, T., et al.
(author)
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Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies
- 2020
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In: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 8:1
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Journal article (peer-reviewed)abstract
- Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.
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| 17. |
- Oskarsson, Trausti, et al.
(author)
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Skeletal adverse events in childhood cancer survivors : An Adult Life after Childhood Cancer in Scandinavia cohort study
- 2021
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In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 149:11, s. 1863-1876
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Journal article (peer-reviewed)abstract
- The dynamic growth of the skeleton during childhood and adolescence renders it vulnerable to adverse effects of cancer treatment. The lifetime risk and patterns of skeletal morbidity have not been described in a population-based cohort of childhood cancer survivors. A cohort of 26 334 1-year cancer survivors diagnosed before 20 years of age was identified from the national cancer registries of Denmark, Finland, Iceland and Sweden as well as a cohort of 127 531 age- and sex-matched comparison subjects randomly selected from the national population registries in each country. The two cohorts were linked with data from the national hospital registries and the observed numbers of first-time hospital admissions for adverse skeletal outcomes among childhood cancer survivors were compared to the expected numbers derived from the comparison cohort. In total, 1987 childhood cancer survivors had at least one hospital admission with a skeletal adverse event as discharge diagnosis, yielding a rate ratio (RR) of 1.35 (95% confidence interval, 1.29-1.42). Among the survivors, we observed an increased risk for osteonecrosis with a RR of 25.9 (15.0-44.5), osteoporosis, RR 4.53 (3.28-6.27), fractures, RR 1.27 (1.20-1.34), osteochondropathies, RR 1.57 (1.28-1.92) and osteoarthrosis, RR 1.48 (1.28-1.72). The hospitalization risk for any skeletal adverse event was higher among survivors up to the age of 60 years, but the lifetime pattern was different for each type of skeletal adverse event. Understanding the different lifetime patterns and identification of high-risk groups is crucial for developing strategies to optimize skeletal health in childhood cancer survivors.
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| 18. |
- Petersen Matjeka, Louise, et al.
(author)
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Restraints as a Mechanic for Bodily Play
- 2021
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In: ICSSP'22: Proceedings of the International Conference on Software and System Processes and International Conference on Global Software Engineering. - New York, NY, USA : Association for Computing Machinery (ACM). - 9781450396745
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Conference paper (peer-reviewed)abstract
- This paper presents restraints - directly imposed restrictions on players' bodily movements, as a mechanic for bodily play in HCI. While this is a familiar mechanic in non-digital movement-based games, its potential in designing bodily play experiences in HCI has been scarcely explored. Three types of restraints observed in non-digital movement-based games, are explored here: fixating body parts, excluding body parts and depriving/manipulating bodily senses. Then, we investigate the experiential dynamics of restraints as a bodily play mechanic bridging a phenomenological perspective on bodily movement with theories on play. These investigations form the theoretical framework for the subsequent analysis of five digital body game examples. Building on this analysis and theoretical framework, we formulate five design strategies for implementing restraints as a mechanic for bodily play in HCI. We propose restraints as a generative resource for researchers and designers interested in understanding and designing bodily play experiences in HCI.
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| 19. |
- Stockfelt, Marit, et al.
(author)
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Plasma interferon-alpha is associated with double-positivity for autoantibodies but is not a predictor of remission in early rheumatoid arthritis-a spin-off study of the NORD-STAR randomized clinical trial
- 2021
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In: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 23:1
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Journal article (peer-reviewed)abstract
- Background The type I interferon (IFN) gene signature is present in a subgroup of patients with early rheumatoid arthritis (RA). Protein levels of IFN alpha have not been measured in RA and it is unknown whether they associate with clinical characteristics or treatment effect. Methods Patients with early untreated RA (n = 347) were randomized to methotrexate combined with prednisone, certolizumab-pegol, abatacept, or tocilizumab. Plasma IFN alpha protein levels were determined by single molecular array (Simoa) before and 24 weeks after treatment initiation and were related to demographic and clinical factors including clinical disease activity index, disease activity score in 28 joints, swollen and tender joint counts, and patient global assessment. Results IFN alpha protein positivity was found in 26% of the patients, and of these, 92% were double-positive for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). IFN alpha protein levels were reduced 24 weeks after treatment initiation, and the absolute change was similar irrespective of treatment. IFN alpha protein positivity was associated neither with disease activity nor with achievement of CDAI remission 24 weeks after randomization. Conclusion IFN alpha protein positivity is present in a subgroup of patients with early RA and associates with double-positivity for autoantibodies but not with disease activity. Pre-treatment IFN alpha positivity did not predict remission in any of the treatment arms, suggesting that the IFN alpha system is distinct from the pathways of TNF, IL-6, and T-cell activation in early RA. A spin-off study of the NORD-STAR randomized clinical trial, NCT01491815 (ClinicalTrials), registered 12/08/2011, .
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| 20. |
- Svensson, Emma, et al.
(author)
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The Effect of Botulinum Toxin Type A Injections on Stricture Formation, Leakage Rates, Esophageal Elongation, and Anastomotic Healing Following Primary Anastomosis in a Long- and Short-Gap Esophageal Atresia Model : A Protocol for a Randomized, Controlled, Blinded Trial in Pigs
- 2021
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In: International Journal of Surgery Protocols. - : IJS Press. - 2468-3574. ; 25:1, s. 171-177
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Journal article (peer-reviewed)abstract
- Background:Esophageal atresia (EA) is a congenital malformation affecting 1:3000-4500 newborns. Approximately 15% have a long-gap EA (LGEA), in which case a primary anastomosis is often impossible to achieve. To create continuity of the esophagus patients instead have to undergo lengthening procedures or organ interpositions; methods associated with high morbidity and poor functional outcomes. Esophageal injections of Botulinum Toxin Type A (BTX-A) could enable primary anastomosis and mitigate stricture formation through decreased tissue tension.Methods and Analysis:In this randomized controlled blinded animal trial, 24 pigs are divided into a long- or short-gap EA group (LGEA and SGEA, respectively) and randomized to receive BTX-A or isotonic saline injections. In the LGEA group, injections are given endoscopically in the esophageal musculature. After seven days, a 3 cm esophageal resection and primary anastomosis is performed. In the SGEA group, a 1 cm esophageal resection and primary anastomosis is performed, followed by intraoperative injections of BTX-A or isotonic saline. After 14 days, stricture formation, presence of leakage, and esophageal compliance is assessed using endoscopic and manometric techniques, and in vivo and ex vivo contrast radiography. Tissue elongation is evaluated in a stretch-tension test, and the esophagus is assessed histologically to evaluate anastomotic healing.Ethics and Dissemination:The study complies with the ARRIVE guidelines for animal studies and has been approved by the Danish Animal Experimentation Council. Results will be published in peer-reviewed journals and presented at national and international conferences.
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| 21. |
- Swift, Imogen J, et al.
(author)
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A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.
- 2024
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In: Alzheimer's Research & Therapy. - 1758-9193. ; 16:1
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Journal article (peer-reviewed)abstract
- Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations.Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data.We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p=0.007) with a trend in non-carriers (p=0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers.These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.
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| 22. |
- Tate, A. E., et al.
(author)
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Association and Familial Coaggregation of Type 1 Diabetes and Eating Disorders: A Register-Based Cohort Study in Denmark and Sweden
- 2021
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In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 44:5, s. 1143-1150
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Journal article (peer-reviewed)abstract
- OBJECTIVE To ascertain the association and coaggregation of eating disorders and childhood-onset type 1 diabetes in families. RESEARCH DESIGN AND METHODS Using population samples from national registers in Sweden (n = 2,517,277) and Demark (n = 1,825,920), we investigated the within-individual association between type 1 diabetes and eating disorders and their familial coaggregation among full siblings, half siblings, full cousins, and half cousins. On the basis of clinical diagnoses, we classified eating disorders into any eating disorder (AED), anorexia nervosa (AN) and atypical AN, and other eating disorder (OED). Associations were determined with hazard ratios (HRs) with 95% CIs from Cox regressions. RESULTS Swedish and Danish individuals with a type 1 diabetes diagnosis had a greater risk of receiving an eating disorder diagnosis (HR [95% CI] Sweden: AED 2.02 [1.80-2.27], AN 1.63 [1.36-1.96], OED 2.34 [2.07-2.63]; Denmark: AED 2.19 [1.84-2.61], AN 1.78 [1.36-2.33], OED 2.65 [2.20-3.21]). We also meta-analyzed the results: AED 2.07 (1.88-2.28), AN 1.68 (1.44-1.95), OED 2.44 (2.17-2.72). There was an increased risk of receiving an eating disorder diagnosis in full siblings in the Swedish cohort (AED 1.25 [1.07-1.46], AN 1.28 [1.04-1.57], OED 1.28 [1.07-1.52]); these results were nonsignificant in the Danish cohort. CONCLUSIONS Patients with type 1 diabetes are at a higher risk of subsequent eating disorders; however, there is conflicting support for the relationship between having a sibling with type 1 diabetes and an eating disorder diagnosis. Diabetes health care teams should be vigilant about disordered eating behaviors in children and adolescents with type 1 diabetes.
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| 23. |
- Tosun, Duygu, et al.
(author)
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Detection of β-amyloid positivity in Alzheimer's Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers.
- 2021
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In: Brain communications. - : Oxford University Press (OUP). - 2632-1297. ; 3:2
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Journal article (peer-reviewed)abstract
- In vivo gold standard for the ante-mortem assessment of brain β-amyloid pathology is currently β-amyloid positron emission tomography or cerebrospinal fluid measures of β-amyloid42 or the β-amyloid42/β-amyloid40 ratio. The widespread acceptance of a biomarker classification scheme for the Alzheimer's disease continuum has ignited interest in more affordable and accessible approaches to detect Alzheimer's disease β-amyloid pathology, a process that often slows down the recruitment into, and adds to the cost of, clinical trials. Recently, there has been considerable excitement concerning the value of blood biomarkers. Leveraging multidisciplinary data from cognitively unimpaired participants and participants with mild cognitive impairment recruited by the multisite biomarker study of Alzheimer's Disease Neuroimaging Initiative, here we assessed to what extent plasma β-amyloid42/β-amyloid40, neurofilament light and phosphorylated-tau at threonine-181 biomarkers detect the presence of β-amyloid pathology, and to what extent the addition of clinical information such as demographic data, APOE genotype, cognitive assessments and MRI can assist plasma biomarkers in detecting β-amyloid-positivity. Our results confirm plasma β-amyloid42/β-amyloid40 as a robust biomarker of brain β-amyloid-positivity (area under curve, 0.80-0.87). Plasma phosphorylated-tau at threonine-181 detected β-amyloid-positivity only in the cognitively impaired with a moderate area under curve of 0.67, whereas plasma neurofilament light did not detect β-amyloid-positivity in either group of participants. Clinical information as well as MRI-score independently detected positron emission tomography β-amyloid-positivity in both cognitively unimpaired and impaired (area under curve, 0.69-0.81). Clinical information, particularly APOE ε4 status, enhanced the performance of plasma biomarkers in the detection of positron emission tomography β-amyloid-positivity by 0.06-0.14 units of area under curve for cognitively unimpaired, and by 0.21-0.25 units for cognitively impaired; and further enhancement of these models with an MRI-score of β-amyloid-positivity yielded an additional improvement of 0.04-0.11 units of area under curve for cognitively unimpaired and 0.05-0.09 units for cognitively impaired. Taken together, these multi-disciplinary results suggest that when combined with clinical information, plasma phosphorylated-tau at threonine-181 and neurofilament light biomarkers, and an MRI-score could effectively identify β-amyloid+ cognitively unimpaired and impaired (area under curve, 0.80-0.90). Yet, when the MRI-score is considered in combination with clinical information, plasma phosphorylated-tau at threonine-181 and plasma neurofilament light have minimal added value for detecting β-amyloid-positivity. Our systematic comparison of β-amyloid-positivity detection models identified effective combinations of demographics, APOE, global cognition, MRI and plasma biomarkers. Promising minimally invasive and low-cost predictors such as plasma biomarkers of β-amyloid42/β-amyloid40 may be improved by age and APOE genotype.
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| 24. |
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| 25. |
- Zhang, Ruyue, et al.
(author)
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Familial co-aggregation of schizophrenia and eating disorders in Sweden and Denmark
- 2021
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In: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 26:9, s. 5389-5397
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Journal article (peer-reviewed)abstract
- Eating disorders and schizophrenia are both moderately to highly heritable and share significant genetic risk despite distinct diagnostic criteria. Large-scale family studies on the co-aggregation of these disorders are lacking. Thus, we aimed to estimate the co-occurrence and familial co-aggregation of these disorders within the entire Swedish and Danish population. The proband cohort consisted of individuals born in Sweden (1977-2003) and Denmark (1984-2006) and still residing in their respective country at age six (NSweden = 2,535,191, NDenmark = 1,382,367). Probands were linked to their biological parents, siblings, grandparents, uncles/aunts, and cousins. Diagnoses for anorexia nervosa (AN) and other eating disorders (OED: bulimia nervosa, binge-eating disorder, and eating disorder not otherwise specified) for probands and schizophrenia diagnoses for both probands and relatives were obtained. The likelihood of having schizophrenia in those with AN or OED and their relatives was compared with individuals without eating disorder diagnoses and their relatives. Probands with AN or OED were more likely to have schizophrenia than probands without these disorders. All relatives of probands with AN or OED (except parents and uncles/aunts of probands with AN) were at increased risk of schizophrenia. In general, the magnitude of odds ratios attenuated with decreasing genetic relatedness. These results suggest familial liability contributes to the association between eating disorders and schizophrenia. Clinicians should be mindful of this comorbid and co-aggregation pattern as it may influence case conceptualization and treatment decisions.
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