| 1. |
- Allentoft, Morten E., et al.
(author)
-
100 ancient genomes show repeated population turnovers in Neolithic Denmark
- 2024
-
In: Nature. - 0028-0836 .- 1476-4687. ; 625, s. 329-337
-
Journal article (peer-reviewed)abstract
- Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1–4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5–7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.
|
|
| 2. |
- Allentoft, Morten E., et al.
(author)
-
Population genomics of post-glacial western Eurasia
- 2024
-
In: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311
-
Journal article (peer-reviewed)abstract
- Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
|
|
| 3. |
- Mortensen, Morten Fischer, et al.
(author)
-
Turfs and Timbers- Resource use in the construction of the Viking Age Ring Fortress Borgring, Southeast Denmark
- 2021
-
In: Danish Journal of Archaeology. - : Det Kgl. Bibliotek/Royal Danish Library. - 2166-2290 .- 2166-2282. ; 10, s. 1-18
-
Journal article (peer-reviewed)abstract
- Viking Age ring fortresses were some of the largest construction projects in Danish prehistory. In this article we reconstruct the amount of turf and timber used in the construction of the Borgring ring fortress and estimate the resource area needed to supply the building materials. Using REVEALS pollen data modelling, we quantify the regional oak land cover and estimate the resource area. The results show that even though Borgring was built in an open cultural landscape, sufficient supply of oak for the construction would have been accessible within a few kilometres from the fortress.
|
|
| 4. |
- Chandrasekaran, Abinaya, et al.
(author)
-
Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3
- 2021
-
In: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; , s. 2736-2751
-
Journal article (peer-reviewed)abstract
- Frontotemporal dementia type 3 (FTD3), caused by a point mutation in the charged multivesicular body protein 2B (CHMP2B), affects mitochondrial ultrastructure and the endolysosomal pathway in neurons. To dissect the astrocyte-specific impact of mutant CHMP2B expression, we generated astrocytes from human induced pluripotent stem cells (hiPSCs) and confirmed our findings in CHMP2B mutant mice. Our data provide mechanistic insights into how defective autophagy causes perturbed mitochondrial dynamics with impaired glycolysis, increased reactive oxygen species, and elongated mitochondrial morphology, indicating increased mitochondrial fusion in FTD3 astrocytes. This shift in astrocyte homeostasis triggers a reactive astrocyte phenotype and increased release of toxic cytokines, which accumulate in nuclear factor kappa b (NF-κB) pathway activation with increased production of CHF, LCN2, and C3 causing neurodegeneration.
|
|
| 5. |
- Groen, Solveig Skovlund, et al.
(author)
-
A serological type II collagen neoepitope biomarker reflects cartilage breakdown in patients with osteoarthritis
- 2021
-
In: Osteoarthritis and Cartilage Open. - : Elsevier BV. - 2665-9131. ; 3:4
-
Journal article (peer-reviewed)abstract
- Objectives: There is an unmet medical need for biomarkers in OA which can be applied in clinical drug development trials. The present study describes the development of a specific and robust assay measuring type II collagen degradation (T2CM) and discusses its potential as a noninvasive translational biomarker. Methods: A type II collagen specific neoepitope (T2CM) was identified by mass spectrometry and monoclonal antibodies were raised towards the epitope, employed in a chemiluminescence immunoassay. T2CM was assessed in bovine cartilage explants with or without MMP-13 inhibitor, and explant supernatants were analyzed by Western blot. T2CM was measured in plasma samples from one study (n = 48 patients) where OA patients were referred to total knee replacement (TKR). Additionally, T2CM was quantified in serum from OA patients receiving salmon calcitonin treatment (sCT) (n = 50) compared to placebo (n = 57). Results: The T2CM assay was technically robust (13/4 % inter/intra-variation) and specific for the type II collagen fragment cleaved by MMP-1 and -13. The MMP-13 inhibitor reduced the T2CM release from bovine cartilage explants receiving catabolic treatment. These results were confirmed by Western blot. In human end-stage OA patients (scheduled for TKR), the T2CM levels were elevated compared to moderate OA (p<0.004). The OA patients receiving sCT had lower levels of T2CM compared to placebo group after 1, 6, and 24 months of treatment (p = 0.0285, p = 0.0484, p = 0.0035). Conclusions: To our knowledge, T2CM is the first technically robust serological biomarker assay which has shown biological relevance in ex vivo models and OA cohorts. This suggests that T2CM may have potential as a translational biomarker for cartilage degradation.
|
|
| 6. |
- Margaryan, Ashot, et al.
(author)
-
Population genomics of the Viking world
- 2020
-
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 585:7825, s. 390-396
-
Journal article (peer-reviewed)abstract
- The maritime expansion of Scandinavian populations during the Viking Age (about ad750–1050) was a far-flung transformation in world history1,2. Here we sequenced the genomes of 442humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci—including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response—in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent.
|
|
| 7. |
- Munch, Marie W., et al.
(author)
-
Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia The COVID STEROID 2 Randomized Trial
- 2021
-
In: Journal of the American Medical Association (JAMA). - : AMER MEDICAL ASSOC. - 0098-7484 .- 1538-3598. ; 326:18, s. 1807-1817
-
Journal article (peer-reviewed)abstract
- Question What is the effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support at 28 days in patients with COVID-19 and severe hypoxemia? Findings In this randomized trial that included 1000 patients with COVID-19 and severe hypoxemia, treatment with 12 mg/d of dexamethasone resulted in 22.0 days alive without life support at 28 days compared with 20.5 days in those receiving 6 mg/d of dexamethasone. This difference was not statistically significant. Meaning Compared with 6 mg of dexamethasone, 12 mg of dexamethasone did not statistically significantly reduce the number of days alive without life support at 28 days. This multicenter randomized clinical trial compares the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. IMPORTANCE A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. OBJECTIVE To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. INTERVENTIONS Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and >= 1 serious adverse reactions at 28 days). RESULTS Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). CONCLUSIONS AND RELEVANCE Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference.
|
|
| 8. |
- Nerenst, Tim Brix, et al.
(author)
-
Probabilistic Performance Evaluation and Optimization of Medical Plastic Moulded Components Subject to Large Scale Production
- 2021
-
In: ASME International Mechanical Engineering Congress and Exposition, Proceedings (IMECE). - 9780791885567 ; 2B-2021
-
Conference paper (peer-reviewed)abstract
- A new medical device can take years to develop from early concept to product launch. The long development process can be attributed to the severe consequences for the patient if the device malfunctions. Three approaches are often combined to mitigate risks: rigorous simulation and modeling, physical test programs, and Failure Mode Effect Analysis (FMEA) - all of which are time-consuming. Physical test programs are often carried out on prototype components from the same batch and, therefore, limited in revealing the actual distribution of performance. The risk probabilities are subsequently based on educated guesses. Furthermore, simulation and modeling are usually performed on nominal geometry - not accounting for variation - and only provide a safety factor against failure. The traditional use of safety factors in structural analysis versus the probabilistic approach to risk management presents an obvious misfit. Therefore, these three approaches are not ideal for addressing the two key questions that the design engineer has: 1) How often will the design fail, and 2) How should the design be changed to improve robustness and failure rates. The present work builds upon the existing Robust and Reliability-Based Design Optimization (R2BDO) and adjusts it to address the key questions above using finite element analysis. The key feature of the new framework is the focus on minimal use of computational resources while being able to screen feasible design concepts early in the embodiment phase and subsequently optimize their probabilistic performance. A case study in collaboration with a medical design and manufacturing company demonstrates the new framework. The case study includes FEA contact modeling between two plastic molded components with twelve geometrical variables. The optimization focuses on minimizing the failure rate (and improving design robustness) concerning three constraint functions (contact pressure, strain, torque). The study finds that the new framework achieves significant improvements to the component’s performance function (failure rate) with minimal computational resources.
|
|
| 9. |
- Tim Brix Nerenst, Tim Brix, et al.
(author)
-
Sequential Design Process for Screening and Optimization of Robust and Reliability Based on Finite Element Analysis and Meta-Modelling
- 2022
-
In: Journal of Computing and Information Science in Engineering. - : ASME International. - 1530-9827 .- 1944-7078. ; 22:4
-
Journal article (peer-reviewed)abstract
- A new medical device can take years to develop from early concept to product launch. Three approaches are often combined to mitigate risks: Failure Modes and Effects Analysis (FMEA), simulation and modeling, and physical test programs. Although widely used, all three approaches are generally time-consuming and have their shortcomings: The risk probabilities in FMEA's are often based on educated guesses, even in later development stages as data on the distribution of performance is not available. Thus, the traditional use of safety factors in structural analysis versus the probabilistic approach to risk management presents an obvious misfit. Therefore, the above three approaches are not ideal for addressing the design engineer's key question; how should the design be changed to improve robustness and failure rates. The present work builds upon the existing Robust and Reliability-Based Design Optimization (R2BDO) and adjusts it to address the key questions above using Finite Element Analysis (FEA). The two main features of the presented framework are screening feasible design concepts early in the embodiment phase and subsequently optimizing the design's probabilistic performance (i.e., reduce failure rates) while using minimal computational resources. A case study in collaboration with a medical design and manufacturing company demonstrates the new framework. The optimization minimizes the failure rate (and improves design robustness) concerning three constraint functions (torque, strain, and contact pressure). Furthermore, the study finds that the new framework significantly improves the design's performance function (failure rate) with limited computational resources.
|
|
| 10. |
- Agrawal, Manasi, et al.
(author)
-
Inflammatory bowel diseases among first-generation and second-generation immigrants in Denmark : a population-based cohort study
- 2021
-
In: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:6, s. 1037-1043
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: Our objective was to estimate the relative risk of IBD among first-generation and second-generation immigrants in Denmark compared with native Danes.DESIGN: Using national registries, we established a cohort of Danish residents between 1977 and 2018. Cohort members with known country of birth were followed for Crohn's disease (CD) and ulcerative colitis (UC) diagnoses. Incidence rate ratios (IRRs) served as measures of relative risk and were calculated by log-linear Poisson regression, using rates among native Danes as reference, stratified by IBD risk in parental country of birth, and among first-generation immigrants by age at immigration and duration of stay in Denmark.RESULTS: Among 8.7 million Danes, 4156 first-generation and 898 second-generation immigrants were diagnosed with CD or UC. Overall, comparing first-generation immigrants with native Danes, the IRR was 0.80 (95% CI 0.76 to 0.84) for CD and 0.74 (95% CI 0.71 to 0.77) for UC. The IRR of IBD increased with ≥20 years stay in Denmark. The IRR of CD increased with immigration at ≥40 years of age. Comparing second-generation immigrants with native Danes, the IRR of IBD was 0.97 (95% CI 0.91 to 1.04). There was significant interaction with sex, with higher IRR of IBD in male than in female immigrants.CONCLUSION: Relative to native Danish men and women, IBD risk among first-generation immigrants was lower, reflected the risk in their parental country of birth and increased with ≥20 years stay in Denmark. For second-generation immigrants, relative risk of IBD was lower only among women. These complex patterns suggest the role of environmental IBD risk factors.
|
|
