| 1. |
- Allentoft, Morten E., et al.
(författare)
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Population genomics of post-glacial western Eurasia
- 2024
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311
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Tidskriftsartikel (refereegranskat)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.
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| 2. |
- Gammeltoft-Hansen, Thomas, et al.
(författare)
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Private Law Enforcement and Control
- 2013
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Ingår i: The Rights of Others: Essays in honour of Jens Vedsted-Hansen.
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 3. |
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| 4. |
- Allentoft, Morten E., et al.
(författare)
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100 ancient genomes show repeated population turnovers in Neolithic Denmark
- 2024
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625, s. 329-337
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Tidskriftsartikel (refereegranskat)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.
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| 5. |
- Anderson, Ryan T, et al.
(författare)
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Association Between Seroclearance of Hepatitis B Surface Antigen and Long-term Clinical Outcomes of Patients With Chronic Hepatitis B Virus Infection : Systematic Review and Meta-analysis.
- 2021
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Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier. - 1542-3565 .- 1542-7714. ; 19:3, s. 463-472
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Seroclearance of hepatitis B surface antigen (HBsAg) is the desired end point of treatment for chronic hepatitis B virus (HBV) infection, according to guidelines. We performed a systematic review and meta-analysis to evaluate the strength of the association between HBsAg seroclearance and long-term clinical outcomes.METHODS: We performed a systematic review of the PubMed, EMBASE, and Cochrane Library databases for articles that assessed HBsAg status and reported the incidence of hepatocellular carcinoma (HCC), liver decompensation, liver transplantation, and/or all-cause mortality during follow-up evaluation. We performed a meta-analysis of rate ratios (RR) using a random-effects model independently for each end point and for a composite end point.RESULTS: We analyzed data from 28 studies, comprising a total of 188,316 patients with chronic HBV infection (treated and untreated), and 1,486,081 person-years (PY) of follow-up evaluation; 26 reported data on HCC, 7 on liver decompensation, and 13 on liver transplantation and/or death. The composite event rates were 0.19/1000 PY for the HBsAg seroclearance group and 2.45/1000 PY for the HBsAg-persistent group. Pooled RRs for the HBsAg seroclearance group were 0.28 for liver decompensation (95% CI, 0.13-0.59; P = .001), 0.30 for HCC (95% CI, 0.20-0.44; P < .001), 0.22 for liver transplantation and/or death (95% CI, 0.13-0.39; P < .001), and 0.31 for the composite end point (95% CI, 0.23-0.43; P < .001). No differences in RR estimates were observed among subgroups of different study or patient characteristics.CONCLUSIONS: In a systematic review and meta-analysis, we found seroclearance of HBsAg to be associated significantly with improved patient outcomes. The results are consistent among different types of studies, in all patient subpopulations examined, and support the use of HBsAg seroclearance as a primary end point of trials of patients with chronic HBV infection.
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| 6. |
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| 7. |
- Bezemer, Geert, et al.
(författare)
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Long-term effects of treatment and response in patients with chronic hepatitis C on quality of life
- 2012
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Ingår i: BMC Gastroenterology. - 1471-230X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background Hepatitis C decreases health related quality of life (HRQL) which is further diminished by antiviral therapy. HRQL improves after successful treatment. This trial explores the course of and factors associated with HRQL in patients given individualized or standard treatment based on early treatment response (Ditto-study). Methods The Short Form (SF)-36 Health Survey was administered at baseline (n = 192) and 24 weeks after the end of therapy (n = 128). Results At baseline HRQL was influenced by age, participating center, severity of liver disease and income. Exploring the course of HRQL (scores at follow up minus baseline), only the dimension general health increased. In this dimension patients with a relapse or sustained response differed from non-responders. Men and women differed in the dimension bodily pain. Treatment schedule did not influence the course of HRQL. Conclusions Main determinants of HRQL were severity of liver disease, age, gender, participating center and response to treatment. Our results do not exclude a more profound negative impact of individualized treatment compared to standard, possibly caused by higher doses and extended treatment duration in the individualized group. Antiviral therapy might have a more intense and more prolonged negative impact on females.
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| 8. |
- Byrne, Rosemary, et al.
(författare)
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International criminal justice, the Gotovina judgment and the making of refugees
- 2013
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Ingår i: Protecting the Rights of Others. Festskrift til Jens Vedsted-Hansen. - 9788757427363 ; , s. 467-486
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Bokkapitel (refereegranskat)abstract
- In this contribution, we reflect on the particular function of international criminal law to prevent refugee crises of the type that provided a major trigger for the debate on military and legal interventionism in the 1990s. Based on the dichotomy of formal and substantive justice, we analyze the achievements of International Criminal Tribunals and look into the Gotovina judgment in particular. We conclude that an insistence on formal models of justice cannot compensate for the shortfalls in legitimacy of international criminal tribunals.
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| 9. |
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| 10. |
- Choi, Woo Jin, et al.
(författare)
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Is it safe to administer neoadjuvant chemotherapy to patients undergoing hepatectomy for intrahepatic cholangiocarcinoma? : ACS-NSQIP propensity-matched analysis
- 2022
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Ingår i: HPB. - : Elsevier. - 1365-182X .- 1477-2574. ; 24:9, s. 1535-1542
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Tidskriftsartikel (refereegranskat)abstract
- Background: The use of neoadjuvant chemotherapy (NAC) in patients with intrahepatic chol-angiocarcinoma (iCCA) is increasing. The objective of this study was to compare the 30-day post-operative complications and length-of-stay (LOS) between patients undergoing hepatectomy for iCCA with and without NAC.Methods: A retrospective study was conducted using the ACS-NSQIP database queried from 2014 to 2018. Patients with NAC receipt were propensity-score matched into 1:3 ratio with controls using the greedy-matching algorithm and a caliper of 0.2. Logistic and Poisson regression models were used to estimate the effect sizes.Results: A total of 1508 patients who underwent hepatectomy for iCCA were included. 706 patients remained after matching and balance were achieved. The NAC group had 110 (60.1%) complications vs. 289 (55.3%) complications in the non-NAC group (p = 0.29). NAC was not associated with worse 30-day postoperative complications [OR 1.24, 95% CI: 0.87-1.76; p = 0.24]. Post-operative LOS in the NAC group was 8.56 days (mean, SD 7.4) vs. non-NAC group 9.27 days (mean, SD 8.41, p = 0.32). NAC was not associated with longer post-operative LOS [RR 0.93, 95% CI:0.80, 1.08; p = 0.32].Conclusion: NAC may be safely administered without increasing the risk of 30-day complications or post-operative hospital LOS.
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| 11. |
- Choi, Woo Jin, et al.
(författare)
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Preoperative neutrophil-to-lymphocyte ratio is prognostic for early recurrence after curative intrahepatic cholangiocarcinoma resection
- 2023
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Ingår i: Annals of Hepato-Biliary-Pancreatic Surgery. - : The Korean Association of Hepato-Biliary-Pancreatic Surgery. - 2508-5778 .- 2508-5859. ; 27:2, s. 158-165
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Tidskriftsartikel (refereegranskat)abstract
- Backgrounds/Aims: Within two years of surgery, 70% of resected intrahepatic cholangiocarcinoma (iCCA) recur. Better biomarkers are needed to identify those at risk of “early recurrence” (ER). In this study, we defined ER and investigated whether preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic-inflammatory index were prognostic of both overall relapse and ER after curative hepatectomy for iCCA.Methods: A retrospective cohort of patients who underwent curative-intent hepatectomy for iCCA between 2005 and 2017 were created. The cut-off timepoint for the ER of iCCA was estimated using a piecewise linear regression model. Univariable analyses of recurrence were conducted for the overall, early, and late recurrence periods. For the early and late recurrence periods, multivariable Cox regression with time-varying regression coefficient analysis was used.Results: A total of 113 patients were included in this study. ER was defined as recurrence within 12 months of a curative resection. Among the included patients, 38.1% experienced ER. In the univariable model, a higher preoperative NLR (> 4.3) was significantly associated with an increased risk of recurrence overall and in the first 12 months after curative surgery. In the multivariable model, a higher NLR was associated with a higher recurrence rate overall and in the ER period (≤ 12 months), but not in the late recurrence period.Conclusions: Preoperative NLR was prognostic of both overall recurrence and ER after curative iCCA resection. NLR is easily obtained before and after surgery and should be integrated into ER prediction tools to guide preoperative treatments and intensify postoperative follow-up.
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| 12. |
- Choi, Woo Jin, et al.
(författare)
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Systematic Review and Meta-Analysis of Prognostic Factors for Early Recurrence in Intrahepatic Cholangiocarcinoma After Curative-Intent Resection
- 2022
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Ingår i: Annals of Surgical Oncology. - : Springer Nature. - 1068-9265 .- 1534-4681. ; 29:7, s. 4337-4353
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Tidskriftsartikel (refereegranskat)abstract
- Background Recurrence rates of intrahepatic cholangiocarcinoma (iCCA) after curative hepatectomy are as high as 50% to 70%, and about half of these recurrences occur within 2 years. This systematic review aims to define prognostic factors (PFs) for early recurrence (ER, within 24 months) and 24-month disease-free survival (DFS) after curative-intent iCCA resections.Methods Systematic searching was performed from database inception to 14 January 2021. Duplicate independent review and data extraction were performed. Data on 13 predefined PFs were collected. Meta-analysis was performed on PFs for ER and summarized using forest plots. The Quality in Prognostic Factor Studies tool was used for risk-of-bias assessment.Results The study enrolled 10 studies comprising 4158 patients during an accrual period ranging from 1990 to 2016. In the risk-of-bias assessment of patients who experienced ER after curative-intent iCCA resection, six studies were rated as low risk and four as moderate risk (49.6%; 95% confidence interval [CI], 49.2-50.0). Nine studies were pooled for meta-analysis. Of the postoperative PFs, multiple tumors, microvascular invasion, macrovascular invasion, lymph node metastasis, and R1 resection were associated with an increased hazard for ER or a reduced 24-month DFS, and the opposite was observed for receipt of adjuvant chemo/radiation therapy. Of the preoperative factors, cirrhosis, sex, HBV status were not associated with ER or 24-month DFS.Conclusion The findings from this systematic review could allow for improved surveillance, prognostication, and treatment decision-making for patients with resectable iCCAs. Further well-designed prospective studies are needed to explore prognostic factors for iCCA ER with a focus on preoperative variables.
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| 13. |
- Clausen, Bettina Hjelm, et al.
(författare)
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Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke.
- 2016
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 131:5, s. 91-775
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Tidskriftsartikel (refereegranskat)abstract
- Cell-based therapies are emerging as new promising treatments in stroke. However, their functional mechanism and therapeutic potential during early infarct maturation has so far received little attention. Here, we asked if cell-based delivery of the interleukin-1 receptor antagonist (IL-1Ra), a known neuroprotectant in stroke, can promote neuroprotection, by modulating the detrimental inflammatory response in the tissue at risk. We show by the use of IL-1Ra-overexpressing and IL-1Ra-deficient mice that IL-1Ra is neuroprotective in stroke. Characterization of the cellular and spatiotemporal production of IL-1Ra and IL-1α/β identifies microglia, not infiltrating leukocytes, as the major sources of IL-1Ra after experimental stroke, and shows IL-1Ra and IL-1β to be produced by segregated subsets of microglia with a small proportion of these cells co-expressing IL-1α. Reconstitution of whole body irradiated mice with IL-1Ra-producing bone marrow cells is associated with neuroprotection and recruitment of IL-1Ra-producing leukocytes after stroke. Neuroprotection is also achieved by therapeutic injection of IL-1Ra-producing bone marrow cells 30 min after stroke onset, additionally improving the functional outcome in two different stroke models. The IL-1Ra-producing bone marrow cells increase the number of IL-1Ra-producing microglia, reduce the availability of IL-1β, and modulate mitogen-activated protein kinase (MAPK) signaling in the ischemic cortex. The importance of these results is underlined by demonstration of IL-1Ra-producing cells in the human cortex early after ischemic stroke. Taken together, our results attribute distinct neuroprotective or neurotoxic functions to segregated subsets of microglia and suggest that treatment strategies increasing the production of IL-1Ra by infiltrating leukocytes or microglia may also be neuroprotective if applied early after stroke onset in patients.
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| 14. |
- Clausen, Bettina Hjelm, et al.
(författare)
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Fumarate decreases edema volume and improves functional outcome after experimental stroke
- 2017
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 295, s. 144-154
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Tidskriftsartikel (refereegranskat)abstract
- Background Oxidative stress and inflammation exacerbate tissue damage in the brain after ischemic stroke. Dimethyl-fumarate (DMF) and its metabolite monomethyl-fumarate (MMF) are known to stimulate anti-oxidant pathways and modulate inflammatory responses. Considering these dual effects of fumarates, we examined the effect of MMF treatment after ischemic stroke in mice. Methods Permanent middle cerebral artery occlusion (pMCAO) was performed using adult, male C57BL/6 mice. Thirty minutes after pMCAO, 20 mg/kg MMF was administered intravenously. Outcomes were evaluated 6, 24 and 48 h after pMCAO. First, we examined whether a bolus of MMF was capable of changing expression of kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor (Nrf)2 in the infarcted brain. Next, we studied the effect of MMF on functional recovery. To explore mechanisms potentially influencing functional changes, we examined infarct volumes, edema formation, the expression of heat shock protein (Hsp)72, hydroxycarboxylic acid receptor 2 (Hcar2), and inducible nitric oxide synthase (iNOS) in the infarcted brain using real-time PCR and Western blotting. Concentrations of a panel of pro- and anti-inflammatory cytokines (IFNγ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, TNF) were examined in both the infarcted brain tissue and plasma samples 6, 24 and 48 h after pMCAO using multiplex electrochemoluminiscence analysis. Results Administration of MMF increased the protein level of Nrf2 6 h after pMCAO, and improved functional outcome at 24 and 48 h after pMCAO. MMF treatment did not influence infarct size, however reduced edema volume at both 24 and 48 h after pMCAO. MMF treatment resulted in increased Hsp72 expression in the brain 6 h after pMCAO. Hcar2 mRNA levels increased significantly 24 h after pMCAO, but were not different between saline- and MMF-treated mice. MMF treatment also increased the level of the anti-inflammatory cytokine IL-10 in the brain and plasma 6 h after pMCAO, and additionally reduced the level of the pro-inflammatory cytokine IL-12p70 in the brain at 24 and 48 h after pMCAO. Conclusions A single intravenous bolus of MMF improved sensory-motor function after ischemic stroke, reduced edema formation, and increased the levels of the neuroprotective protein Hsp72 in the brain. The early increase in IL-10 and reduction in IL-12p70 in the brain combined with changes in systemic cytokine levels may also contribute to the functional recovery after pMCAO.
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| 15. |
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| 16. |
- Epishin, Alexander, et al.
(författare)
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Synchrotron Sub-μ X-ray Tomography of Kirkendall Porosity in a Diffusion Couple of Nickel-Base Superalloy and Nickel after Annealing at 1250 °C
- 2021
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Ingår i: Advanced Engineering Materials. - : Wiley. - 1527-2648 .- 1438-1656. ; 23:4
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Tidskriftsartikel (refereegranskat)abstract
- Kirkendall porosity that forms during interdiffusion in a diffusion couple of nickel-base superalloy CMSX-10 with pure nickel is investigated. The diffusion experiments are conducted at a temperature of 1250 °C, where the strengthening γ′-phase is partially dissolved. The porosity is studied by X-ray sub-μ tomography with a spatial resolution of about 0.353 μm3 at the European Synchrotron Radiation Facility (ESRF) in Grenoble, France. It is found that depending on the distance from the interface the Kirkendall pores take different shapes: octahedral, rounded pyramidal, drop shaped, dendritic, pear shaped, and joint shapes. Such a variety of pore morphologies indicates a complex multistage process of porosity nucleation and growth under vacancy supersaturation of different degrees. The experimental findings are interpreted on the basis of the results of diffusion modeling. It is shown that the kinetics of porosity growth is essentially influenced by the dissolution of the γ′-phase.
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| 17. |
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| 18. |
- Ivanics, Tommy, et al.
(författare)
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Dynamic risk profiling of HCC recurrence after curative intent liver resection
- 2022
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Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 76:5, s. 1291-1301
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aim: Following liver resection (LR) for HCC, the likelihood of survival is dynamic, in that multiple recurrences and/or metastases are possible, each having variable impacts on outcomes. We sought to evaluate the natural progression, pattern, and timing of various disease states after LR for HCC using multistate modeling and to create a practical calculator to provide prognostic information for patients and clinicians.Approach and Results: Adult patients undergoing LR for HCC between January 2000 and December 2018 were retrospectively identified at a single center. Multistate analysis modeled post-LR tumor progression by describing transitions between distinct disease states. In this model, the states included surgery, intrahepatic recurrence (first, second, third, fourth, fifth), distant metastasis with or without intrahepatic recurrence, and death. Of the 486 patients included, 169 (34.8%) remained recurrence-free, 205 (42.2%) developed intrahepatic recurrence, 80 (16.5%) developed distant metastasis, and 32 (7%) died. For an average patient having undergone LR, there was a 33.1% chance of remaining disease-free, a 31.0% chance of at least one intrahepatic recurrence, a 16.3% chance of distant metastasis, and a 19.8% chance of death within the first 60 months post-LR. The transition probability from surgery to first intrahepatic recurrence, without a subsequent state transition, increased from 3% (3 months) to 17.4% (30 months) and 17.2% (60 months). Factors that could modify these probabilities included tumor size, satellite lesions, and microvascular invasion. The online multistate model calculator can be found on https://multistatehcc.shinyapps.io/home/.Conclusions: In contrast to standard single time-to-event estimates, multistate modeling provides more realistic prognostication of outcomes after LR for HCC by taking into account many postoperative disease states and transitions between them. Our multistate modeling calculator can provide meaningful data to guide the management of patients undergoing postoperative surveillance and therapy.
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| 19. |
- Ivanics, Tommy, et al.
(författare)
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Long-term outcomes of laparoscopic liver resection for hepatocellular carcinoma : A propensity score matched analysis of a high-volume North American center
- 2022
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Ingår i: Surgery. - : Elsevier. - 0039-6060 .- 1532-7361. ; 171:4, s. 982-991
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Tidskriftsartikel (refereegranskat)abstract
- Background: Laparoscopic liver resections for malignancy are increasing worldwide, and yet data from North America are lacking. We aimed to assess the long-term outcomes of patients undergoing laparoscopic liver resection and open liver resection as a treatment for hepatocellular carcinoma.Methods: Patients undergoing liver resection for hepatocellular carcinoma between January 2008 and December 2019 were retrospectively studied. A propensity score matching was performed using patient demographics, laboratory parameters, etiology of liver disease, liver function, and tumor characteristics. Primary outcomes included overall survival and cumulative incidence of recurrence. Kaplan-Meier and competing risk cumulative incidence were used for survival analyses. Multivariable Cox regression and Fine-Gray proportional hazard regression were performed to determine hazard for death and recurrence, respectively.Results: Three hundred and ninety-one patients were identified (laparoscopic liver resection: 110; open liver resection: 281). After propensity score matching, 149 patients remained (laparoscopic liver resection: 57; open liver resection: 92). There were no significant differences between groups with regard to extent of hepatectomy performed and tumor characteristics. The laparoscopic liver resection group experienced a lower proportion of >= Clavien-Dindo grade III complications (14% vs 29%; P = .01). In the matched cohort, the 1-, 3-, and 5-year overall survival rate in the laparoscopic liver resection versus open liver resection group was 90.9%, 79.3%, 70.5% vs 91.3%, 88.5%, 83.1% (P = .26), and the cumulative incidence of recurrence 31.1%, 59.7%, 62.9% vs 18.9%, 40.6%, 49.2% (P = .06), respectively.Conclusion: This study represents the largest single institutional study from North America comparing long-term oncologic outcomes of laparoscopic liver resection and open liver resection as a treatment for primary hepatocellular carcinoma. The combination of reduced short-term complications and equivalent long-term oncologic outcomes favor the laparoscopic approach when feasible.
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| 20. |
- Ivanics, Tommy, et al.
(författare)
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Reply
- 2022
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Ingår i: Hepatology. - : John Wiley & Sons. - 0270-9139 .- 1527-3350. ; 76:5, s. E98-E99
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 21. |
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| 22. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)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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| 23. |
- Lambertsen, Kate L, et al.
(författare)
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Differences in Origin of Reactive Microglia in Bone Marrow Chimeric Mouse and Rat After Transient Global Ischemia.
- 2011
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Ingår i: Journal of Neuropathology and Experimental Neurology. - 1554-6578. ; 70:6, s. 481-494
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Tidskriftsartikel (refereegranskat)abstract
- Current understanding of microglial involvement in disease is influenced by the observation that recruited bone marrow (BM)-derived cells contribute to reactive microgliosis in BM-chimeric mice. In contrast, a similar phenomenon has not been reported for BM-chimeric rats. We investigated the recruitment and microglial transformation of BM-derived cells in radiation BM-chimeric mice and rats after transientglobal cerebral ischemia, which elicits a characteristic microglialreaction. Both species displayed microglial hyperplasia and rod cell transformation in the hippocampal CA1 region. In mice, a subpopulation of lesion-reactive microglia originated from transformed BM-derived cells. By contrast, no recruitment or microglial transformation of BM-derived cells was observed in BM-chimeric rats. These results suggest that reactive microglia in rats originate from resident microglia, whereas they have a mixed BM-derived and resident origin in mice, depending on the severity of ischemic tissue damage.
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| 24. |
- Lambertsen, Kate Lykke, et al.
(författare)
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Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor
- 2009
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Ingår i: The Journal of Neuroscience. - 1529-2401. ; 29:5, s. 1319-1330
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Tidskriftsartikel (refereegranskat)abstract
- Microglia and infiltrating leukocytes are considered major producers of tumor necrosis factor (TNF), which is a crucial player in cerebral ischemia and brain inflammation. We have identified a neuroprotective role for microglial-derived TNF in cerebral ischemia in mice. We show that cortical infarction and behavioral deficit are significantly exacerbated in TNF-knock-out (KO) mice compared with wild-type mice. By using in situ hybridization, immunohistochemistry, and green fluorescent protein bone marrow (BM)-chimeric mice, TNF was shown to be produced by microglia and infiltrating leukocytes. Additional analysis demonstrating that BM-chimeric TNF-KO mice grafted with wild-type BM cells developed larger infarcts than BM-chimeric wild-type mice grafted with TNF-KO BM cells provided evidence that the neuroprotective effect of TNF was attributable to microglial-not leukocyte-derived TNF. In addition, observation of increased infarction in TNF-p55 receptor (TNF-p55R)-KO mice compared with TNF-p75R and wild-type mice suggested that microglial-derived TNF exerts neuroprotective effects through TNF-p55R. We finally report that TNF deficiency is associated with reduced microglial population size and Toll-like receptor 2 expression in unmanipulated brain, which might also influence the neuronal response to injury. Our results identify microglia and microglial-derived TNF as playing a key role in determining the survival of endangered neurons in cerebral ischemia.
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| 25. |
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| 26. |
- Murillo Perez, Carla F., et al.
(författare)
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Trends in liver transplantation for autoimmune liver diseases : a Canadian study
- 2022
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Ingår i: Canadian journal of surgery. - : CMA Impact Inc.. - 0008-428X .- 1488-2310. ; 65:5, s. E665-E674
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Tidskriftsartikel (refereegranskat)abstract
- Background: To our knowledge, no analysis of data from liver transplantation registries exists in Canada. We aimed to describe temporal trends in the number of liver transplantation procedures, patient characteristics and posttransplantation outcomes for autoimmune liver diseases (AILDs) in Canada.Methods: We used administrative data from the Canadian Organ Replacement Register, which contains liver transplantation information from 6 centres in Canada. This study included transplantation information from 5 of the centres, as liver transplantation procedures in children were not included. We included adult (age ≥ 18 yr) patients with a diagnosis of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH) or overlap syndrome (PBC–AIH or PSC–AIH) who received a liver transplant from 2000 to 2018.Results: Of 5722 primary liver transplantation procedures performed over the study period, 1070 (18.7%) were for an AILD: 489 (45.7%) for PSC, 341 (31.9%) for PBC, 220 (20.6%) for AIH and 20 (1.9%) for overlap syndrome. There was a significant increase in the absolute number of procedures for PSC, with a yearly increase of 0.6 (95% confidence interval 0.1 to 1.2), whereas the absolute number of procedures for PBC and AIH remained stable. The proportion of transplantation procedures decreased for PBC and AIH but remained stable for PSC. Recipient age at transplantation increased over time for males with PBC (median 53 yr in 2000–2005 to 57 yr in 2012–2018, p = 0.03); whereas the median age among patients with AIH decreased, from 53 years in 2000–2005 to 44 years in 2006–2011 (p = 0.03). The Model for Endstage Liver Disease score at the time of transplantation increased over time for all AILDs, particularly AIH (median 16 in 2000–2005 v. 24 in 2012–2018, p < 0.001). There was a trend toward improved survival in the PBC group, with a 5-year survival rate of 81% in 2000–2005 and 90% in 2012–2018 (p = 0.06).Conclusion: Between 2000 and 2018, the absolute number of liver transplantation procedures in Canada increased for PSC but remained stable for PBC and AIH; proportionally, PBC and AIH decreased as indications for transplantation. Posttransplantation survival improved only for the PBC group. An improved understanding of trends and outcomes on a national scale among patients with AILD undergoing liver transplantation can identify disparities and areas for potential health care improvement.
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| 27. |
- Nevens, Frederik, et al.
(författare)
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A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis.
- 2016
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Ingår i: The New England journal of medicine. - 1533-4406. ; 375:7, s. 631-43
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Tidskriftsartikel (refereegranskat)abstract
- Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease.
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| 28. |
- Rajendran, Luckshi, et al.
(författare)
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Outcomes of liver transplantation in non-alcoholic steatohepatitis (NASH) versus non-NASH associated hepatocellular carcinoma
- 2023
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Ingår i: HPB. - : Elsevier BV. - 1365-182X .- 1477-2574. ; 25:5, s. 556-567
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Tidskriftsartikel (refereegranskat)abstract
- Background: Non-alcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC) is a rising indication for liver transplantation. This unique population, with multiple comorbidities, has po-tential for worse post-transplant outcomes. We compared post-transplant survival of NASH and non-NASH HCC patients using a large cohort.Methods: Adults transplanted for HCC between 2008 and 2018, from United Network for Organ Sharing (UNOS) and University Health Network (UHN) databases were divided into two populations: NASH and non-NASH. Recipient characteristics and post-transplant survival were compared. Subgroup analyses were performed within and beyond Milan criteria.Results: 2071 of 20,672 (10.0%) patients underwent transplantation for NASH HCC, with annual pro-portional increase of 1.2%UHN (p = 0.02) and 1.3%UNOS (p < 0.001). The 1-,3-,5-year post-transplant survival were 90.8%, 83.9%, 76.3% NASH HCC versus 91.9%, 82.1%, 74.9% non-NASH HCC (p = 0.94). No survival differences were observed in populations within or beyond Milan. Competing-risk analysis demonstrated no differences in risk for cardiovascular-related death (HR1.24, 95%CI 0.87-1.55, p = 0.16), or HCC recurrence-related death (HR1.21, 95%CI 0.89-1.65, p = 0.23). NASH HCC patients had lower risk of liver-related deaths (HR0.57, 95%CI 0.34-0.98, p = 0.04).Discussion: NASH HCC is a rising indication for liver transplantation. Despite demographic differences, no post-transplantation survival differences were observed between NASH and non-NASH HCC. This justifies equivalent organ allocation, irrespective of NASH status.
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| 29. |
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| 30. |
- Thell, Arne, et al.
(författare)
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The distribution of Parmelia ernstiae in Denmark.
- 2007
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Ingår i: Lichenologische Nebenstunden. Contributions to lichen taxonomy in honour of Klaus Kalb.. - 9783443580759 ; 96, s. 299-304
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- The distribution of Parmelia ernstiae in Denmark and neighbouring areas has been determined from herbarium studies and DNA analyses of fresh material. It occurs on bark, mainly deciduous, and wood, in all parts of the country except for western Jutland.
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| 31. |
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