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Sökning: WFRF:(Nielsen Kari)

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1.
  • Oddsson, Asmundur, et al. (författare)
  • Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
  • 2023
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.
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2.
  • Turcot, Valerie, et al. (författare)
  • Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
  • 2018
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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3.
  • Erzurumluoglu, A. Mesut, et al. (författare)
  • Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
  • 2020
  • Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:10, s. 2392-2409
  • Tidskriftsartikel (refereegranskat)abstract
    • Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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4.
  • Freitag, Daniel F., et al. (författare)
  • Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
  • 2015
  • Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
  • Tidskriftsartikel (refereegranskat)abstract
    • Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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5.
  • Gaillard, Marie-José, et al. (författare)
  • Causes of Regional Change : Land Cover
  • 2015
  • Ingår i: Second Assessment of Climate Change for the Baltic Sea Basin. - Cham : Springer. - 9783319160054 - 9783319160061 ; , s. 453-477
  • Bokkapitel (refereegranskat)abstract
    • Anthropogenic land-cover change (ALCC) is one of the few climate forcings for which the net direction of the climate response over the last two centuries is still not known. The uncertainty is due to the often counteracting temperature responses to the many biogeophysical effects and to the biogeochemical versus biogeophysical effects. Palaeoecological studies show that the major transformation of the landscape by anthropogenic activities in the southern zone of the Baltic Sea basin occurred between 6000 and 3000/2500 cal year BP. The only modelling study of the biogeophysical effects of past ALCCs on regional climate in north-western Europe suggests that deforestation between 6000 and 200 cal year BP may have caused significant change in winter and summer temperature. There is no indication that deforestation in the Baltic Sea area since AD 1850 would have been a major cause of the recent climate warming in the region through a positive biogeochemical feedback. Several model studies suggest that boreal reforestation might not be an effective climate warming mitigation tool as it might lead to increased warming through biogeophysical processes.
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6.
  • Kanoni, Stavroula, et al. (författare)
  • Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
  • 2022
  • Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
  • 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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7.
  • Mahajan, Anubha, et al. (författare)
  • Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
  • 2018
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
  • Tidskriftsartikel (refereegranskat)abstract
    • We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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8.
  • Marouli, Eirini, et al. (författare)
  • Rare and low-frequency coding variants alter human adult height
  • 2017
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
  • Tidskriftsartikel (refereegranskat)abstract
    • Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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9.
  • Nielsen, Mette Lykke, et al. (författare)
  • New forms of work among young people: Implications for the working environment.
  • 2019
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • Changes in the labor marked globally and in the Nordic countries involve new forms of work and atypical employment among young workers. A significant proportion of young workers are in temporary positions, working irregular working hours, and part-time work. This also applies to the young workers portrayed in this report. They are working at online platforms as e-sport gamers, YouTuber or Influencers, an thus move into the borderland of the meanings we usually ascribe to the categories ‘work’ and ‘working environment’. This development also apply to traditional professions, such as carpentry work or service work, but the new aspect is that the work is mediated through online platforms, which seems to affect the working environment for those young workers. It is important to know more about new employment forms if we are to improve working environment among these young workers.
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10.
  • Solé Navais, Pol, et al. (författare)
  • Genetic effects on the timing of parturition and links to fetal birth weight.
  • 2023
  • Ingår i: Nature genetics. - 1546-1718. ; 55:4, s. 559-567
  • Tidskriftsartikel (refereegranskat)abstract
    • The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n=195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n=136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.
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11.
  • Surendran, Praveen, et al. (författare)
  • Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
  • 2020
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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12.
  • Ahnlide, Ingela, et al. (författare)
  • Diagnosis of Pigmented Skin Tumours in a Dermatological Setting: Different Aspects of the Number Needed to Excise as a Measure of Efficiency.
  • 2014
  • Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 1651-2057 .- 0001-5555. ; 94:6, s. 683-686
  • Tidskriftsartikel (refereegranskat)abstract
    • The increasing incidence of melanoma prompts a need for efficient management of this patient group. In this study, we use the number needed to excise (NNE), as a measurement of the efficiency of diagnosing melanoma. From January 2009 to December 2012, postoperative records from all patients were prospectively registered. All excised tumours with the histopathological diagnosis of naevus, melanoma or seborrhoeic keratosis were included. NNE values, both excluding and including seborrhoeic keratosis, changes over time, as well as patient- and tumour-related factors influencing NNE were determined. In total, 1,717 cases were included. The overall NNE value was 6.5, and the value fell significantly (r = 0.959, p = 0.041) during the 4-year study period from 8.2 to 4.8. NNE values decreased with increasing patient age to 1.8 in patients ≥ 80 years of age. The overall NNE value including seborrhoeic keratosis was 6.8.
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14.
  • Ahnlide, Ingela, et al. (författare)
  • Validity of ABCD Rule of Dermoscopy in Clinical Practice.
  • 2016
  • Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 1651-2057 .- 0001-5555. ; 96:3, s. 367-367
  • Tidskriftsartikel (refereegranskat)abstract
    • The ABCD rule of dermoscopy was developed to facilitate diagnosis in the dermoscopy of pigmented lesions. However, there is a lack of studies on its validity in clinical practice. The aim of this study was to evaluate the accuracy of the algorithm used bedside, compared with the accuracy of the preliminary preoperative diagnosis, and to rate physicians' level of confidence in the diagnosis. Melanocytic tumours were preoperatively scored bedside, according to the ABCD algorithm; 309 cases (46 melanomas and 263 naevi) were included. A sensitivity of 83% and specificity of 45% were found for the ABCD algorithm. A comparable sensitivity (74%), but a significantly higher specificity (91%), was found for the preliminary diagnosis. Interestingly, there was a considerable percentage (19.6%) of early melanomas for which a malignant diagnosis was not preoperatively expected, indicating that it is important to maintain generous indications for excision or to practise short-term follow-up of ambiguous lesions in order to detect early melanomas.
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15.
  • Brikell, Isabell, et al. (författare)
  • ADHD medication discontinuation and persistence across the lifespan : a retrospective observational study using population-based databases
  • 2024
  • Ingår i: Lancet psychiatry. - : Elsevier. - 2215-0374 .- 2215-0366. ; 11:1, s. 16-26
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Although often intended for long-term treatment, discontinuation of medication for ADHD is common. However, cross-national estimates of discontinuation are missing due to the absence of standardised measures. The aim of this study was to determine the rate of ADHD treatment discontinuation across the lifespan and to describe similarities and differences across countries to guide clinical practice.METHODS: We did a retrospective, observational study using population-based databases from eight countries and one Special Administrative Region (Australia, Denmark, Hong Kong, Iceland, the Netherlands, Norway, Sweden, the UK, and the USA). We used a common analytical protocol approach and extracted prescription data to identify new users of ADHD medication. Eligible individuals were aged 3 years or older who had initiated ADHD medication between 2010 and 2020. We estimated treatment discontinuation and persistence in the 5 years after treatment initiation, stratified by age at initiation (children [age 4-11 years], adolescents [age 12-17 years], young adults [age 18-24 years], and adults [age ≥25 years]) and sex. Ethnicity data were not available.FINDINGS: 1 229 972 individuals (735 503 [60%] males, 494 469 females [40%]; median age 8-21 years) were included in the study. Across countries, treatment discontinuation 1-5 years after initiation was lowest in children, and highest in young adults and adolescents. Within 1 year of initiation, 65% (95% CI 60-70) of children, 47% (43-51) of adolescents, 39% (36-42) of young adults, and 48% (44-52) of adults remained on treatment. The proportion of patients discontinuing was highest between age 18 and 19 years. Treatment persistence for up to 5 years was higher across countries when accounting for reinitiation of medication; at 5 years of follow-up, 50-60% of children and 30-40% of adolescents and adults were covered by treatment in most countries. Patterns were similar across sex.INTERPRETATION: Early medication discontinuation is prevalent in ADHD treatment, particularly among young adults. Although reinitiation of medication is common, treatment persistence in adolescents and young adults is lower than expected based on previous estimates of ADHD symptom persistence in these age groups. This study highlights the scope of medication treatment discontinuation and persistence in ADHD across the lifespan and provides new knowledge about long-term ADHD medication use.FUNDING: European Union Horizon 2020 Research and Innovation Programme.
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16.
  • Broström, Anna, et al. (författare)
  • Pollen productivity estimates of key European plant taxa for quantitative reconstruction of past vegetation : a review
  • 2008
  • Ingår i: Vegetation History and Archaeobotany. - : Springer Science and Business Media LLC. - 0939-6314 .- 1617-6278. ; 17:5, s. 461-478
  • Tidskriftsartikel (refereegranskat)abstract
    • Information on the spatial distribution of past vegetation on local, regional and global scales is increasingly used within climate modelling, nature conservancy and archaeology. It is possible to obtain such information from fossil pollen records in lakes and bogs using the landscape reconstruction algorithm (LRA) and its two models, REVEALS and LOVE. These models assume that reliable pollen productivity estimates (PPEs) are available for the plant taxa involved in the quantitative reconstructions of past vegetation, and that PPEs are constant through time. This paper presents and discusses the PPEs for 15 tree and 18 herb taxa obtained in nine study areas of Europe. Observed differences in PPEs between regions may be explained by methodological issues and environmental variables, of which climate and related factors such as reproduction strategies and growth forms appear to be the most important. An evaluation of the PPEs at hand so far suggests that they can be used in modelling applications and quantitative reconstructions of past vegetation, provided that consideration of past environmental variability within the region is used to inform selection of PPEs, and bearing in mind that PPEs might have changed through time as a response to climate change. Application of a range of possible PPEs will allow a better evaluation of the results.
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17.
  • Burisch, Johan, et al. (författare)
  • Costs and resource utilization for diagnosis and treatment during the initial year in a European inflammatory bowel disease inception cohort : an ECCO-EpiCom Study
  • 2015
  • Ingår i: Inflammatory Bowel Diseases. - 1078-0998 .- 1536-4844. ; 21:1, s. 121-131
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: No direct comparison of health care cost in patients with inflammatory bowel disease across the European continent exists. The aim of this study was to assess the costs of investigations and treatment for diagnostics and during the first year after diagnosis in Europe.METHODS: The EpiCom cohort is a prospective population-based inception cohort of unselected inflammatory bowel disease patients from 31 Western and Eastern European centers. Patients were followed every third month from diagnosis, and clinical data regarding treatment and investigations were collected. Costs were calculated in euros (&OV0556;) using the Danish Health Costs Register.RESULTS: One thousand three hundred sixty-seven patients were followed, 710 with ulcerative colitis, 509 with Crohn's disease, and 148 with inflammatory bowel disease unclassified. Total expenditure for the cohort was &OV0556;5,408,174 (investigations: &OV0556;2,042,990 [38%], surgery: &OV0556;1,427,648 [26%], biologicals: &OV0556;781,089 [14%], and standard treatment: &OV0556;1,156,520 [22%)]). Mean crude expenditure per patient in Western Europe (Eastern Europe) with Crohn's disease: investigations &OV0556;1803 (&OV0556;2160) (P = 0.44), surgery &OV0556;11,489 (&OV0556;13,973) (P = 0.14), standard treatment &OV0556;1027 (&OV0556;824) (P = 0.51), and biologicals &OV0556;7376 (&OV0556;8307) (P = 0.31). Mean crude expenditure per patient in Western Europe (Eastern Europe) with ulcerative colitis: investigations &OV0556;1189 (&OV0556;1518) (P < 0.01), surgery &OV0556;18,414 (&OV0556;12,395) (P = 0.18), standard treatment &OV0556;896 (&OV0556;798) (P < 0.05), and biologicals &OV0556;5681 (&OV0556;72) (P = 0.51).CONCLUSIONS: In this population-based unselected cohort, costs during the first year of disease were mainly incurred by investigative procedures and surgeries. However, biologicals accounted for >15% of costs. Long-term follow-up of the cohort is needed to assess the cost-effectiveness of biological agents.
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18.
  • Burisch, Johan, et al. (författare)
  • Disease course of inflammatory bowel disease unclassified in a European population-based inception cohort : an Epi-IBD study
  • 2019
  • Ingår i: Journal of Gastroenterology and Hepatology. - : John Wiley & Sons. - 0815-9319 .- 1440-1746. ; 34:6, s. 996-1003
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: A definitive diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) is not always possible and a proportion of patients will be diagnosed as inflammatory bowel disease unclassified (IBDU). The aim of the study was to investigate the prognosis of patients initially diagnosed with IBDU and the disease course during the following five years.METHODS: The Epi-IBD study is a prospective population-based cohort of 1,289 IBD patients diagnosed in centres across Europe. Clinical data were captured prospectively throughout the follow-up period.RESULTS: Overall, 476 (37%) patients were initially diagnosed with CD, 701 (54%) with UC, and 112 (9%) with IBDU. During follow-up, 28 (25%) IBDU patients were changed diagnoses to either UC (n=20, 71%) or CD (n=8, 29%) after a median of six months (IQR: 4-12), while 84 (7% of the total cohort) remained IBDU. A total of 17 (15%) IBDU patients were hospitalized for their IBD during follow-up, while 8 (7%) patients underwent surgery. Most surgeries (n=6, 75%) were performed on patients whose diagnosis was later changed to UC; three of these colectomies led to a definitive diagnosis of UC. Most patients (n=107, 96%) received 5-aminosalicylic acid, while 11 (10%) patients received biologicals, of whom five remained classified as IBDU.CONCLUSIONS: In a population-based inception cohort, 7% of IBD patients were not given a definitive diagnosis of IBD after five years of follow-up. One in four patients with IBDU eventually were classified as CD or UC. Overall, the disease course and medication burden in IBDU patients were mild.
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19.
  • Burisch, Johan, et al. (författare)
  • Initial Disease Course and Treatment in an Inflammatory Bowel Disease Inception Cohort in Europe : The ECCO-EpiCom Cohort
  • 2014
  • Ingår i: Inflammatory Bowel Diseases. - : Lippincott Williams & Wilkins. - 1078-0998 .- 1536-4844. ; 20:1, s. 36-46
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:The EpiCom cohort is a prospective, population-based, inception cohort of inflammatory bowel disease (IBD) patients from 31 European centers covering a background population of 10.1 million. The aim of this study was to assess the 1-year outcome in the EpiCom cohort.Methods:Patients were followed-up every third month during the first 12 (3) months, and clinical data, demographics, disease activity, medical therapy, surgery, cancers, and deaths were collected and entered in a Web-based database (www.epicom-ecco.eu).Results:In total, 1367 patients were included in the 1-year follow-up. In western Europe, 65 Crohn's disease (CD) (16%), 20 ulcerative colitis (UC) (4%), and 4 IBD unclassified (4%) patients underwent surgery, and in eastern Europe, 12 CD (12%) and 2 UC (1%) patients underwent surgery. Eighty-one CD (20%), 80 UC (14%), and 13 (9%) IBD unclassified patients were hospitalized in western Europe compared with 17 CD (16%) and 12 UC (8%) patients in eastern Europe. The cumulative probability of receiving immunomodulators was 57% for CD in western (median time to treatment 2 months) and 44% (1 month) in eastern Europe, and 21% (5 months) and 5% (6 months) for biological therapy, respectively. For UC patients, the cumulative probability was 22% (4 months) and 15% (3 months) for immunomodulators and 6% (3 months) and 1% (12 months) for biological therapy, respectively in the western and eastern Europe.Discussion:In this cohort, immunological therapy was initiated within the first months of disease. Surgery and hospitalization rates did not differ between patients from eastern and western Europe, although more western European patients received biological agents and were comparable to previous population-based inception cohorts.
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20.
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21.
  • Burisch, Johan, et al. (författare)
  • Natural Disease Course of Ulcerative Colitis During the First Five Years of Follow-up in a European Population-based Inception Cohort-An Epi-IBD Study
  • 2019
  • Ingår i: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 13:2, s. 198-208
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Aims: Few population-based cohort studies have assessed the disease course of ulcerative colitis [UC] in the era of biological therapy and widespread use of immunomodulators. The aim of this study was to assess the 5-year outcome and disease course of patients with UC in the Epi-IBD cohort.Methods: In a prospective, population-based inception cohort of unselected patients with UC, patients were followed up from the time of their diagnosis, which included the collection of their clinical data, demographics, disease activity, medical therapy, and rates of surgery, cancers, and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis.Results: A total of 717 patients were included in the study. During follow-up, 43 [6%] patients underwent a colectomy and 163 [23%] patients were hospitalised. Of patients with limited colitis [distal to the left flexure], 90 [21%] progressed to extensive colitis. In addition, 92 [27%] patients with extensive colitis experienced a regression in disease extent, which was associated with a reduced risk of hospitalisation (hazard ratio [HR]: 0.5 95% CI: 0.3-0.8]. Overall, patients were treated similarly in both geographical regions; 80 [11%] patients needed biological therapy and 210 [29%] patients received immunomodulators. Treatment with immunomodulators was found to reduce the risk of hospitalisation [HR: 0.5 95% CI: 0.3-0.8].Conclusions: Although patients in this population-based cohort were treated more aggressively with immunomodulators and biological therapy than in cohorts from the previous two decades, their disease outcomes, including colectomy rates, were no different. However, treatment with immunomodulators was found to reduce the risk of hospitalisation.
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22.
  • Burisch, Johan, et al. (författare)
  • Occurrence of anaemia in the first year of inflammatory bowel disease in a European population-based inception cohort : An ECCO-EpiCom study
  • 2017
  • Ingår i: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 11:10, s. 1213-1222
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and aims: Anaemia is an important complication of inflammatory bowel disease (IBD). The aim of this study was to determine the prevalence of anaemia and the practice of anaemia screening during the first year following diagnosis in a European prospective population-based inception cohort.Methods: Newly diagnosed IBD patients were included and followed prospectively for one year in 29 European and 1 Australian centre. Clinical data including demographics, medical therapy, surgery and blood samples were collected. Anaemia was defined according to the World Health Organization.Results: A total of 1,871 patients (CD: 686, 88%; UC: 1,021, 87%; IBDU 164. 81%) were included in the study. The prevalence of anaemia was higher in CD than in UC patients and overall, 49% of CD and 39% of UC patients had at least one instance of anaemia during the first 12 months after diagnosis. UC patients with more extensive disease and those from Eastern European countries, and CD patients with penetrating disease or colonic disease location, had higher risks of anaemia. CD and UC patients in need of none or only mild anti-inflammatory treatment had a lower risk of anaemia. In a significant proportion of patients, anaemia was not assessed until several months after diagnosis, and in almost half of all cases of anaemia a thorough work-up was not performed.Conclusions: Overall, 42% of patients had at least one instance of anaemia during the first year following diagnosis. Most patients were assessed for anaemia regularly; however, a full anaemia work-up was frequently neglected in this community setting.
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23.
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24.
  • Börschel, Christin S., et al. (författare)
  • Risk prediction of atrial fibrillation and its complications in the community using hs troponin I
  • 2023
  • Ingår i: European Journal of Clinical Investigation. - : John Wiley & Sons. - 0014-2972 .- 1365-2362. ; 53:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: Atrial fibrillation (AF) is becoming increasingly common. Traditional cardiovascular risk factors (CVRF) do not explain all AF cases. Blood-based biomarkers reflecting cardiac injury such as high-sensitivity troponin I (hsTnI) may help close this gap.Methods: We investigated the predictive ability of hsTnI for incident AF in 45,298 participants (median age 51.4 years, 45.0% men) across European community cohorts in comparison to CVRF and established biomarkers (C-reactive protein, N-terminal pro B-type natriuretic peptide).Results: During a median follow-up of 7.7 years, 1734 (3.8%) participants developed AF. Those in the highest hsTnI quarter (≥4.2 ng/L) had a 3.91-fold (95% confidence interval (CI) 3.30, 4.63; p <.01) risk for developing AF compared to the lowest quarter (<1.4 ng/L). In multivariable-adjusted Cox proportional hazards models a statistically significant association was seen between hsTnI and AF (hazard ratio (HR) per 1 standard deviation (SD) increase in log10(hsTnI) 1.08; 95% CI 1.01, 1.16; p =.03). Inclusion of hsTnI did improve model discrimination (C-index CVRF 0.811 vs. C-index CVRF and hsTnI 0.813; p <.01). Higher hsTnI concentrations were associated with heart failure (HR per SD 1.37; 95% CI 1.12, 1.68; p <.01) and overall mortality (HR per SD 1.24; 95% CI 1.09, 1.41; p <.01).Conclusion: hsTnI as a biomarker of myocardial injury does not improve prediction of AF incidence beyond classical CVRF and NT-proBNP. However, it is associated with the AF-related disease heart failure and mortality likely reflecting underlying subclinical cardiovascular impairment.
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25.
  • Camen, Stephan, et al. (författare)
  • Cardiac Troponin I and Incident Stroke in European Cohorts : Insights From the BiomarCaRE Project
  • 2020
  • Ingår i: Stroke. - : Lippincott Williams & Wilkins. - 0039-2499 .- 1524-4628. ; 51:9, s. 2770-2777
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Purpose: Stroke is a common cause of death and a leading cause of disability and morbidity. Stroke risk assessment remains a challenge, but circulating biomarkers may improve risk prediction. Controversial evidence is available on the predictive ability of troponin concentrations and the risk of stroke in the community. Furthermore, reports on the predictive value of troponin concentrations for different stroke subtypes are scarce.Methods: High-sensitivity cardiac troponin I (hsTnI) concentrations were assessed in 82 881 individuals (median age, 50.7 years; 49.7% men) free of stroke or myocardial infarction at baseline from 9 prospective European community cohorts. We used Cox proportional hazards regression to determine relative risks, followed by measures of discrimination and reclassification using 10-fold cross-validation to control for overoptimism. Follow-up was based upon linkage with national hospitalization registries and causes of death registries.Results: Over a median follow-up of 12.7 years, 3033 individuals were diagnosed with incident nonfatal or fatal stroke (n=1654 ischemic strokes, n=612 hemorrhagic strokes, and n=767 indeterminate strokes). In multivariable regression models, hsTnI concentrations were associated with overall stroke (hazard ratio per 1-SD increase, 1.15 [95% CI, 1.10-1.21]), ischemic stroke (hazard ratio, 1.14 [95% CI, 1.09-1.21]), and hemorrhagic stroke (hazard ratio, 1.10 [95% CI, 1.01-1.20]). Adding hsTnI concentrations to classical cardiovascular risk factors (C indices, 0.809, 0.840, and 0.736 for overall, ischemic, and hemorrhagic stroke, respectively) increased the C index significantly but modestly. In individuals with an intermediate 10-year risk (5%-20%), the net reclassification improvement for overall stroke was 0.038 (P=0.021).Conclusions: Elevated hsTnI concentrations are associated with an increased risk of incident stroke in the community, irrespective of stroke subtype. Adding hsTnI concentrations to classical risk factors only modestly improved estimation of 10-year risk of stroke in the overall cohort but might be of some value in individuals at an intermediate risk.
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26.
  • Camen, Stephan, et al. (författare)
  • Risk Factors, Subsequent Disease Onset, and Prognostic Impact of Myocardial Infarction and Atrial Fibrillation
  • 2022
  • Ingår i: Journal of the American Heart Association. - : American Heart Association. - 2047-9980. ; 11:7
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Although myocardial infarction (MI) and atrial fibrillation (AF) are frequent comorbidities and share common cardiovascular risk factors, the direction and strength of the association of the risk factors with disease onset, subsequent disease incidence, and mortality are not completely understood.METHODS AND RESULTS: In pooled multivariable Cox regression analyses, we examined temporal relations of disease onset and identified predictors of MI, AF, and all-cause mortality in 108 363 individuals (median age, 46.0 years; 48.2% men) free of MI and AF at baseline from 6 European population-based cohorts. During a maximum follow-up of 10.0 years, 3558 (3.3%) individuals were diagnosed exclusively with MI, 1922 (1.8%) with AF but no MI, and 491 (0.5%) individuals developed both MI and AF. Association of sex, systolic blood pressure, antihypertensive treatment, and diabetes appeared to be stronger with incident MI than with AF, whereas increasing age and body mass index showed a higher risk for incident AF. Total cholesterol and daily smoking were significantly related to incident MI but not AF. Combined population attributable fraction of cardiovascular risk factors was >70% for incident MI, whereas it was only 27% for AF. Subsequent MI after AF (hazard ratio [HR], 1.68; 95% CI, 1.03–2.74) and subsequent AF after MI (HR, 1.75; 95% CI, 1.31–2.34) both significantly increased overall mortality risk.CONCLUSIONS: We observed different associations of cardiovascular risk factors with both diseases indicating distinct pathophysiological pathways. Subsequent diagnoses of MI and AF significantly increased mortality risk.
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27.
  • Camen, Stephan, et al. (författare)
  • Temporal relations between atrial fibrillation and ischaemic stroke and their prognostic impact on mortality
  • 2020
  • Ingår i: Europace. - : Oxford University Press. - 1099-5129 .- 1532-2092. ; 22:4, s. 522-529
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims Limited evidence is available on the temporal relationship between atrial fibrillation (AF) and ischaemic stroke and their impact on mortality in the community. We sought to understand the temporal relationship of AF and ischaemic stroke and to determine the sequence of disease onset in relation to mortality. Methods and results Across five prospective community cohorts of the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project we assessed baseline cardiovascular risk factors in 100 132 individuals, median age 46.1 (25th-75th percentile 35.8-57.5) years, 48.4% men. We followed them for incident ischaemic stroke and AF and determined the relation of subsequent disease diagnosis with overall mortality. Over a median follow-up of 16.1 years, N = 4555 individuals were diagnosed solely with AF, N = 2269 had an ischaemic stroke but no AF diagnosed, and N = 898 developed both, ischaemic stroke and AF. Temporal relationships showed a clustering of diagnosis of both diseases within the years around the diagnosis of the other disease. In multivariable-adjusted Cox regression analyses with time-dependent covariates subsequent diagnosis of AF after ischaemic stroke was associated with increased mortality [hazard ratio (HR) 4.05, 95% confidence interval (CI) 2.17-7.54; P < 0.001] which was also apparent when ischaemic stroke followed after the diagnosis of AF (HR 3.08, 95% CI 1.90-5.00; P < 0.001). Conclusion The temporal relations of ischaemic stroke and AF appear to be bidirectional. Ischaemic stroke may precede detection of AF by years. The subsequent diagnosis of both diseases significantly increases mortality risk. Future research needs to investigate the common underlying systemic disease processes.
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28.
  • Christensen, Gustav Boelsgaard, et al. (författare)
  • Clinical performance of a novel hyperspectral imaging device for cutaneous melanoma and pigmented skin lesions in Caucasian skin
  • 2021
  • Ingår i: Skin Research and Technology. - : Wiley. - 0909-752X .- 1600-0846.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The quest for diagnostic tools for the detection of cutaneous malignant melanoma (cMM) is ongoing. A challenge in cMM care is not overlooking cMM at an early stage, while simultaneously avoiding unnecessary biopsies or excisions of benign pigmented skin lesions (PSLs). A novel hyperspectral imaging (HSI) device is shown to have potential for differentiating equivocal PSLs in Asian skin types. Our objective was to assess the accuracy of the HSI device in distinguishing between cMM and benign PSLs in patients with Caucasian skin types. Methods: Patients with Caucasian skin types (Fitzpatrick I-II), enrolled for excisional biopsies of PSLs were included and examined using the HSI device. The discrimination index (DI) was used to demonstrate the sensitivity (SE) and specificity (SP) in comparison with the re-evaluated histopathology diagnoses. Results: In 186 patients, 202 pigmented skin lesions were included. The sensitivity to detect cMM was 96.7% (87/90), and the specificity for benign lesions was 42.1% (45/107). The AUC was 0.800 (95% confidence interval (CI): 0.740-0.861). Conclusions: Our novel HSI device showed a high sensitivity in detecting malignant lesions in patients with Caucasian skin types. Compared with analogous technologies, as multispectral imaging or electrical impedance spectroscopy, our device showed similar or better accuracy in differentiating cMM from benign PSLs. Therefore, it might be a useful clinical tool in skin types I-IV and where further triage of pigmented skin lesions is important.
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29.
  • Christensen, Gustav Boelsgaard, et al. (författare)
  • Clinical performance of a novel hyperspectral imaging device for cutaneous melanoma and pigmented skin lesions in Caucasian skin.
  • 2021
  • Ingår i: Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI). - : Wiley-Blackwell. - 1600-0846. ; 27:5, s. 803-809
  • Tidskriftsartikel (refereegranskat)abstract
    • The quest for diagnostic tools for the detection of cutaneous malignant melanoma (cMM) is ongoing. A challenge in cMM care is not overlooking cMM at an early stage, while simultaneously avoiding unnecessary biopsies or excisions of benign pigmented skin lesions (PSLs). A novel hyperspectral imaging (HSI) device is shown to have potential for differentiating equivocal PSLs in Asian skin types. Our objective was to assess the accuracy of the HSI device in distinguishing between cMM and benign PSLs in patients with Caucasian skin types.Patients with Caucasian skin types (Fitzpatrick I-II), enrolled for excisional biopsies of PSLs were included and examined using the HSI device. The discrimination index (DI) was used to demonstrate the sensitivity (SE) and specificity (SP) in comparison with the re-evaluated histopathology diagnoses.In 186 patients, 202 pigmented skin lesions were included. The sensitivity to detect cMM was 96.7% (87/90), and the specificity for benign lesions was 42.1% (45/107). The AUC was 0.800 (95% confidence interval (CI): 0.740-0.861).Our novel HSI device showed a high sensitivity in detecting malignant lesions in patients with Caucasian skin types. Compared with analogous technologies, as multispectral imaging or electrical impedance spectroscopy, our device showed similar or better accuracy in differentiating cMM from benign PSLs. Therefore, it might be a useful clinical tool in skin types I-IV and where further triage of pigmented skin lesions is important.
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30.
  • Christensen, Gustav Boelsgaard, et al. (författare)
  • Sunbed Use Increases Cutaneous Squamous Cell Carcinoma Risk in Women : A Large-scale, Prospective Study in Sweden
  • 2019
  • Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 1651-2057 .- 0001-5555. ; 99:10, s. 878-883
  • Tidskriftsartikel (refereegranskat)abstract
    • The incidence of cutaneous squamous cell carcinoma has increased rapidly in Sweden in the past decades. Here, we present a prospective study of the Melanoma in Southern Sweden (MISS)-cohort, with 29,460 participating women in southern Sweden that investigates the risk factors for cutaneous squamous cell carcinoma. Data on the host and skin cancer risk factors were collected through questionnaires and then matched with the National Cancer Registry. Statistical analyses were based on uni- and multivariable Cox proportional hazards models, using age as the time-scale. We found that sunbed use (hazard ratio (HR) 1.2, 95% CI: 1.1-1.4), red and light blond hair (HR 1.6, 95% CI: 1.1-2.3), freckles (HR 1.4, 95% CI: 1.1-1.8) and immunosuppressive medications (HR 2.1, 95% CI: 1.3-4.5) were independent risk factors. Furthermore, we observed a dose-dependent relationship between sunbed use and the development of cutaneous squamous cell carcinoma. Our findings support the idea of integrating dermatological follow-up examinations for immunosuppressed patients and banning the use of sunbeds in order to prevent cutaneous squamous cell carcinoma.
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31.
  • Cirenajwis, Helena, et al. (författare)
  • Molecular stratification of metastatic melanoma using gene expression profiling: prediction of survival outcome and benefit from molecular targeted therapy.
  • 2015
  • Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:14, s. 12297-12309
  • Tidskriftsartikel (refereegranskat)abstract
    • Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.
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32.
  • Csengeri, Dora, et al. (författare)
  • Alcohol consumption, cardiac biomarkers, and risk of atrial fibrillation and adverse outcomes
  • 2021
  • Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 42:12, s. 1170-1177
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: There is inconsistent evidence on the relation of alcohol intake with incident atrial fibrillation (AF), in particular at lower doses. We assessed the association between alcohol consumption, biomarkers, and incident AF across the spectrum of alcohol intake in European cohorts.METHODS AND RESULTS: In a community-based pooled cohort, we followed 107 845 individuals for the association between alcohol consumption, including types of alcohol and drinking patterns, and incident AF. We collected information on classical cardiovascular risk factors and incident heart failure (HF) and measured the biomarkers N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I. The median age of individuals was 47.8 years, 48.3% were men. The median alcohol consumption was 3 g/day. N = 5854 individuals developed AF (median follow-up time: 13.9 years). In a sex- and cohort-stratified Cox regression analysis alcohol consumption was non-linearly and positively associated with incident AF. The hazard ratio for one drink (12 g) per day was 1.16, 95% CI 1.11-1.22, P < 0.001. Associations were similar across types of alcohol. In contrast, alcohol consumption at lower doses was associated with reduced risk of incident HF. The association between alcohol consumption and incident AF was neither fully explained by cardiac biomarker concentrations nor by the occurrence of HF.CONCLUSIONS: In contrast to other cardiovascular diseases such as HF, even modest habitual alcohol intake of 1.2 drinks/day was associated with an increased risk of AF, which needs to be considered in AF prevention.
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33.
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34.
  • Eriksson, Hanna, et al. (författare)
  • Trend shifts in age-specific incidence for in situ and invasive cutaneous melanoma in sweden
  • 2021
  • Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The incidence of invasive cutaneous melanoma (CM) is increasing in Sweden. The aim was to present age-and sex-specific trends of the age-standardised incidence and the average annual percentage change (AAPC) for in situ and invasive CM. Methods: Joinpoint regression models were used to analyse data from the Swedish Cancer Register and the Swedish Melanoma Registry 1997–2018 (N = 35,350 in situ CM; 59,932 CM). Results: The AAPC of CM for women was 4.5 (4.1–5.0; p < 0.001) for the period 1997–2018. For men, the APCC was 4.2 (3.0–5.4; p < 0.001), with a significantly higher annual percentage change (APC) for the period 2000–2018 (5.0; 4.6–5.4; p < 0.001) compared to 1997–1999. An increasing annual incidence of CM ≤ 0.6 mm and 0.7 mm Breslow tumour thickness was found for men with a significant incidence shift for the period 2006–2015, respectively. Similarly for women, with a significantly higher APC for CM ≤ 0.6 mm from 2005. The incidence of intermediate thick CM (2.1–4.0 mm) has not increased since 2011. The incidence of CM > 4.0 mm has been increasing among both sexes, with a significantly lower APC among women from 2005. Conclusions: The incidence of in situ and low-risk CM ≤ 1.0 mm in tumour thickness has been rising among both sexes since the 2000s.
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35.
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36.
  • Fang, Jun, et al. (författare)
  • Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148
  • 2017
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele.
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37.
  • Forsea, A M, et al. (författare)
  • Factors driving the use of dermoscopy in Europe : a pan-European survey
  • 2016
  • Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 1365-2133 .- 0007-0963. ; 175:6, s. 1329-1337
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: When used correctly, dermoscopy is an essential tool for helping clinicians in the diagnosis of skin diseases and the early detection of skin cancers. Despite its proven benefits, there is a lack of data about how European dermatologists use dermoscopy in everyday practice.OBJECTIVES: To identify the motivations, obstacles and modifiable factors influencing the use of dermoscopy in daily dermatology practice across Europe.METHODS: All registered dermatologists in 32 European countries were invited to complete an online survey of 20 questions regarding demographic and practice characteristics, dermoscopy training and self-confidence in dermoscopic skills, patterns of dermoscopy use, reasons for not using dermoscopy and attitudes relating to dermoscopy utility.RESULTS: We collected 7480 valid answers, of which 89% reported use of dermoscopy. The main reasons for not using dermoscopy were lack of equipment (58% of nonusers) and lack of training (42%). Dermoscopy training during residency was reported by 41% of dermoscopy users and by 12% of nonusers (P < 0·001). Dermatologists working in public hospitals were the least likely to use dermoscopy. High use of dermoscopy across the spectrum of skin diseases was reported by 62% of dermoscopy users and was associated with dermoscopy training during residency, the use of polarized light and digital dermoscopy devices, longer dermoscopy practice, younger age and female gender.CONCLUSIONS: Expanding access to dermoscopy equipment, especially in public healthcare facilities and establishing dermoscopy training during dermatology residency would further enhance the substantially high dermoscopy use across European countries.
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38.
  • Forsea, Ana-Maria, et al. (författare)
  • Inequalities in the patterns of dermoscopy use and training across Europe : conclusions of the Eurodermoscopy pan-European survey
  • 2020
  • Ingår i: European journal of dermatology : EJD. - : John Libbey Eurotext. - 1167-1122 .- 1952-4013. ; 30:5, s. 524-531
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Dermoscopy is a widely used technique, recommended in clinical practice guidelines worldwide for the early diagnosis of skin cancers. Intra-European disparities are reported for early detection and prognosis of skin cancers, however, no information exists about regional variation in patterns of dermoscopy use across Europe.OBJECTIVE: To evaluate the regional differences in patterns of dermoscopy use and training among European dermatologists.MATERIALS & METHODS: An online survey of European-registered dermatologists regarding dermoscopy training, practice and attitudes was established. Answers from Eastern (EE) versus Western European (WE) countries were compared and their correlation with their respective countries' gross domestic product/capita (GDPc) and total and government health expenditure/capita (THEc and GHEc) was analysed.RESULTS: We received 4,049 responses from 14 WE countries and 3,431 from 18 EE countries. A higher proportion of WE respondents reported dermoscopy use (98% vs. 77%, p<0.001) and training during residency (43% vs. 32%) or anytime (96.5% vs. 87.6%) (p<0.001) compared to EE respondents. The main obstacles in dermoscopy use were poor access to dermoscopy equipment in EE and a lack of confidence in one's skills in WE. GDPc, THEc and GHEc correlated with rate of dermoscopy use and dermoscopy training during residency (Spearman rho: 0.5-0.7, p<0.05), and inversely with availability of dermoscopy equipment.CONCLUSION: The rates and patterns of dermoscopy use vary significantly between Western and Eastern Europe, on a background of economic inequality. Regionally adapted interventions to increase access to dermoscopy equipment and training might enhance the use of this technique towards improving the early detection of skin cancers.
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39.
  • Forsea, A M, et al. (författare)
  • The impact of dermoscopy on melanoma detection in the practice of dermatologists in Europe : results of a pan-European survey
  • 2017
  • Ingår i: Journal of the European Academy of Dermatology and Venereology. - : Wiley. - 1468-3083 .- 0926-9959. ; 31:7, s. 1148-1156
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Dermoscopy is a widely used technique that can increase the sensitivity and specificity of melanoma detection. Information is lacking on the impact of dermoscopy use on the detection of melanoma in the real-life practice of European dermatologists.OBJECTIVE: To identify factors that influence the benefit of using dermoscopy for increasing melanoma detection and lowering the number of unnecessary biopsies in the practice of European dermatologists.METHODS: We conducted a survey of dermatologists registered in 32 European countries regarding the following: the demographic and practice characteristics, dermoscopy training and use, opinions on dermoscopy and the self-estimated impact of dermoscopy use on the number of melanomas detected and the number of unnecessary biopsies performed in practice.RESULTS: Valid answers were collected for 7480 respondents, of which 6602 reported using dermoscopy. Eighty-six per cent of dermoscopy users reported that dermoscopy increased the numbers of melanomas they detected, and 70% reported that dermoscopy decreased the number of unnecessary biopsies of benign lesions they performed. The dermatologists reporting these benefits were more likely to have received dermoscopy training during residency, to use dermoscopy frequently and intensively, and to use digital dermoscopy systems and pattern analysis compared to dermatologists who did not perceive any benefit of dermoscopy for the melanoma recognition in their practice.CONCLUSIONS: Improving dermoscopy training, especially during residency and increasing access to digital dermoscopy equipment are important paths to enhance the benefit of dermoscopy for melanoma detection in the practice of European dermatologists.
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40.
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41.
  • Gaillard, Marie-José, et al. (författare)
  • From land cover-climate relationships at the subcontinental scale to land cover-environment relationships at the regional and local spatial scale – the contribution of pollen-based quantitative reconstructions of vegetation cover using the Landscape Reconstruction Algorithm approach
  • 2014
  • Ingår i: Towards a more accurate quantification of human-environment interactions in the past. ; , s. 25-26
  • Konferensbidrag (refereegranskat)abstract
    • The Landscape Reconstruction Algorithm (Sugita 2007a,b) includes two models, REVEALS (Regional Estimates of VEgetation Abundance from Large Sites) that estimates vegetation abundance (% cover) within an area of ca. 100 km x 100 km, and LOVE (LOcal Vegetation Estimates) that estimates vegetation abundance at the local spatial scale, i.e. within the Relevant Source Area of Pollen (RSAP sensu Sugita, 2004) that is the smallest area around the study site for which the reconstruction is valid. The RSAP is estimated by the LOVE model and varies between sites and vegetation settings; so far, it was estimated to vary between < 1 - < 10 km in most ecological settings of the Holocene in NW Europe. We used the REVEALS model and over 600 pollen records from pollen data bases and individual researchers to reconstruct land-cover in NW Europe N of the Alps for key time windows of the Holocene in order to assess model-based reconstructions of anthropogenic land-cover change (ALCC) (e.g. Kaplan et al., 2009) and model (LPJ-GUESS) simulations of past potential (climate-induced vegetation), and to study past land cover – climate interactions using a regional climate model (RCA3). We used the REVEALS model and the complete LRA approach (REVEALS + LOVE models) along with two pollen records from large lakes and three pollen records from small bogs to reconstruct the local-scale land-cover in central Småland, southern Sweden, to study the relationship between vegetation composition, fire, climate and human impact at the regional and local spatial scales with the objective to discuss biodiversity issues. Our results suggest that i) past subcontinental to regional ALCC did influence regional climate through biogeophysical processes at the landatmosphere interface (Strandberg et al., submitted), and ii) local land-cover change, both natural and anthropogenic, govern environmental changes such as fire and biodiversity (Cui et al., 2013; Cui et al., submitted).
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42.
  • Gaillard, Marie-José, et al. (författare)
  • Has anthropogenic land-cover change been a significant climate forcing in the past? : An assessment for the Baltic Sea catchment area based on a literature review
  • 2015
  • Ingår i: Geophysical Research Abstracts.
  • Konferensbidrag (refereegranskat)abstract
    • We reviewed the recent published scientific literature on land cover-climate interactions at the global and regional spatial scales with the aim to assess whether it is convincingly demonstrated that anthropogenic land-cover change (ALCC) has been (over the last centuries and millennia) a significant climate forcing at the global scale, and more specifically at the scale of the Baltic Sea catchment area. The conclusions from this review are as follows: i) anthropogenic land-cover change (ALCC) is one of the few climate forcings for which the net direction of the climate response in the past is still not known. The uncertainty is due to the often counteracting temperature responses to the many biogeophysical effects, and to the biogeochemical vs biogeophysical effects; ii) there is no indication that deforestation in the Baltic Sea area since AD 1850 would have been a major cause of the recent climate warming in the region through a positive biogeochemical feedback; iii) several model studies suggest that boreal reforestation might not be an effective climate warming mitigation tool as it might lead to increased warming through biogeophysical processes; iv) palaeoecological studies indicate a major transformation of the landscape by anthropogenic activities in the southern zone of the study region occurring between 6000 and 3000/2500 calendar years before present (cal. BP) (1) ; v) the only modelling study so far of the biogeophysical effects of past ALCCs on regional climate in Europe suggests that a deforestation of the magnitude of that reconstructed for the past (between 6000 and 200 cal BP) can produce changes in winter and summer temperatures of +/- 1, the sign of the change depending on the season and the region (2). Thus, if ALCC and their biogeophysical effects did matter in the past, they should matter today and in the future. A still prevailing idea is that planting trees will mitigate climate warming through biogeochemical effects. Therefore, there is still an urgent need to better understand the biogeophysical effects on regional and continental climate of afforestation in the hemiboreal and boreal regions, and their significance in relation to the biogeochemical effects.
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43.
  • Gaillard, Marie-José, 1953-, et al. (författare)
  • Holocene land-cover reconstructions for studies on land cover-climate feedbacks
  • 2010
  • Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 6, s. 483-499
  • Tidskriftsartikel (refereegranskat)abstract
    • The major objectives of this paper are: (1) to review the pros and cons of the scenarios of past anthropogenic land cover change (ALCC) developed during the last ten years, (2) to discuss issues related to pollen-based reconstruction of the past land-cover and introduce a new method, REVEALS (Regional Estimates of VEgetation Abundance from Large Sites), to infer long-term records of past land-cover from pollen data, (3) to present a new project (LANDCLIM: LAND cover – CLIMate interactions in NW Europe during the Holocene) currently underway, and show preliminary results of REVEALS reconstructions of the regional land-cover in the Czech Republic for five selected time windows of the Holocene, and (4) to discuss the implications and future directions in climate and vegetation/land-cover modeling, and in the assessment of the effects of human-induced changes in land-cover on the regional climate through altered feedbacks. The existing ALCC scenarios show large discrepancies between them, and few cover time periods older than AD 800. When these scenarios are used to assess the impact of human land-use on climate, contrasting results are obtained. It emphasizes the need for methods such as the REVEALS model-based land-cover reconstructions. They might help to fine-tune descriptions of past land-cover and lead to a better understanding of how long-term changes in ALCC might have influenced climate. The REVEALS model is demonstrated to provide better estimates of the regional vegetation/landcover changes than the traditional use of pollen percentages. This will achieve a robust assessment of land cover at regional- to continental-spatial scale throughout the Holocene. We present maps of REVEALS estimates for the percentage cover of 10 plant functional types (PFTs) at 200 BP and 6000 BP, and of the two open-land PFTs “grassland” and “agricultural land” at five time-windows from 6000 BP to recent time. The LANDCLIM results are expected to provide crucial data to reassess ALCC estimates for a better understanding of the land suface-atmosphere interactions.
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44.
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45.
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46.
  • Gaillard, Marie-Jose, et al. (författare)
  • The use of modelling and simulation approach in reconstructing past landscapes from fossil pollen data: a review and results from the POLLANDCAL network
  • 2008
  • Ingår i: Vegetation History and Archaeobotany. - : Springer Science and Business Media LLC. - 0939-6314 .- 1617-6278. ; 17:5, s. 419-443
  • Tidskriftsartikel (refereegranskat)abstract
    • Information on past land cover in terms of absolute areas of different landscape units (forest, open land, pasture land, cultivated land, etc.) at local to regional scales is needed to test hypotheses and answer questions related to climate change (e.g. feedbacks effects of land-cover change), archaeological research, and nature conservancy (e.g. management strategy). The palaeoecological technique best suited to achieve quantitative reconstruction of past vegetation is pollen analysis. A simulation approach developed by Sugita (the computer model POLLSCAPE) which uses models based on the theory of pollen analysis is presented together with examples of application. POLLSCAPE has been adopted as the central tool for POLLANDCAL (POLlen/LANdscape CALibration), an international research network focusing on this topic. The theory behind models of the pollen-vegetation relationship and POLLSCAPE is reviewed. The two model outputs which receive greatest attention in this paper are the relevant source area of pollen (RSAP) and pollen loading in mires and lakes. Six examples of application of POLLSCAPE are presented, each of which explores a possible use of the POLLANDCAL tools and a means of validating or evaluating the models with empirical data. The landscape and vegetation factors influencing the size of the RSAP, the importance of pollen productivity estimates (PPEs) for the model outputs, the detection of small and rare patches of plant taxa in pollen records, and quantitative reconstructions of past vegetation and landscapes are discussed on the basis of these examples. The simulation approach is seen to be useful both for exploring different vegetation/landscape scenarios and for refuting hypotheses.
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47.
  • Githumbi, Esther, et al. (författare)
  • European pollen-based REVEALS land-cover reconstructions for the Holocene : Methodology, mapping and potentials
  • 2022
  • Ingår i: Earth System Science Data. - : Copernicus GmbH. - 1866-3508 .- 1866-3516. ; 14:4, s. 1581-1619
  • Tidskriftsartikel (refereegranskat)abstract
    • Quantitative reconstructions of past land cover are necessary to determine the processes involved in climate-human-land-cover interactions. We present the first temporally continuous and most spatially extensive pollen-based land-cover reconstruction for Europe over the Holocene (last 11g€¯700g€¯calg€¯yrg€¯BP). We describe how vegetation cover has been quantified from pollen records at a 11 spatial scale using the "Regional Estimates of VEgetation Abundance from Large Sites"(REVEALS) model. REVEALS calculates estimates of past regional vegetation cover in proportions or percentages. REVEALS has been applied to 1128 pollen records across Europe and part of the eastern Mediterranean-Black Sea-Caspian corridor (30-75° N, 25° W-50° E) to reconstruct the percentage cover of 31 plant taxa assigned to 12 plant functional types (PFTs) and 3 land-cover types (LCTs). A new synthesis of relative pollen productivities (RPPs) for European plant taxa was performed for this reconstruction. It includes multiple RPP values (≥2 values) for 39 taxa and single values for 15 taxa (total of 54 taxa). To illustrate this, we present distribution maps for five taxa (Calluna vulgaris, Cerealia type (t)., Picea abies, deciduous Quercus t. and evergreen Quercus t.) and three land-cover types (open land, OL; evergreen trees, ETs; and summer-green trees, STs) for eight selected time windows. The reliability of the REVEALS reconstructions and issues related to the interpretation of the results in terms of landscape openness and human-induced vegetation change are discussed. This is followed by a review of the current use of this reconstruction and its future potential utility and development. REVEALS data quality are primarily determined by pollen count data (pollen count and sample, pollen identification, and chronology) and site type and number (lake or bog, large or small, one site vs. multiple sites) used for REVEALS analysis (for each grid cell). A large number of sites with high-quality pollen count data will produce more reliable land-cover estimates with lower standard errors compared to a low number of sites with lower-quality pollen count data. The REVEALS data presented here can be downloaded from https://doi.org/10.1594/PANGAEA.937075 (Fyfe et al., 2022).
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48.
  • Githumbi, Esther, et al. (författare)
  • Pollen-Based Maps of Past Regional Vegetation Cover in Europe Over 12 Millennia-Evaluation and Potential
  • 2022
  • Ingår i: Frontiers in Ecology and Evolution. - : Frontiers Media S.A.. - 2296-701X. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Realistic and accurate reconstructions of past vegetation cover are necessary to study past environmental changes. This is important since the effects of human land-use changes (e.g. agriculture, deforestation and afforestation/reforestation) on biodiversity and climate are still under debate. Over the last decade, development, validation, and application of pollen-vegetation relationship models have made it possible to estimate plant abundance from fossil pollen data at both local and regional scales. In particular, the REVEALS model has been applied to produce datasets of past regional plant cover at 1 degrees spatial resolution at large subcontinental scales (North America, Europe, and China). However, such reconstructions are spatially discontinuous due to the discrete and irregular geographical distribution of sites (lakes and peat bogs) from which fossil pollen records have been produced. Therefore, spatial statistical models have been developed to create continuous maps of past plant cover using the REVEALS-based land cover estimates. In this paper, we present the first continuous time series of spatially complete maps of past plant cover across Europe during the Holocene (25 time windows covering the period from 11.7 k BP to present). We use a spatial-statistical model for compositional data to interpolate REVEALS-based estimates of three major land-cover types (LCTs), i.e., evergreen trees, summer-green trees and open land (grasses, herbs and low shrubs); producing spatially complete maps of the past coverage of these three LCTs. The spatial model uses four auxiliary data sets-latitude, longitude, elevation, and independent scenarios of past anthropogenic land-cover change based on per-capita land-use estimates ("standard" KK10 scenarios)-to improve model performance for areas with complex topography or few observations. We evaluate the resulting reconstructions for selected time windows using present day maps from the European Forest Institute, cross validate, and compare the results with earlier pollen-based spatially-continuous estimates for five selected time windows, i.e., 100 BP-present, 350-100 BP, 700-350 BP, 3.2-2.7 k BP, and 6.2-5.7 k BP. The evaluations suggest that the statistical model provides robust spatial reconstructions. From the maps we observe the broad change in the land-cover of Europe from dominance of naturally open land and persisting remnants of continental ice in the Early Holocene to a high fraction of forest cover in the Mid Holocene, and anthropogenic deforestation in the Late Holocene. The temporal and spatial continuity is relevant for land-use, land-cover, and climate research.
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49.
  • Gopalakrishnan, Shyam, et al. (författare)
  • The population genomic legacy of the second plague pandemic
  • 2022
  • Ingår i: Current Biology. - : Elsevier. - 0960-9822 .- 1879-0445. ; 32:21, s. 4743-4751.e6
  • Tidskriftsartikel (refereegranskat)abstract
    • Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%–40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th–19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics.
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50.
  • Gusarova, Viktoria, et al. (författare)
  • Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes
  • 2018
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9, s. 1-11
  • Tidskriftsartikel (refereegranskat)abstract
    • Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10-10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.
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