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1.	Papadopoulos, Nikolaos G, et al. (author) Research needs in allergy: an EAACI position paper, in collaboration with EFA. 2012 In: Clinical and translational allergy. - : Wiley. - 2045-7022. ; 2:1 Journal article (peer-reviewed)abstract ABSTRACT: In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21st century.The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients' Associations (EFA) is a non-profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients' organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels.Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re-categorize clinical syndromes into more coherent, uniform and treatment-responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient-oriented diagnostic and treatment protocols. Several allergic diseases require well-controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult-to-manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders, including Patient Organizations and policy makers are necessary to achieve the aims emphasized herein.
2.	Hibar, Derrek P., et al. (author) Novel genetic loci associated with hippocampal volume 2017 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8 Journal article (peer-reviewed)abstract The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
3.	Kalscheuer, Vera M, et al. (author) Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation 2003 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 35:4, s. 313-315 Journal article (peer-reviewed)abstract We found mutations in the gene PQBP1 in 5 of 29 families with nonsyndromic (MRX) and syndromic (MRXS) forms of X-linked mental retardation (XLMR). Clinical features in affected males include mental retardation, microcephaly, short stature, spastic paraplegia and midline defects. PQBP1 has previously been implicated in the pathogenesis of polyglutamine expansion diseases. Our findings link this gene to XLMR and shed more light on the pathogenesis of this common disorder.
4.	Klimek, Ludger, et al. (author) In-vivo diagnostic test allergens in Europe : A call to action and proposal for recovery plan-An EAACI position paper 2020 In: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 75:9, s. 2161-2169 Journal article (peer-reviewed)abstract Diagnostic allergens are defined as medicinal products in the EU. Marketing authorization by national authorities is necessary; however, diagnostic allergens are not homogeneously regulated in different EU member states. Allergen manufacturers argue with increasing costs forcing them to continuously reduce the diagnostic allergen portfolios offered to allergists. In contrast, EAACI and national European Allergy Societies see the need for the availability of a wide range of high‐quality diagnostic allergens for in vivo diagnosis of IgE‐mediated allergies not only covering predominant but also less frequent allergen sources. In a recent EAACI task force survey, the current practice of allergy diagnosis was shown to rely on skin tests as first option in almost 2/3 of all types of allergic diseases and in 90% regarding respiratory allergies.With the need to ensure the availability of high‐quality diagnostic allergens in the EU, an action plan has been set up by EAACI to analyse the current regulatory demands in EU member states and to define possible solutions stated in this document: (a) simplification of authorization for diagnostic allergens; (b) specific regulation of special types of diagnostic allergens; (c) new models beyond the current model of homologous groups; (d) simplification of pharmacovigilance reporting; (e) reduction of regulation fees for diagnostic allergens; (f) reimbursement for diagnostic allergens.Joining forces of allergists, manufacturers and authorities are of high importance to ensure remaining relevant allergens in the EU markets to facilitate a sustainable and comprehensive service for the diagnosis and treatment of allergic diseases.
5.	Menkveld, Albert J., et al. (author) Nonstandard Errors 2024 In: JOURNAL OF FINANCE. - : Wiley-Blackwell. - 0022-1082 .- 1540-6261. ; 79:3, s. 2339-2390 Journal article (peer-reviewed)abstract In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants.
6.	Satizabal, Claudia L., et al. (author) Genetic architecture of subcortical brain structures in 38,851 individuals 2019 In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624- Journal article (peer-reviewed)abstract Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
7.	Schuette, Moritz, et al. (author) Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors 2017 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8 Journal article (peer-reviewed)abstract Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling 44,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab.
8.	Shungin, Dmitry, et al. (author) New genetic loci link adipose and insulin biology to body fat distribution. 2015 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378 Journal article (peer-reviewed)abstract Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
9.	Smith, Jennifer A, et al. (author) Genome-wide association study identifies 74 loci associated with educational attainment 2016 In: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542 Journal article (peer-reviewed)abstract Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
10.	Sonderby, Ida E., et al. (author) Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia 2020 In: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:3, s. 584-602 Journal article (peer-reviewed)abstract Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
11.	Anthoni, Heidi, et al. (author) A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia. 2007 In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 16:6, s. 667-77 Journal article (peer-reviewed)abstract DYX3, a locus for dyslexia, resides on chromosome 2p11-p15. We have refined its location on 2p12 to a 157 kb region in two rounds of linkage disequilibrium (LD) mapping in a set of Finnish families. The observed association was replicated in an independent set of 251 German families. Two overlapping risk haplotypes spanning 16 kb were identified in both sample sets separately as well as in a joint analysis. In the German sample set, the odds ratio for the most significantly associated haplotype increased with dyslexia severity from 2.2 to 5.2. The risk haplotypes are located in an intergenic region between FLJ13391 and MRPL19/C2ORF3. As no novel genes could be cloned from this region, we hypothesized that the risk haplotypes might affect long-distance regulatory elements and characterized the three known genes. MRPL19 and C2ORF3 are in strong LD and were highly co-expressed across a panel of tissues from regions of adult human brain. The expression of MRPL19 and C2ORF3, but not FLJ13391, were also correlated with the four dyslexia candidate genes identified so far (DYX1C1, ROBO1, DCDC2 and KIAA0319). Although several non-synonymous changes were identified in MRPL19 and C2ORF3, none of them significantly associated with dyslexia. However, heterozygous carriers of the risk haplotype showed significantly attenuated expression of both MRPL19 and C2ORF3, as compared with non-carriers. Analysis of C2ORF3 orthologues in four non-human primates suggested different evolutionary rates for primates when compared with the out-group. In conclusion, our data support MRPL19 and C2ORF3 as candidate susceptibility genes for DYX3.
12.	Arthur Hvidtfeldt, Ulla, et al. (author) Long-term exposure to fine particle elemental components and lung cancer incidence in the ELAPSE pooled cohort 2021 In: Environmental Research. - : Elsevier BV. - 0013-9351 .- 1096-0953. ; 193 Journal article (peer-reviewed)abstract Background: An association between long-term exposure to fine particulate matter (PM2.5) and lung cancer has been established in previous studies. PM2.5 is a complex mixture of chemical components from various sources and little is known about whether certain components contribute specifically to the associated lung cancer risk. The present study builds on recent findings from the Effects of Low-level Air Pollution: A Study in Europe (ELAPSE) collaboration and addresses the potential association between specific elemental components of PM2.5 and lung cancer incidence.Methods: We pooled seven cohorts from across Europe and assigned exposure estimates for eight components of PM2.5 representing non-tail pipe emissions (copper (Cu), iron (Fe), and zinc (Zn)), long-range transport (sulfur (S)), oil burning/industry emissions (nickel (Ni), vanadium (V)), crustal material (silicon (Si)), and biomass burning (potassium (K)) to cohort participants' baseline residential address based on 100 m by 100 m grids from newly developed hybrid models combining air pollution monitoring, land use data, satellite observations, and dispersion model estimates. We applied stratified Cox proportional hazards models, adjusting for potential confounders (age, sex, calendar year, marital status, smoking, body mass index, employment status, and neighborhood-level socio-economic status).Results: The pooled study population comprised 306,550 individuals with 3916 incident lung cancer events during 5,541,672 person-years of follow-up. We observed a positive association between exposure to all eight components and lung cancer incidence, with adjusted HRs of 1.10 (95% CI 1.05, 1.16) per 50 ng/m(3) PM2.5 K, 1.09 (95% CI 1.02, 1.15) per 1 ng/m3 PM2.5 Ni, 1.22 (95% CI 1.11, 1.35) per 200 ng/m(3) PM2.5 S, and 1.07 (95% CI 1.02, 1.12) per 200 ng/m(3) PM2.5 V. Effect estimates were largely unaffected by adjustment for nitrogen dioxide (NO2). After adjustment for PM2.5 mass, effect estimates of K, Ni, S, and V were slightly attenuated, whereas effect estimates of Cu, Si, Fe, and Zn became null or negative.Conclusions: Our results point towards an increased risk of lung cancer in connection with sources of combustion particles from oil and biomass burning and secondary inorganic aerosols rather than non-exhaust traffic emissions. Specific limit values or guidelines targeting these specific PM2.5 components may prove helpful in future lung cancer prevention strategies.
13.	Beelen, Rob, et al. (author) Effects of long-term exposure to air pollution on natural-cause mortality : an analysis of 22 European cohorts within the multicentre ESCAPE project 2014 In: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 383:9919, s. 785-795 Journal article (peer-reviewed)abstract Background Few studies on long-term exposure to air pollution and mortality have been reported from Europe. Within the multicentre European Study of Cohorts for Air Pollution Effects (ESCAPE), we aimed to investigate the association between natural-cause mortality and long-term exposure to several air pollutants. Methods We used data from 22 European cohort studies, which created a total study population of 367 251 participants. All cohorts were general population samples, although some were restricted to one sex only. With a strictly standardised protocol, we assessed residential exposure to air pollutants as annual average concentrations of particulate matter (PM) with diameters of less than 2.5 mu m (PM2.5), less than 10 mu m (PM10), and between 10 mu m and 2.5 mu m (PMcoarse), PM2.5 absorbance, and annual average concentrations of nitrogen oxides (NO2 and NOx), with land use regression models. We also investigated two traffic intensity variables-traffic intensity on the nearest road (vehicles per day) and total traffic load on all major roads within a 100 m buff er. We did cohort-specific statistical analyses using confounder models with increasing adjustment for confounder variables, and Cox proportional hazards models with a common protocol. We obtained pooled effect estimates through a random-effects meta-analysis. Findings The total study population consisted of 367 251 participants who contributed 5 118 039 person-years at risk (average follow-up 13.9 years), of whom 29 076 died from a natural cause during follow-up. A significantly increased hazard ratio (HR) for PM2.5 of 1.07 (95% CI 1.02-1.13) per 5 mu g/m(3) was recorded. No heterogeneity was noted between individual cohort effect estimates (I-2 p value=0.95). HRs for PM2.5 remained significantly raised even when we included only participants exposed to pollutant concentrations lower than the European annual mean limit value of 25 mu g/m(3) (HR 1.06, 95% CI 1.00-1.12) or below 20 mu g/m(3) (1.07, 1.01-1.13). Interpretation Long-term exposure to fine particulate air pollution was associated with natural-cause mortality, even within concentration ranges well below the present European annual mean limit value.
14.	Beelen, Rob, et al. (author) Long-term Exposure to Air Pollution and Cardiovascular Mortality An Analysis of 22 European Cohorts 2014 In: Epidemiology. - : Lippincott Williams & Wilkins. - 1044-3983 .- 1531-5487. ; 25:3, s. 368-378 Journal article (peer-reviewed)abstract Background: Air pollution has been associated with cardiovascular mortality, but it remains unclear as to whether specific pollutants are related to specific cardiovascular causes of death. Within the multicenter European Study of Cohorts for Air Pollution Effects (ESCAPE), we investigated the associations of long-term exposure to several air pollutants with all cardiovascular disease (CVD) mortality, as well as with specific cardiovascular causes of death. Methods: Data from 22 European cohort studies were used. Using a standardized protocol, study area-specific air pollution exposure at the residential address was characterized as annual average concentrations of the following: nitrogen oxides (NO2 and NOx); particles with diameters of less than 2.5 mu m (PM2.5), less than 10 mu m (PM10), and 10 mu m to 2.5 mu m (PMcoarse); PM2.5 absorbance estimated by land-use regression models; and traffic indicators. We applied cohort-specific Cox proportional hazards models using a standardized protocol. Random-effects meta-analysis was used to obtain pooled effect estimates. Results: The total study population consisted of 367,383 participants, with 9994 deaths from CVD (including 4,992 from ischemic heart disease, 2264 from myocardial infarction, and 2484 from cerebrovascular disease). All hazard ratios were approximately 1.0, except for particle mass and cerebrovascular disease mortality; for PM2.5, the hazard ratio was 1.21 (95% confidence interval = 0.87-1.69) per 5 mu g/m(3) and for PM10, 1.22 (0.91-1.63) per 10 mu g/m(3). Conclusion: In a joint analysis of data from 22 European cohorts, most hazard ratios for the association of air pollutants with mortality from overall CVD and with specific CVDs were approximately 1.0, with the exception of particulate mass and cerebrovascular disease mortality for which there was suggestive evidence for an association.
15.	Beelen, Rob, et al. (author) Natural-Cause Mortality and Long-Term Exposure to Particle Components : An Analysis of 19 European Cohorts within the Multi-Center ESCAPE Project 2015 In: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 123:6, s. 525-533 Research review (peer-reviewed)abstract Background: Studies have shown associations between mortality and long-term exposure to particulate matter air pollution. Few cohort studies have estimated the effects of the elemental composition of particulate matter on mortality. Objectives: Our aim was to study the association between natural-cause mortality and long-term exposure to elemental components of particulate matter. Methods: Mortality and confounder data from 19 European cohort studies were used. Residential exposure to eight a priori-selected components of particulate matter ( PM) was characterized following a strictly standardized protocol. Annual average concentrations of copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc within PM size fractions <= 2.5 mu m (PM2.5) and <= 10 mu m (PM10) were estimated using land-use regression models. Cohort-specific statistical analyses of the associations between mortality and air pollution were conducted using Cox proportional hazards models using a common protocol followed by meta-analysis. Results: The total study population consisted of 291,816 participants, of whom 25,466 died from a natural cause during follow-up (average time of follow-up, 14.3 years). Hazard ratios were positive for almost all elements and statistically significant for PM2.5 sulfur (1.14; 95% CI: 1.06, 1.23 per 200ng/m(3)). In a two-pollutant model, the association with PM2.5 sulfur was robust to adjustment for PM2.5 mass, whereas the association with PM2.5 mass was reduced. Conclusions: Long-term exposure to PM2.5 sulfur was associated with natural-cause mortality. This association was robust to adjustment for other pollutants and PM2.5.
16.	Bergqvist, Anders, et al. (author) Marked epithelial cell pathology and leukocyte paucity in persistently symptomatic severe asthma. 2013 In: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 188:12, s. 1475-1477 Journal article (peer-reviewed)
17.	Björkman, Per, et al. (author) GB virus C/hepatitis G virus infection in patients investigated for chronic liver disease and in the general population in southern Sweden 2001 In: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 1651-1980 .- 0036-5548. ; 33:8, s. 611-617 Journal article (peer-reviewed)abstract Serum samples from patients referred for liver biopsy for investigation of suspected chronic liver disease (n = 286) and from healthy middle-aged volunteers (n = 445) were analyzed for markers of exposure to GB virus C/hepatitis G virus (GBV-C/HGV), hepatitis B virus and hepatitis C virus. GBV-C/HGV analyses included GBV-C/HGV PCR for detection of viremia and GBV-C/HGV enzyme-linked immunosorbent assay for anti-GBV-C/HGV E2 antibodies. Liver biopsies were re-evaluated by a hepatopathologist. GBV-C/HGV markers were detected in 97/286 (34%) patients (GBV-C/HGV RNA = 26; anti-GBV-C/HGV E2 antibodies = 74) compared to 86/445 (19%; p < 0.0001) controls (GBV-C/HGV RNA = 7, anti-GBB-C/HGV E2 antibodies = 79). A significantly higher proportion of GBV-C/HGV-exposed subjects in the patient group were viremic compared to controls (27% vs. 8.1%; p = 0.0015). GBV-C/HGV markers were more commonly found in patients with chronic hepatitis B and C. In patients with GBV-C/HGV viremia, a higher occurrence of bile duct degeneration was detected than in non-viremic patients. Markers of GBV-C/HGV infection were over-represented among patients investigated for chronic liver disease, and ongoing GBV-C/HGV viremia was more common in this group than in controls. Apart from a higher prevalence of bile duct degeneration in viremic patients, infection with GBV-C/HGV did not confer any specific histological characteristics.
18.	Chen, Dorothy M, et al. (author) Transcriptome-Wide Association Analysis Identifies Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer In: Human Genetics and Genomics Advances. - 2666-2477. Journal article (peer-reviewed)abstract Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10×10 -6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61×10 -6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25×10 -6) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single-tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a genome-wide association study (GWAS). Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability > 0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.
19.	Chen, Dorothy M, et al. (author) Transcriptome-Wide Association Analysis Identifies Novel Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer 2023 Other publication (other academic/artistic)abstract Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility to screen for prostate cancer (PCa). We thus conducted a transcriptome-wide association study (TWAS) of PSA levels using genome-wide summary statistics from 95,768 PCa-free men, the MetaXcan framework, and gene prediction models trained in Genotype-Tissue Expression (GTEx) project data. Tissue-specific analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10e-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61e-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses that combined associations across 45 tissues identified 155 genes that were statistically significantly (p < 0.05/22,249 = 2.25e-6) associated with PSA levels. Based on conditional analyses that assessed whether TWAS associations were attributable to a lead GWAS variant, we found 20 novel genes (11 single-tissue, 9 cross-tissue) that were associated with PSA levels in the TWAS. Of these novel genes, five showed evidence of colocalization (colocalization probability > 0.5): EXOSC9, CCNA2, HIST1H2BN, RP11-182L21.6 , and RP11-327J17.2 . Six of the 20 novel genes are not known to impact PCa risk. These findings yield new hypotheses for genetic factors underlying PSA levels that should be further explored toward improving our understanding of PSA biology.
20.	Claussnitzer, Melina, et al. (author) Leveraging cross-species transcription factor binding site patterns: from diabetes risk Loci to disease mechanisms. 2014 In: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 156:1-2, s. 343-358 Journal article (peer-reviewed)abstract Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.
21.	Cole-Hunter, Thomas, et al. (author) Long-term air pollution exposure and Parkinson's disease mortality in a large pooled European cohort : An ELAPSE study 2023 In: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 171 Journal article (peer-reviewed)abstract Background: The link between exposure to ambient air pollution and mortality from cardiorespiratory diseases is well established, while evidence on neurodegenerative disorders including Parkinson’s Disease (PD) remains limited.Objective: We examined the association between long-term exposure to ambient air pollution and PD mortality in seven European cohorts.Methods: Within the project ‘Effects of Low-Level Air Pollution: A Study in Europe’ (ELAPSE), we pooled data from seven cohorts among six European countries. Annual mean residential concentrations of fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC), and ozone (O3), as well as 8 PM2.5 components (copper, iron, potassium, nickel, sulphur, silicon, vanadium, zinc), for 2010 were estimated using Europe-wide hybrid land use regression models. PD mortality was defined as underlying cause of death being either PD, secondary Parkinsonism, or dementia in PD. We applied Cox proportional hazard models to investigate the associations between air pollution and PD mortality, adjusting for potential confounders.Results: Of 271,720 cohort participants, 381 died from PD during 19.7 years of follow-up. In single-pollutant analyses, we observed positive associations between PD mortality and PM2.5 (hazard ratio per 5 µg/m3: 1.25; 95% confidence interval: 1.01–1.55), NO2 (1.13; 0.95–1.34 per 10 µg/m3), and BC (1.12; 0.94–1.34 per 0.5 × 10-5m-1), and a negative association with O3 (0.74; 0.58–0.94 per 10 µg/m3). Associations of PM2.5, NO2, and BC with PD mortality were linear without apparent lower thresholds. In two-pollutant models, associations with PM2.5 remained robust when adjusted for NO2 (1.24; 0.95–1.62) or BC (1.28; 0.96–1.71), whereas associations with NO2 or BC attenuated to null. O3 associations remained negative, but no longer statistically significant in models with PM2.5. We detected suggestive positive associations with the potassium component of PM2.5.Conclusion: Long-term exposure to PM2.5, at levels well below current EU air pollution limit values, may contribute to PD mortality.
22.	Corrado, Domenico, et al. (author) Cardiovascular pre-participation screening of young competitive athletes for prevention of sudden death : proposal for a common European protocol. Consensus Statement of the Study Group of Sport Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. 2005 In: Eur Heart J. - 0195-668X. ; 26:5, s. 516-24 Journal article (peer-reviewed)
23.	Dimakopoulou, Konstantina, et al. (author) Air Pollution and Nonmalignant Respiratory Mortality in 16 Cohorts within the ESCAPE Project 2014 In: American Journal of Respiratory and Critical Care Medicine. - : American Thoracic Society. - 1073-449X .- 1535-4970. ; 189:6, s. 684-696 Journal article (peer-reviewed)abstract Rationale: Prospective cohort studies have shown that chronic exposure to particulate matter and traffic-related air pollution is associated with reduced survival. However, the effects on nonmalignant respiratory mortality are less studied, and the data reported are less consistent. Objectives: We have investigated the relationship of long-term exposure to air pollution and nonmalignant respiratory mortality in 16 cohorts with individual level data within the multicenter European Study of Cohorts for Air Pollution Effects (ESCAPE). Methods: Data from 16 ongoing cohort studies from Europe were used. The total number of subjects was 307,553. There were 1,559 respiratory deaths during follow-up. Measurements and Main Results: Air pollution exposure was estimated by land use regression models at the baseline residential addresses of study participants and traffic-proximity variables were derived from geographical databases following a standardized procedure within, the ESCAPE study. Cohort-specific hazard ratios obtained by Cox proportional hazard models from standardized individual cohort analyses were combined using metaanalyses. We found no significant associations between air pollution exposure and nonmalignant respiratory mortality. Most hazard ratios were slightly below unity, with the exception of the traffic-proximity indicators. Conclusions: In this study of 16 cohorts, there was no-association between air pollution exposure and nonmalignant respiratory mortality.
24.	Docherty, Anna R, et al. (author) GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors. 2023 In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738 Journal article (peer-reviewed)abstract Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
25.	Flory, Stephan, et al. (author) How to hit the allergy target: A critical appraisal of intralymphatic immunotherapy with practical recommendations on ultrasound-guided injections 2024 In: Allergy. European Journal of Allergy and Clinical Immunology. - : WILEY. - 0105-4538 .- 1398-9995. Journal article (peer-reviewed)abstract BackgroundIntralymphatic immunotherapy (ILIT) represents a promising novel approach treating allergic diseases. However, no standardized procedures or recommendations have been established or reported, despite the recognized fact that treatment efficacy relies on the ability to inject the allergen intranodally.ObjectiveWe aim to provide a critical appraisal of ILIT as a method of allergen immunotherapy and to deliver practical recommendations for accurate ILIT.MethodsOne hundred and seventy-three ILIT injections were performed in 28 (47%) women and 32 (53%) men with median age of 29 years (21-59). The injections were ultrasound-guided and recorded for retrospective analysis with respect to injection location, needle visibility, medication release, and patient characteristics.ResultsThe results show that the correct positioning of the needle within the lymph node (LN) was most critical. If the whole length of the needle bevel was not inserted into the LN, substance backflush into the interstitium was observed. Selecting a more superficial LN and inserting the needle at a smaller angle towards the LN significantly improved needle visibility in the ultrasound. Longitudinal results showed that continuous practice significantly correlated with improved needle visibility and more accurate ILIT injections.ConclusionBased on our results and practical experience, we propose several recommendations for LN selection and the correct handling of ultrasound probe and needle. We are confident that ILIT standardization and training will be important as to meet the goals of good safety and efficacy of ILIT. Ultrasound-guided ILIT holds promise for treatment of allergy. Correct positioning of the needle within the lymph node is critical for efficacy and safety, and practice correlate with improved needle visibility and more accurate ILIT injections. A guideline is proposed for effective ILIT. Abbreviations: ILIT, intralymphatic immunotherapy; LN, lymph node; SCIT, subcutaneous immunotherapy.image
26.	George, Julie, et al. (author) Comprehensive genomic profiles of small cell lung cancer 2015 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 524:7563, s. 47-U73 Journal article (peer-reviewed)abstract We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
27.	Hess, Timo, et al. (author) Dissecting the genetic heterogeneity of gastric cancer 2023 In: EBioMedicine. - : Elsevier. - 2352-3964. ; 92 Journal article (peer-reviewed)abstract Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.
28.	Hjort, Charlotte, et al. (author) The number and affinity of productive IgE pairs determine allergen activation of mast cells 2017 In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749. ; 140:4, s. 2-1170 Journal article (peer-reviewed)
29.	Hoffman, Robert D., et al. (author) Gender differences in self-care for common colds by primary care patients : a European multicenter survey on the prevalence and patterns of practices (the COCO study) 2021 In: Journal of Gender Studies. - : Taylor & Francis Group. - 0958-9236 .- 1465-3869. ; 30:7, s. 756-771 Journal article (peer-reviewed)abstract Although generally harmless, the common cold disturbs the lives of billions yearly. It is frequently treated by self-care, yet little is known about the effect gender may have on self-care. Our study set out to discover whether self-care for common colds differs by gender. We also wanted to test the 'Man cold' belief: that men 'break down' when they have a cold and suffer more than women when they are sick. We distributed questionnaires asking for a selection of self-care practices in eight categories to 3,240 consecutive patients in 14 Eurasian countries at 27 primary care sites. Of 2,654 patients included, 99% reported engaging in self-care for common colds. Discomfort was reported more frequently by women (74.7% vs. 66.5%, p < 0.001). There were gender differences in several self-care categories. The mean use of self-care items was higher in women than in men (12.0 vs. 10.3, p < 0.001). Women reported a greater variety of self-care items than men. However, more men reported using alcohol (17.8% vs. 8.4%, p < 0.001). This cross-national study documented gender differences in self-care for common colds.
30.	Hoffmann, Gunilla, et al. (author) Prevalence and clinical spectrum of chronic viral hepatitis in a middle-aged Swedish general urban population 2000 In: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 35:8, s. 861-865 Journal article (peer-reviewed)abstract BACKGROUND: Although abundant data are available regarding the prevalence of chronic hepatitis B or C virus (HBV, HCV) among both blood donors and patients with liver diseases, corresponding data for the general population are scarce. Accordingly, this study was designed to investigate the prevalence and clinical spectrum of HBV and HCV in a general Swedish middle-aged urban population. METHODS: Demographic data and blood samples were collected from subjects enrolled in a prospective study of cancer development in the city of Malmo (population 250,000). The participation rate in the preliminary examination was 46.2%. From 12,445 individuals born between 1926 and 1945 and included in the study, a statistically representative subsample of 6103 persons was selected. Blood samples were available from 5533 of these. The mean age of the subjects in the series was 58.5 +/- 5.9 years, and 59% were women. The HBV markers used were anti-HBc and HBsAg. HCV antibodies were detected with a third generation anti-HCV ELISA, followed by immunoblotting (RIBA 3) if the test was positive. Immunoblot-reactive samples were analysed for HCV-RNA by polymerase chain reaction and genotyped. In all patients with signs of chronic HBV or HCV, epidemiological data were evaluated and liver biopsies obtained. RESULTS: Of the series as a whole (n = 5533), 4.2% (n = 211) tested positive for anti-HBc and 0.2% (n = 10) for HBsAg. RIBA 3 analysis showed 0.37% (18/5533) to be anti-HCV-positive, of whom 83% (15/18) were HCV-RNA-positive. Apart from two (both from HBsAg carriers) with normal histology, all liver biopsies manifested various degrees of inflammation and fibrosis. Among anti-HCV-positives, median grade was 6 and median stage 1 (Knodell score). CONCLUSION: The prevalence of both chronic HBV and HCV is low in the Swedish general urban middle-aged population. Nonetheless, the long-term effects on the population and the health care system may be significant.
31.	Hoffmann, Ruben, et al. (author) Djurvälfärd och lönsamhet - var står vi idag? 2010 Reports (other academic/artistic)abstract Även om djurs välbefinnande länge har debatterats i många länder är frågor som rör djurvälfärd högaktuella. EU har de senaste åren beslutat om flera nya minimiregler och i Sverige pågår för tillfället en översyn av lagstiftningen. I konsumentundersökningar framgår det att en majoritet av medborgare i såväl Sverige som inom övriga EU anser att djurvälfärd är en viktig fråga och att bättre information och ytterligare insatser på detta område önskas. Mot bakgrund av det stora intresset för djurvälfärd är syftet med denna rapport att undersöka hur skillnader i lagstiftade minimiregler vad gäller ur djurvälfärds-synpunkt viktiga aspekter påverkar lönsamheten för svenska animalieproducenter jämfört med producenter i några andra länder. Studien fokuserar således på vissa av de aspekter av djurvälfärd som regleras i lagstiftning och är inte avsedd att ge någon fullständig bild av alla merkostnader som svenska regleringar kan ge upphov till jämfört med situationen för konkurrerande import. För att undersöka detta måste följande frågor adresseras: • Hur definieras och operationaliseras djurvälfärd? Det föreligger i dagsläget inte konsensus vare sig angående en generellt accepterad definition av djurväl-färd eller rörande hur olika välfärdsaspekter ska vägas mot varandra. I denna rapport har vi i möjligaste mån utgått från riskbedömningar som kan relateras till de så kallade ”fem friheterna” och som bland annat används av EFSA för att bedöma riskerna för nedsatt djurvälfärd i en viss population. Sådana risk-bedömningar möjliggör en jämförelse mellan inhysningssystem som ur policysynpunkt kan vara av intresse och tydliggör de avvägningar som måste göras mellan olika djurvälfärdsaspekter. Det resulterar inte i något enskilt aggregerat mått men kan lyfta fram de fördelar och nackdelar som olika inhysningssystem vanligtvis har. • Vilka skillnader i lagstiftade minimiregler föreligger mellan Sverige och omvärlden vad gäller ur djurvälfärdssynpunkt viktiga aspekter? Snarare än att försöka kartlägga alla existerande skillnader i lagstiftning har vår utgångspunkt varit de ur djurvälfärdssynpunkt viktigaste lagstiftade minimikrav som lyfts fram i WelfareQuality® – projektet. Sverige har vad gäller centrala djurvälfärdsaspekter i flera fall striktare minimikrav än vad som gäller enligt EU:s minimilagstiftning. Som exempel kan för värphöns nämnas det svenska förbudet mot oinredda burar (från 2012 även enligt EU:s minimilagstiftning) och förbudet mot näbbtrimmning, för slaktkycklingar och svin finns i Sverige krav på större yta och för nötkreatur en specifik lagstiftning vilket (förutom för kalv) inte finns inom EU. • Hur påverkas de fysiska produktionsresultaten av dessa skillnader i lagstiftade minimikrav? Striktare djurskyddslagstiftning kan indirekt påverka produktionskostnaderna positivt eller negativt via förändringar i dödlighet, foderförbrukning, foderomvandling etc. Som exempel kan nämnas att flera av de svenska minimikraven som rör produktionen av slaktsvin och mjölkkor kan förväntas ha en positiv inverkan medan förbudet mot oinredda burar för värphöns inte tydligt påverkar de fysiska produktionsresultaten. • Vilka skillnader i produktionskostnader föreligger mellan svenska och utländska animalieproducenter och i vilken utsträckning kan dessa skillnader hänföras till lagstiftade minimikrav vad gäller ur djurvälfärdssynpunkt viktiga aspekter? Striktare djurskyddslagstiftning kan påverka produktionskostnaderna positivt eller negativt både direkt via förändrade insatsbehov (kapital, arbete, strömedel etc.) och indirekt via förändringar i fysiska produktionsresultat. Svenska animalieproducenter har i många fall högre kostnader än konkurrerande producenter inom EU, men detta kan endast delvis förklaras av ur djurvälfärdssynpunkt viktiga skillnader i lagstiftade minimiregler. • Hur påverkas lönsamheten för svenska animalieproducenter av ur djurvälfärdssynpunkt viktiga skillnader i djurskyddslagstiftning mellan Sverige och omvärlden? I de fall lagstiftningen inte i sig medför en ökad produktivitet behöver producenterna få täckning för sina merkostnader. Svårigheten med att bedöma djurvälfärd och livsmedelskedjans struktur gör det dock svårt att kommunicera djurvälfärdsaspekter till konsument. Eftersom lagstiftningen omfattar all inhemsk produktion är det, även om en stor andel av konsumenterna är villiga att betala ett avsevärt merpris, svårt att erhålla en hög premie för de djurvälfärdsaspekter som regleras. En avvägning mellan marknadsandelar och det merpris som kan erhållas måste alltid göras. Med en betydande marknadsandel krävs för en hög premie produktdifferentiering frikopplad från lagstiftningen. Eftersom svensk produktion konkurrerar med importerade varor som inte behöver följa svenska regler riskerar striktare nationella minimikrav att få motsatt. Det är därför viktigt att arbetet med att förbättra djurskyddet bedrivs internationellt
32.	Hoffmann, Thomas J., et al. (author) Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer 2017 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8 Journal article (peer-reviewed)abstract Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa - such as genetics - can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10-8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.
33.	Hoffmann, Thomas J, et al. (author) Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction 2023 Other publication (other academic/artistic)abstract We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.
34.	Hudson, Lawrence N, et al. (author) The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project 2017 In: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188 Journal article (peer-reviewed)abstract The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
35.	Hvidtfeldt, Ulla Arthur, et al. (author) Long-term low-level ambient air pollution exposure and risk of lung cancer - A pooled analysis of 7 European cohorts 2021 In: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 146 Journal article (peer-reviewed)abstract Background/aim: Ambient air pollution has been associated with lung cancer, but the shape of the exposure-response function - especially at low exposure levels - is not well described. The aim of this study was to address the relationship between long-term low-level air pollution exposure and lung cancer incidence.Methods: The Effects of Low-level Air Pollution: a Study in Europe (ELAPSE) collaboration pools seven cohorts from across Europe. We developed hybrid models combining air pollution monitoring, land use data, satellite observations, and dispersion model estimates for nitrogen dioxide (NO2), fine particulate matter (PM2.5), black carbon (BC), and ozone (O-3) to assign exposure to cohort participants' residential addresses in 100 m by 100 m grids. We applied stratified Cox proportional hazards models, adjusting for potential confounders (age, sex, calendar year, marital status, smoking, body mass index, employment status, and neighborhood-level socioeconomic status). We fitted linear models, linear models in subsets, Shape-Constrained Health Impact Functions (SCHIF), and natural cubic spline models to assess the shape of the association between air pollution and lung cancer at concentrations below existing standards and guidelines.Results: The analyses included 307,550 cohort participants. During a mean follow-up of 18.1 years, 3956 incident lung cancer cases occurred. Median (Q1, Q3) annual (2010) exposure levels of NO2, PM2.5, BC and O-3 (warm season) were 24.2 mu g/m(3) (19.5, 29.7), 15.4 mu g/m(3) (12.8, 17.3), 1.6 10(-5)m(-1) (1.3, 1.8), and 86.6 mu g/m(3) (78.5, 92.9), respectively. We observed a higher risk for lung cancer with higher exposure to PM2.5 (HR: 1.13, 95% CI: 1.05, 1.23 per 5 mu g/m(3)). This association was robust to adjustment for other pollutants. The SCHIF, spline and subset analyses suggested a linear or supra-linear association with no evidence of a threshold. In subset analyses, risk estimates were clearly elevated for the subset of subjects with exposure below the EU limit value of 25 mu g/m(3). We did not observe associations between NO2, BC or O-3 and lung cancer incidence.Conclusions: Long-term ambient PM2.5 exposure is associated with lung cancer incidence even at concentrations below current EU limit values and possibly WHO Air Quality Guidelines.
36.	Jungo, Katharina Tabea, et al. (author) General practitioners' deprescribing decisions in older adults with polypharmacy : a case vignette study in 31 countries 2021 In: BMC Geriatrics. - : BioMed Central (BMC). - 1471-2318. ; 21:1, s. 1-12 Journal article (peer-reviewed)abstract Background General practitioners (GPs) should regularly review patients' medications and, if necessary, deprescribe, as inappropriate polypharmacy may harm patients' health. However, deprescribing can be challenging for physicians. This study investigates GPs' deprescribing decisions in 31 countries. Methods In this case vignette study, GPs were invited to participate in an online survey containing three clinical cases of oldest-old multimorbid patients with potentially inappropriate polypharmacy. Patients differed in terms of dependency in activities of daily living (ADL) and were presented with and without history of cardiovascular disease (CVD). For each case, we asked GPs if they would deprescribe in their usual practice. We calculated proportions of GPs who reported they would deprescribe and performed a multilevel logistic regression to examine the association between history of CVD and level of dependency on GPs' deprescribing decisions. Results Of 3,175 invited GPs, 54% responded (N = 1,706). The mean age was 50 years and 60% of respondents were female. Despite differences across GP characteristics, such as age (with older GPs being more likely to take deprescribing decisions), and across countries, overall more than 80% of GPs reported they would deprescribe the dosage of at least one medication in oldest-old patients (> 80 years) with polypharmacy irrespective of history of CVD. The odds of deprescribing was higher in patients with a higher level of dependency in ADL (OR =1.5, 95%CI 1.25 to 1.80) and absence of CVD (OR =3.04, 95%CI 2.58 to 3.57). Interpretation The majority of GPs in this study were willing to deprescribe one or more medications in oldest-old multimorbid patients with polypharmacy. Willingness was higher in patients with increased dependency in ADL and lower in patients with CVD.
37.	Kachuri, Linda, et al. (author) Genetically adjusted PSA levels for prostate cancer screening 2023 In: Nature Medicine. - 1546-170X. ; 29:6, s. 1412-1423 Journal article (peer-reviewed)abstract Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10 -8) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGS PSA) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10 -14, area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10 -12, AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10 -4). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.
38.	Kulmala, M., et al. (author) General overview: European Integrated project on Aerosol Cloud Climate and Air Quality interactions (EUCAARI) - integrating aerosol research from nano to global scales 2011 In: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 11:24, s. 13061-13143 Journal article (peer-reviewed)abstract In this paper we describe and summarize the main achievements of the European Aerosol Cloud Climate and Air Quality Interactions project (EUCAARI). EUCAARI started on 1 January 2007 and ended on 31 December 2010 leaving a rich legacy including: (a) a comprehensive database with a year of observations of the physical, chemical and optical properties of aerosol particles over Europe, (b) comprehensive aerosol measurements in four developing countries, (c) a database of airborne measurements of aerosols and clouds over Europe during May 2008, (d) comprehensive modeling tools to study aerosol processes fron nano to global scale and their effects on climate and air quality. In addition a new Pan-European aerosol emissions inventory was developed and evaluated, a new cluster spectrometer was built and tested in the field and several new aerosol parameterizations and computations modules for chemical transport and global climate models were developed and evaluated. These achievements and related studies have substantially improved our understanding and reduced the uncertainties of aerosol radiative forcing and air quality-climate interactions. The EUCAARI results can be utilized in European and global environmental policy to assess the aerosol impacts and the corresponding abatement strategies.
39.	Laake, J. H., et al. (author) The SSAI fully supports the suspension of hydroxyethyl-starch solutions commissioned by the European Medicines Agency 2018 In: Acta Anaesthesiologica Scandinavica. - : John Wiley & Sons. - 0001-5172 .- 1399-6576. ; 62:6, s. 874-875 Journal article (peer-reviewed)
40.	Lamb, David, et al. (author) RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma 2021 In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 22:1 Journal article (peer-reviewed)abstract Background: RORγt is a transcription factor that enables elaboration of Th17-associated cytokines (including IL-17 and IL-22) and is proposed as a pharmacological target for severe asthma. Methods: IL-17 immunohistochemistry was performed in severe asthma bronchial biopsies (specificity confirmed with in situ hybridization). Primary human small airway epithelial cells in air liquid interface and primary bronchial smooth muscle cells were stimulated with recombinant human IL-17 and/or IL-22 and pro-inflammatory cytokines measured. Balb/c mice were challenged intratracheally with IL-17 and/or IL-22 and airway hyperreactivity, pro-inflammatory cytokines and airway neutrophilia measured. Balb/c mice were sensitized intraperitoneally and challenged intratracheally with house dust mite extract and the effect of either a RORγt inhibitor (BIX119) or an anti-IL-11 antibody assessed on airway hyperreactivity, pro-inflammatory cytokines and airway neutrophilia measured. Results: We confirmed in severe asthma bronchial biopsies both the presence of IL-17-positive lymphocytes and that an IL-17 transcriptome profile in a severe asthma patient sub-population. Both IL-17 and IL-22 stimulated the release of pro-inflammatory cytokine and chemokine release from primary human lung cells and in mice. Furthermore, IL-22 in combination with IL-17, but neither alone, elicits airway hyperresponsiveness (AHR) in naïve mice. A RORγt inhibitor specifically blocked both IL-17 and IL-22, AHR and neutrophilia in a mouse house dust mite model unlike other registered or advanced pipeline modes of action. Full efficacy versus these parameters was associated with 90% inhibition of IL-17 and 50% inhibition of IL-22. In contrast, anti-IL-17 also blocked IL-17, but not IL-22, AHR or neutrophilia. Moreover, the deregulated genes in the lungs from these mice correlated well with deregulated genes from severe asthma biopsies suggesting that this model recapitulates significant severe asthma-relevant biology. Furthermore, these genes were reversed upon RORγt inhibition in the HDM model. Cell deconvolution suggested that the responsible cells were corticosteroid insensitive γδ-T-cells. Conclusion: These data strongly suggest that both IL-17 and IL-22 are required for Th2-low endotype associated biology and that a RORγt inhibitor may provide improved clinical benefit in a severe asthma sub-population of patients by blocking both IL-17 and IL-22 biology compared with blocking IL-17 alone.
41.	Legall, H., et al. (author) Compact X-ray microscope for the water window based on a high brightness laser plasma source 2012 In: Optics Express. - 1094-4087. ; 20:16, s. 18362-18369 Journal article (peer-reviewed)abstract We present a laser plasma based x-ray microscope for the water window employing a high-average power laser system for plasma generation. At 90 W laser power a brightness of 7.4 x 10(11) photons/(s x sr x mu m(2)) was measured for the nitrogen Ly alpha line emission at 2.478 nm. Using a multilayer condenser mirror with 0.3 % reflectivity 10(6) photons/(mu m(2) x s) were obtained in the object plane. Microscopy performed at a laser power of 60 W resolves 40 nm lines with an exposure time of 60 s. The exposure time can be further reduced to 20 s by the use of new multilayer condenser optics and operating the laser at its full power of 130 W.
42.	Lindberg, Sara, et al. (author) Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity From Stereotactic Body Radiation Therapy of Central and Ultracentral Lung Tumors 2023 In: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS. - 0360-3016 .- 1879-355X. ; 117:5, s. 1222-1231 Journal article (peer-reviewed)abstract Purpose: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects. Methods and Materials: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses.Results: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopul-monary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively.Conclusions: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Simi-lar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi.
43.	Manry, Jérémy, et al. (author) The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies. 2022 In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:21 Journal article (peer-reviewed)abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
44.	Matsson, Elin, 1979-, et al. (author) Biliary Excretion of Ximelagatran and Its Metabolites and the Influence of Erythromycin Following Intraintestinal Administration to Healthy Volunteers 2011 In: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 51:5, s. 770-783 Journal article (peer-reviewed)abstract The biliary excretion of the oral thrombin inhibitor ximelagatran and its metabolites was investigated by using duodenal aspiration in healthy volunteers following intraintestinal dosing. In the first investigation, radiolabeled [C-14] ximelagatran was administered, enabling quantification of the biliary excretion and identification of metabolites in the bile. In the second study, the effect of erythromycin on the biliary clearance of ximelagatran and its metabolites was investigated to clarify the reported ximelagatran-erythromycin interaction. Approximately 4% of the intraintestinal dose was excreted into bile with ximelagatran and its active form, melagatran, being the most abundant compounds. Four novel ximelagatran metabolites were identified in bile (< 0.1% of dose). Erythromycin changed the pharmacokinetics of ximelagatran and its metabolites, with an elevated ximelagatran (78% increase), OH-melagatran (89% increase), and melagatran (86% increase) plasma exposure and higher peak plasma concentrations of the compounds being measured. In parallel, the biliary clearance was moderately reduced. The results suggest that inhibition of hepatobiliary transport is a likely mechanism for the interaction between erythromycin and ximelagatran. Furthermore, the study demonstrated the value of direct bile sampling in humans for the identification of primary biliary metabolites.
45.	Mullins, Niamh, et al. (author) Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors 2022 In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327 Journal article (peer-reviewed)abstract BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
46.	Mullins, Niamh, et al. (author) GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores 2019 In: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 176:8, s. 651-660 Journal article (peer-reviewed)abstract Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.
47.	Petrazzuoli, Ferdinando, et al. (author) Exploring dementia management attitudes in primary care : a key informant survey to primary care physicians in 25 European countries 2017 In: International psychogeriatrics. - : Cambridge University Press. - 1041-6102 .- 1741-203X. ; 29:9, s. 1413-1423 Journal article (peer-reviewed)abstract Background: Strategies for the involvement of primary care in the management of patients with presumed or diagnosed dementia are heterogeneous across Europe. We wanted to explore attitudes of primary care physicians (PCPs) when managing dementia: (i) the most popular cognitive tests, (ii) who had the right to initiate or continue cholinesterase inhibitor or memantine treatment, and (iii) the relationship between the permissiveness of these rules/guidelines and PCP's approach in the dementia investigations and assessment. Methods: Key informant survey. Setting: Primary care practices across 25 European countries. Subjects: Four hundred forty-five PCPs responded to a self-administered questionnaire. Two-step cluster analysis was performed using characteristics of the informants and the responses to the survey. Main outcome measures: Two by two contingency tables with odds ratios and 95% confidence intervals were used to assess the association between categorical variables. A multinomial logistic regression model was used to assess the association of multiple variables (age class, gender, and perceived prescription rules) with the PCPs' attitude of trying to establish a diagnosis of dementia on their own. Results: Discrepancies between rules/guidelines and attitudes to dementia management was found in many countries. There was a strong association between the authorization to prescribe dementia drugs and pursuing dementia diagnostic work-up (odds ratio, 3.45; 95% CI 2.28-5.23). Conclusions: Differing regulations about who does what in dementia management seemed to affect PCP's engagement in dementia investigations and assessment. PCPs who were allowed to prescribe dementia drugs also claimed higher engagement in dementia work-up than PCPs who were not allowed to prescribe.
48.	Petrazzuoli, Ferdinando, et al. (author) Unburdening dementia a basic social process grounded theory - based on a primary care physician survey from 25 countries 2020 In: Scandinavian Journal of Primary Health Care. - : Taylor & Francis Group. - 0281-3432 .- 1502-7724. ; 38:3, s. 253-264 Journal article (peer-reviewed)abstract Objective To explore dementia management from a primary care physician perspective. Design One-page seven-item multiple choice questionnaire; free text space for every item; final narrative question of a dementia case story. Inductive explorative grounded theory analysis. Derived results in cluster analyses. Appropriateness of dementia drugs assessed by tertiary care specialist. Setting Twenty-five European General Practice Research Network member countries. Subjects Four hundred and forty-five key informant primary care physician respondents of which 106 presented 155 case stories. Main outcome measures Processes and typologies of dementia management. Proportion of case stories with drug treatment and treatment according to guidelines. Results Unburdeningdementia - a basic social process - explained physicians' dementia management according to a grounded theory analysis using both qualitative and quantitative data. Unburdening starts withRecognizingthe dementia burden byBurden IdentificationandBurden Assessmentfollowed byBurden Relief. Drugs to relieve the dementia burden were reported for 130 of 155 patients; acetylcholinesterase inhibitors or memantine treatment in 89 of 155 patients - 60% appropriate according to guidelines and 40% outside of guidelines. More Central and Northern primary care physicians were allowed to prescribe, and more were engaged in dementia management than Eastern and Mediterranean physicians according to cluster analyses. Physicians typically identified and assessed the dementia burden and then tried to relieve it, commonly by drug prescriptions, but also by community health and home help services, mentioned in more than half of the case stories. Conclusions Primary care physician dementia management was explained by anUnburdeningprocess with the goal to relieve the dementia burden, mainly by drugs often prescribed outside of guideline indications. Implications:Unique data about dementia management by European primary care physicians to inform appropriate stakeholders.
49.	Raaschou-Nielsen, Ole, et al. (author) Air pollution and lung cancer incidence in 17 European cohorts : prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE) 2013 In: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 14:9, s. 813-822 Journal article (peer-reviewed)abstract BACKGROUND: Ambient air pollution is suspected to cause lung cancer. We aimed to assess the association between long-term exposure to ambient air pollution and lung cancer incidence in European populations.METHODS: This prospective analysis of data obtained by the European Study of Cohorts for Air Pollution Effects used data from 17 cohort studies based in nine European countries. Baseline addresses were geocoded and we assessed air pollution by land-use regression models for particulate matter (PM) with diameter of less than 10 μm (PM10), less than 2·5 μm (PM2·5), and between 2·5 and 10 μm (PMcoarse), soot (PM2·5absorbance), nitrogen oxides, and two traffic indicators. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effects models for meta-analyses.FINDINGS: The 312 944 cohort members contributed 4 013 131 person-years at risk. During follow-up (mean 12·8 years), 2095 incident lung cancer cases were diagnosed. The meta-analyses showed a statistically significant association between risk for lung cancer and PM10 (hazard ratio [HR] 1·22 [95% CI 1·03-1·45] per 10 μg/m(3)). For PM2·5 the HR was 1·18 (0·96-1·46) per 5 μg/m(3). The same increments of PM10 and PM2·5 were associated with HRs for adenocarcinomas of the lung of 1·51 (1·10-2·08) and 1·55 (1·05-2·29), respectively. An increase in road traffic of 4000 vehicle-km per day within 100 m of the residence was associated with an HR for lung cancer of 1·09 (0·99-1·21). The results showed no association between lung cancer and nitrogen oxides concentration (HR 1·01 [0·95-1·07] per 20 μg/m(3)) or traffic intensity on the nearest street (HR 1·00 [0·97-1·04] per 5000 vehicles per day).INTERPRETATION: Particulate matter air pollution contributes to lung cancer incidence in Europe.FUNDING: European Community's Seventh Framework Programme.
50.	Radstake, Timothy R. D. J., et al. (author) Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus 2010 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 71-426 Journal article (peer-reviewed)abstract Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.

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