Search

Natural environments have been associated with mental health benefits, but globally access to these benefits is threatened by urban development and densification. However, it remains unclear how natural environments relate to mental health and how consistent the association is across populations. Here we use a life-course approach with a population consisting of 66 194 individuals from the Danish Blood Donor Study (DBDS) to investigate the association between green and blue space (e.g. parks and lakes) and self-evaluated mental well-being. Green and blue space was identified from remotely-sensed images from the Landsat program, while mental well-being was based on the mental component score (MCS) calculated using the 12-item short form health survey. We use multivariate linear regression models and logistic regression models to quantify the associations. We adjust for additional environmental (urbanization, and air pollution) and lifestyle factors (smoking, body mass index, socioeconomic status, and physical activity) and specifically evaluate the role of physical activity and air pollution as possible mediating factors. We found a positive association between the MCS and current and childhood green space, and a non-significant association for current and childhood blue space. Adjusting for environmental and the other factors attenuated the effect sizes indicating that a broad range of factors determine mental well-being. Physical activity and air pollution were both associated with the MCS as possible mediators of green space associations. In addition, the odds for successfully completing tasks’, seeing others, and feeling less downhearted increased with higher levels of green space, and the odds of feeling calm increased with higher levels of blue space. In conclusion, we found support for an association between green and, to less degree, blue space and mental well-being throughout different life stages. In addition, we found a positive association with individual indicators of mental well-being such as being productive, feeling less downhearted and calmer, and being social. The healthy blood donor effect and the bias towards urban residency may explain why we found smaller effect sizes between green and blue space and mental well-being for this generally healthy and resourceful cohort compared to previous studies.

Background Although the vast majority of individuals succumbing to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are elderly, infection fatality rate (IFR) estimates for the age group ≥70 years are still scarce. To this end, we assessed SARS-CoV-2 seroprevalence among retired blood donors and combined it with national coronavirus disease 2019 (COVID-19) survey data to provide reliable population-based IFR estimates for this age group. Methods We identified 60 926 retired blood donors aged ≥70 years in the rosters of 3 regionwide Danish blood banks and invited them to fill in a questionnaire on COVID-19–related symptoms and behaviors. Among 24 861 (40.8%) responders, we invited a random sample of 3200 individuals for blood testing. Overall, 1201 (37.5%) individuals were tested for SARS-CoV-2 antibodies (Wantai) and compared with 1110 active blood donors aged 17–69 years. Seroprevalence 95% confidence intervals (CIs) were adjusted for assay sensitivity and specificity. Results Among retired (aged ≥70 years) and active (aged 17–69 years) blood donors, adjusted seroprevalences were 1.4% (95% CI, .3–2.5%) and 2.5% (95% CI, 1.3–3.8%), respectively. Using available population data on COVID-19–related fatalities, IFRs for patients aged ≥70 years and for 17–69 years were estimated at 5.4% (95% CI, 2.7–6.4%) and .083% (95% CI, .054–.18%), respectively. Only 52.4% of SARS-CoV-2–seropositive retired blood donors reported having been sick since the start of the pandemic. Conclusions COVID-19 IFR in the age group >69 years is estimated to be 65 times the IFR for people aged 18–69 years.

Most individuals seroconvert after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but being seronegative is observed in 1 to 9%. We aimed to investigate the risk factors associated with being seronegative following PCR-confirmed SARS-CoV-2 infection. In a prospective cohort study, we screened health care workers (HCW) in the Capital Region of Denmark for SARS-CoV-2 antibodies. We performed three rounds of screening from April to October 2020 using an enzyme-linked immunosorbent assay (ELISA) method targeting SARS-CoV-2 total antibodies. Data on all participants’ PCR for SARS-CoV-2 RNA were captured from national registries. The Kaplan-Meier method and Cox proportional hazards models were applied to investigate the probability of being seronegative and the related risk factors, respectively. Of 36,583 HCW, 866 (2.4%) had a positive PCR before or during the study period. The median (interquartile range [IQR]) age of 866 HCW was 42 (31 to 53) years, and 666 (77%) were female. After a median of 132 (range, 35 to 180) days, 21 (2.4%) of 866 were seronegative. In a multivariable model, independent risk factors for being seronegative were self-reported asymptomatic or mild infection hazard ratio (HR) of 6.6 (95% confidence interval [CI], 2.6 to 17; P < 0.001) and body mass index (BMI) of ≥30, HR 3.1 (95% CI, 1.1 to 8.8; P = 0.039). Only a few (2.4%) HCW were not seropositive. Asymptomatic or mild infection as well as a BMI above 30 were associated with being seronegative. Since the presence of antibodies against SARS-CoV-2 reduces the risk of reinfection, efforts to protect HCW with risk factors for being seronegative may be needed in future COVID-19 surges. IMPORTANCE Most individuals seroconvert after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but negative serology is observed in 1 to 9%. We found that asymptomatic or mild infection as well as a BMI above 30 were associated with being seronegative. Since the presence of antibodies against SARS-CoV-2 reduces the risk of reinfection, efforts to protect HCW with risk factors for being seronegative may be needed in future COVID-19 surges.

BackgroundNational data on the spread of SARS-CoV-2 infection and knowledge on associated risk factors are important for understanding the course of the pandemic. “Testing Denmark” is a national large-scale epidemiological surveillance study of SARS-CoV-2 in the Danish population.MethodsBetween September and October 2020, approximately 1.3 million of 5.8 million Danish citizens (age > 15 years) were randomly invited to fill in an electronic questionnaire covering COVID-19 exposures and symptoms. The prevalence of SARS-CoV-2 antibodies was determined by Point-of Care rapid Test (POCT) distributed to participants home addresses.FindingsIn total 318,552 participants (24.5% invitees) completed the questionnaire and provided the result of the POCT. Of these, 2,519 (0.79%) were seropositive (median age 55 years) and women were more often seropositive than men, interquartile range (IQR) 42-64, 40.2% males. Of participants with a prior positive Polymerase Chain Reaction (PCR) test (n=1,828), 29.1% were seropositive in the POCT. Seropositivity increased with age irrespective of sex. Elderly participants (>61 years) reported less symptoms and had less frequently been tested for SARS-CoV-2 compared to younger participants. Seropositivity was associated with physical contact with SARS-CoV-2 infected individuals (Risk ratio (RR) 7.43, 95% CI: 6.57-8.41) and in particular household members (RR 17.70, 95% CI: 15.60-20.10). Home care workers had a higher risk of seropositivity (RR 2.09 (95% CI: 1.58-2.78) as compared to office workers. Geographic population density was not associated to seropositivity. A high degree of compliance with national preventive recommendations was reported (e.g., > 80% use of face masks), but no difference was found between seropositive and seronegative participants.InterpretationThis study provides insight into the immunity of the Danish population seven to eight months after the first COVID-19 case in Denmark. The seroprevalence was lower than expected probably due to a low sensitivity of the POCT used or due to challenges relating to the reading of test results. Occupation or exposure in local communities were major routes of infection. As elderly participants were more often seropositive despite fewer symptoms and less PCR tests performed, more emphasis should be placed on testing this age group.

BACKGROUND AND OBJECTIVES: A donor health questionnaire (DHQ) aims to ensure the safety of donors and recipients of transfusions or transplantations with blood components, plasma-derived medicinal products, tissues, haematopoietic stem cells and medically assisted reproduction (in short substances of human origin; SoHO). Currently, many different DHQs exist across countries and SoHO. TRANSPOSE (TRANSfusion and transplantation PrOtection and SElection of donors) developed and validated a standardized DHQ to use across countries and SoHO. We tested whether participants understand the questions and provide honest answers.METHODS: For the validation of the standardized DHQ, two demographically representative online surveys were conducted in Germany (N = 3329) and Austria (N = 3432). We surveyed whether participants understood each DHQ question and would answer the questions truthfully. We used experimental settings to test whether there is a difference between mode of administration (print vs. online), the order of the questions (subject vs. chronological order), and the positioning of the general state of health question (beginning vs. end) in the DHQ. Using regression models, we tested the DHQ's impact on participant mood after completion and on socially desirable response behaviour.RESULTS: Participants understood the DHQ questions well and would answer them honestly. Nevertheless, the data show different levels of understanding and honesty when responding. Administration mode was the only characteristic that had a significant influence on mood, with the online version resulting in a more favourable mood in comparison to the printed version.CONCLUSION: The DHQ was well understood and had a low dishonest tendency. Our findings can serve as an impulse for further research on DHQ criteria across other SoHO and countries.

CD8+ T cells are involved in the pathogenesis of multiple sclerosis (MS). The interleukin-2 receptor α (IL-2Rα) is important for CD8+ T cell function, and single nucleotide polymorphisms (SNPs) in the IL2RA gene encoding IL-2Rα increase the risk of MS. Therefore, in isolated CD8+ T cells we investigated IL2RA gene methylation and gene expression in relation to the MS-associated IL2RA SNP rs2104286 and soluble IL-2Rα (sIL-2Rα). We have identified allele specific methylation of the CpG-site located in intron 1 that is perturbed by the rs2104286 SNP in CD8+ T cells from genotype-selected healthy subjects (HS). However, methylation of selected CpG-sites in the promotor or 5’UTR region of the IL2RA gene was neither associated with the rs2104286 SNP nor significantly correlated with IL2RA gene expression in HS. In CD8+ T cells from HS, we explored expression of immune relevant genes but observed only few associations with the rs2104286 SNP. However, we found that sIL-2Rα correlated negatively with expression of 55 immune relevant genes, including the IL-7 receptor gene, with Spearman’s rho between -0.49 and -0.32. Additionally, in HS by use of flow cytometry we observed that the IL-7 receptor on naïve CD8+ T cells correlated negatively with sIL-2Rα and was downregulated in carriers of the rs2104286 MS-associated risk genotype. Collectively, our study of resting CD8+ T cells indicates that the rs2104286 SNP has a minor effect and sIL-2Rα may negatively regulate the CD8+ T cell response.

The everyday lives of Danish inhabitants have been affected by the COVID-19 pandemic, e.g., by social distancing, which was employed by the government in March 2020 to prevent the spread of SARS-CoV-2. Moreover, the pandemic has entailed economic consequences for many people. This study aims to assess changes in physical and mental health-related quality of life (MCS, PCS), in stress levels, and quality of sleep during the COVID-19 pandemic and to identify factors that impact such changes, using a prospective national cohort study including 26,453 participants from the Danish Blood Donor Study who answered a health questionnaire before the pandemic and during the pandemic. Descriptive statistics, multivariable linear and multinomial logistic regression analyses were applied. A worsening of MCS and quality of sleep was found, and an overall decrease in stress levels was observed. PCS was decreased in men and slightly increased in women. The extent of health changes was mainly affected by changes in job situation, type of job, previous use of anti-depressive medication and the participants’ level of personal stamina. Thus, living under the unusual circumstances that persisted during the COVID-19 pandemic has had a negative impact on the health of the general population. This may, in time, constitute a public health problem.

Reports of persistent symptoms after hospitalization with COVID-19 have raised concern of a “long COVID” syndrome. This study aimed at determining the prevalence of and risk factors for acute and persistent symptoms in non-hospitalized patients with polymerase chain reaction (PCR) confirmed COVID-19. We conducted a cohort study of non-hospitalized participants identified via the Danish Civil Registration System with a SARS-CoV-2-positive PCR-test and available biobank samples. Participants received a digital questionnaire on demographics and COVID-19-related symptoms. Persistent symptoms: symptoms > 4 weeks (in sensitivity analyses > 12 weeks). We included 445 participants, of whom 34% were asymptomatic. Most common acute symptoms were fatigue, headache, and sneezing, while fatigue and reduced smell and taste were most severe. Persistent symptoms, most commonly fatigue and memory and concentration difficulties, were reported by 36% of 198 symptomatic participants with follow-up > 4 weeks. Risk factors for persistent symptoms included female sex (women 44% vs. men 24%, odds ratio 2.7, 95% CI 1.4–5.1, p = 0.003) and BMI (odds ratio 1.1, 95% CI 1.0–1.2, p = 0.001). In conclusion, among non-hospitalized PCR-confirmed COVID-19 patients one third were asymptomatic while one third of symptomatic participants had persistent symptoms illustrating the heterogeneity of disease presentation. These findings should be considered in health care planning and policy making related to COVID-19.

Soluble urokinase-type plasminogen activator receptor (suPAR) is a chronic inflammation marker associated with the development of a range of diseases, including cancer and cardiovascular disease. The genetics of suPAR remain unexplored but may shed light on the biology of the marker and its connection to outcomes. We report a heritability estimate of 60% for the variation in suPAR and performed a genome-wide association meta-analysis on suPAR levels measured in Iceland (N = 35,559) and in Denmark (N = 12,177). We identified 13 independently genome-wide significant sequence variants associated with suPAR across 11 distinct loci. Associated variants were found in and around genes encoding uPAR (PLAUR), its ligand uPA (PLAU), the kidney-disease-associated gene PLA2R1 as well as genes with relations to glycosylation, glycoprotein biosynthesis, and the immune response. These findings provide new insight into the causes of variation in suPAR plasma levels, which may clarify suPAR’s potential role in associated diseases, as well as the underlying mechanisms that give suPAR its prognostic value as a unique marker of chronic inflammation., Dowsett and colleagues used a genome-wide association approach to investigate the genetic influence on soluble urokinase-type plasminogen activator receptor presence in the plasma of humans. Their findings indicate a 60% heritability factor in British twins, and using a wide sample of Northern European genome samples they identify eleven genetic loci associated with an increase or decrease of this chronic inflammation marker.

Background The pathophysiology of xerosis depends on extrinsic and intrinsic exposures. Residential hard water may constitute such an exposure. Objectives To estimate the prevalence of xerosis and to compare water hardness exposure in blood donors with and without xerosis. Methods In this retrospective cohort study in 2018–2019, blood donors with self-reported moderately or severely dry skin were compared to blood donors without dry skin. Blood donors with ichthyosis, lichen planus and psoriasis were excluded. Water hardness data was collected from the Geology Survey of Denmark and Greenland. Results Overall, 4,748 of 30,721 (15.5%; 95% confidence interval 15.1–15.9%) blood donors had xerosis. After excluding blood donors with ichthyosis, lichen planus and psoriasis, 4,416 blood donors (2,559 females; median age 38.4 years [interquartile range 28.0–49.8]; 700 smokers) remained in this study. Water softer than 12–24 degrees Deutsche härte was associated with decreased probability of xerosis (odds ratio 0.83; 95% confidence interval 0.74–0.94) and water harder than 12–24 degrees Deutsche härte was associated with increased probability of xerosis (odds ratio 1.22; 95% confidence interval 1.03–1.45). The association between water hardness and xerosis remained significant after excluding blood donors with dermatitis. Conclusions Water hardness is associated with xerosis independent of other dermatoses.

Description of a perpetrator’s eye colour can be an important investigative lead in a forensic case with no apparent suspects. Herein, we present 11 SNPs (Eye Colour 11-EC11) that are important for eye colour prediction and eye colour prediction models for a two-category reporting system (blue and brown) and a three-category system (blue, intermediate, and brown). The EC11 SNPs were carefully selected from 44 pigmentary variants in seven genes previously found to be associated with eye colours in 757 Europeans (Danes, Swedes, and Italians). Mathematical models using three different reporting systems: a quantitative system (PIE-score), a two-category system (blue and brown), and a three-category system (blue, intermediate, brown) were used to rank the variants. SNPs with a sufficient mean variable importance (above 0.3%) were selected for EC11. Eye colour prediction models using the EC11 SNPs were developed using leave-one-out cross-validation (LOOCV) in an independent data set of 523 Norwegian individuals. Performance of the EC11 models for the two- and three-category system was compared with models based on the IrisPlex SNPs and the most important eye colour locus, rs12913832. We also compared model performances with the IrisPlex online tool (IrisPlex Web). The EC11 eye colour prediction models performed slightly better than the IrisPlex and rs12913832 models in all reporting systems and better than the IrisPlex Web in the three-category system. Three important points to consider prior to the implementation of eye colour prediction in a forensic genetic setting are discussed: (1) the reference population, (2) the SNP set, and (3) the reporting strategy.

BackgroundPeople experiencing homelessness (PEH) and associated shelter workers may be at higher risk of infection with “Severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2). The aim of this study was to determine the prevalence of SARS-CoV-2 among PEH and shelter workers in Denmark.Design and methodsIn November 2020, we conducted a nationwide cross-sectional seroprevalence study among PEH and shelter workers at 21 recruitment sites in Denmark. The assessment included a point-of-care test for antibodies against SARS-CoV-2, followed by a questionnaire. The seroprevalence was compared to that of geographically matched blood donors considered as a proxy for the background population, tested using a total Ig ELISA assay.ResultsWe included 827 participants in the study, of whom 819 provided their SARS-CoV-2 antibody results. Of those, 628 were PEH (median age 50.8 (IQR 40.9-59.1) years, 35.5% female) and 191 were shelter workers (median age 46.6 (IQR 36.1-55.0) years and 74.5% female). The overall seroprevalence was 6.7% and was similar among PEH and shelter workers (6.8% vs 6.3%, p=0.87); and 12.2% among all participants who engaged in sex work. The overall participant seroprevalence was significantly higher than that of the background population (2.9%, p InterpretationsThe prevalence of SARS-CoV-2 antibodies was more than twice as high among PEH and associated shelter workers, compared to the background population. The subset of the study participants who were also sex workers were at particularly high risk of COVID-19 infection.FundingTrygFonden and HelseFonden.

BackgroundCOVID-19 is suggested to be more prevalent among ethnic minorities and individuals with low socioeconomic status. We aimed to investigate the prevalence of SARS-CoV-2 antibodies during the COVID-19 pandemic among citizens 15 years or older in Denmark living in social housing (SH) areas.MethodsAs part of “Testing Denmark”, a nationwide sero-epidemiological surveillance survey, we conducted a study between January 8th and January 31st, 2021 with recruitment in 13 selected SH areas in Denmark. Participants were offered a point-of-care rapid SARS-CoV-2 IgM and IgG antibody test and a questionnaire concerning previous testing (viral throat- and nasopharyngeal swab or antibody test), test results for COVID-19, demographics, household characteristics, employment, risk factors for SARS-CoV-2 infection and history of symptoms associated with COVID-19. Data on seroprevalence from Danish blood donors in same period using a total Ig ELISA assay were used as a proxy for the general Danish population.FindingsOf the 13,279 included participants, 2,296 (17.3%) were seropositive (mean age 46.6 (SD 16.4) years, 54.2% female), which was 3 times higher than in the general Danish population (mean age 41.7 (SD 14.1) years, 48.5% female) in the same period (5.8%, risk ratios (RR) 2.96, 95% CI 2.78-3.16, p>0.001). Seropositivity was higher among males than females (RR 1.1, 95% CI 1.05-1.22%, p=0.001) and increased with age, with an OR seropositivity of 1.03 for each 10-year increase in age (95% CI 1.00-1.06, p=0.031). Close contact with COVID-19-infected individuals was associated with a higher risk of infection, especially among members of the same households (OR 5.0, 95% CI 4.1-6.2 pInterpretationDanish citizens living in SH areas of low socioeconomic status had a three times higher SARS-CoV-2 seroprevalence compared to the general Danish population. The seroprevalence was significantly higher in males and increased with age. Living in multiple generations or more than four persons in a household was an independent risk factor for being seropositive. Results of this study can be used for future consideration of the need for preventive measures in the populations living in SH areas.

Aims The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1–1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10−20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS., Graphical Abstract Summary of genetic insight into the pathogenesis of SSS and the role of risk factors in its development. Variants at six loci (named by corresponding gene names) were identified through GWAS and their unique phenotypic associations provide insight into distinct pathways underlying SSS. Investigation of the role of risk factors in SSS development supported a causal role for AF and heart rate and provided convincing evidence against causality for BMI, cholesterol (HDL and non-HDL), triglycerides and T2D. Mendelian randomization did not support causality for CAD, ischaemic stroke, heart failure, PR interval or QRS duration (not shown in figure). Red and blue arrows represent positive and negative associations, respectively.

Background Blood donors are at increased risk of developing iron deficiency, and several studies have recommended iron supplementation for this group. The aim of this study was to investigate the effect of oral iron supplementation on risk of infections among healthy blood donors. Study design and methods We included 82,062 participants from the Danish Blood Donor Study who completed a questionnaire on health-related items including use of oral iron supplementation. Infection outcomes were ascertained by using ICD-10 codes in the Danish National Patient Register and Anatomical Therapeutic Chemical codes in the Danish Prescription Register. Multivariable Cox proportional hazards analysis was used as the statistical model. Risk estimates are presented as crude hazard ratios (HRs) with 95% confidence intervals (CIs). Results During 19,978 person-years of observation, 6983 donors redeemed at least one prescription of antimicrobials. Similarly, during 19,829 person-years of observation, 242 donors were treated for infection at a hospital. Use of oral iron supplementation was not associated with redeemed prescriptions of antimicrobials in any strata: premenopausal women-HR 1.00, 95% CI 0.91-1.10; postmenopausal women-HR 1.07, 95% CI 0.87-1.32; and men-HR 1.01, 95% CI 0.84-1.21. In addition, use of oral iron supplementation was not associated with risk of hospital-based treatment for infection. Conclusion In a large cohort of blood donors, use of oral iron supplementation was not associated with subsequent short-term risk of infection. These findings are important to help understanding the safety of using oral iron supplementation among blood donors and the general population.

Background The prevalence of iron depletion is high among premenopausal women who donate blood frequently. Studies in nondonor populations indicate that iron deficiency anemia is associated with an increased risk of low birth weight. This prompts concerns that iron deficiency induced by frequent blood donation might impair subsequent fetal development. Study design and methods The aim of this study was to assess whether prepregnancy donation intensity affects the birth weight of singletons born at term (gestational week 38 or later) to nulliparous female donors in Denmark. We identified 293,897 first live singleton births to Danish women between 1997 and 2012 with complete information on gestational age, birth weight, child sex, parental age, maternal smoking status during pregnancy, and parental education length and annual income. Linear regression analysis was applied, with birth weight as outcome, number of donations within the 3 years before pregnancy as the explanatory variable, and confounding variables as described. Results Birth weight among children of low-intensity donors (n = 22,120) was 12.6 g (95% confidence interval, 6.7-18.6) higher than nondonors (n = 268,253) after controlling for the above-mentioned factors. The higher birth weight among low-intensity donors can be explained by the healthy donor effect. In fully adjusted analyses, birth weight among children of high-intensity donors (n = 3,524) was 20.2 g (95% confidence interval, 5.1-35.3 g) lower compared with low-intensity donors. This reduced birth weight among high-intensity donors compared to low-intensity donors may reflect blood donation-induced iron deficiency. Conclusions Our results show that high prepregnancy donation intensity is inversely associated with birth weight of singletons born at term to nulliparous women.

Hernias are characterized by protrusion of an organ or tissue through its surrounding cavity and often require surgical repair. We identified 65,492 cases for five hernia types in the UK Biobank and performed genome-wide association study scans for these five types and two combined groups. The results showed associated variants in all scans. Inguinal hernia had the most associations and we conducted a replication study with 23,803 additional cases from four study groups giving 84 independently associated variants. Identified variants from all scans were collapsed into 81 independent loci. Further testing showed that 26 loci were associated with more than one hernia type, suggesting substantial overlap between the underlying genetic mechanisms. Pathway analysis identified several genes with a strong link to collagen and/or elastin (ADAMTS6, ADAMTS16, ADAMTSL3, LOX, ELN) in the vicinity of associated loci for inguinal hernia, which substantiates an essential role of connective tissue morphology.

Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients.The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema.A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model.The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P 5 × 10In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B

Restless legs syndrome (RLS) is a common sensorimotor disorder, which can disrupt sleep and is thought to be caused in part by low cellular iron stores. Proton pump inhibitors (PPI) and histamine H2-receptor antagonists (H2A) are among the most commonly used drugs worldwide and show evidence of causing iron deficiency. We conducted a case/non-case observational study of blood donors in the United States (N = 13,403; REDS-III) and Denmark (N = 50,323; Danish Blood Donor Study, DBDS), both of which had complete blood count measures and a completed RLS assessment via the Cambridge–Hopkins RLS questionnaire. After adjusting for age, sex, race, BMI, blood donation frequency, smoking, hormone use, and iron supplement use, PPI/H2A use was associated with RLS (odds ratio [OR] = 1.41; 95% confidence interval [CI], 1.13–1.76; p = 0.002) in REDS-III for both PPI (OR = 1.43; CI, 1.03–1.95; p = 0.03) and H2A (OR = 1.56; CI, 1.10–2.16; p = 0.01). DBDS exhibited a similar association with PPIs/H2As (OR = 1.29; CI, 1.20–1.40; p < 0.001), and for PPIs alone (OR = 1.27; CI, 1.17–1.38; p < 0.001), but not H2As alone (OR = 1.18; CI, 0.92–1.53; p = 0.2). We found no evidence of blood iron stores mediating this association. The association of PPI, and possibly H2A, consumption with RLS independent of blood iron status and other factors which contribute to RLS risk suggest the need to re-evaluate use of PPI/H2A in populations at particular risk for RLS.

Serological assays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to support clinical diagnosis and epidemiological investigations. Recently, assays for large-scale detection of total antibodies (Ab), immunoglobulin G (IgG), and IgM against SARS-CoV-2 antigens have been developed, but there are limited data on the diagnostic accuracy of these assays., Serological assays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to support clinical diagnosis and epidemiological investigations. Recently, assays for large-scale detection of total antibodies (Ab), immunoglobulin G (IgG), and IgM against SARS-CoV-2 antigens have been developed, but there are limited data on the diagnostic accuracy of these assays. This study was a Danish national collaboration and evaluated 15 commercial and one in-house anti-SARS-CoV-2 assays in 16 laboratories. Sensitivity was evaluated using 150 samples from individuals with asymptomatic, mild, or moderate COVID-19, nonhospitalized or hospitalized, confirmed by nucleic acid amplification tests (NAAT); samples were collected 13 to 73 days either from symptom onset or from positive NAAT (patients without symptoms). Specificity and cross-reactivity were evaluated in samples collected prior to the SARS-CoV-2 epidemic from >586 blood donors and patients with autoimmune diseases, cytomegalovirus or Epstein-Barr virus infections, and acute viral infections. A specificity of ≥99% was achieved by all total-Ab and IgG assays except one, DiaSorin Liaison XL IgG (97.2%). Sensitivities in descending order were Wantai ELISA total Ab (96.7%), CUH-NOVO in-house ELISA total Ab (96.0%), Ortho Vitros total Ab (95.3%), YHLO iFlash IgG (94.0%), Ortho Vitros IgG (93.3%), Siemens Atellica total Ab (93.2%), Roche Elecsys total Ab (92.7%), Abbott Architect IgG (90.0%), Abbott Alinity IgG (median 88.0%), DiaSorin Liaison XL IgG (median 84.6%), Siemens Vista total Ab (81.0%), Euroimmun/ELISA IgG (78.0%), and Snibe Maglumi IgG (median 78.0%). However, confidence intervals overlapped for several assays. The IgM results were variable, with the Wantai IgM ELISA showing the highest sensitivity (82.7%) and specificity (99%). The rate of seropositivity increased with time from symptom onset and symptom severity.

The risk factors and disease implications of hyperhidrosis are unknown. The objectives of this retrospective cohort study were to estimate the prevalence of hyperhidrosis and to compare demographic, life-style, and socioeconomic parameters in blood donors with and without self-reported or hospital-diagnosed hyperhidrosis. The study included blood donors from the Danish Blood Donor Study for the period 2010-2019. Registry data were collected from Statistics Denmark. Overall, 2,794 of 30,808 blood donors (9.07 9595 8.75-9.40) had self-reported hyperhidrosis and 284 of 122,225 (0.23 95.21-0.26) had hospital-diagnosed hyperhidrosis. Self-reported hyperhidrosis was associated with smoking (odds ratio (OR) 1.17; 95.05-1.31), overweight (OR 1.72; 95.58-1.87), ``unemployed'' (OR 1.60; 95.24-2.08), ``short education'' (OR 0.76; 95.64-0.90), and lower income (beta-coefficient -26,121; 9537,931, -14,311). Hospital-diagnosed hyperhidrosis did not differ from controls. Thus, self-reported hyperhidrosis was associated with potential hyperhidrosis risk factors (smoking, overweight) and disease implications (unemployment, low education level and income). The risk factors and disease implications of hyper-hidrosis are unknown. The objectives of this retrospec-tive cohort study were to estimate the prevalence of hyperhidrosis and to compare demographic, life style, and socioeconomic parameters in blood donors with and without self-reported or hospital-diagnosed hyper-hidrosis. The study included blood donors from the Danish Blood Donor Study for the period 2010–2019. Registry data were collected from Statistics Denmark. Overall, 2,794 of 30,808 blood donors (9.07%; 95% confidence interval (95% CI) 8.75–9.40) had self-reported hyperhidrosis and 284 of 122,225 (0.23%; 95% CI 0.21–0.26) had hospital-diagnosed hyper-hidrosis. Self-reported hyperhidrosis was associated with smoking (odds ratio (OR) 1.17; 95% CI 1.05– 1.31), overweight (OR 1.72; 95% CI 1.58–1.87), “unemployed” (OR 1.60; 95% CI 1.24–2.08), “short education” (OR 0.76; 95% CI 0.64–0.90), and lower income (beta-coefficient –26,121; 95% CI –37,931, –14,311). Hospital-diagnosed hyperhidrosis did not differ from controls. Thus, self-reported hyperhidrosis was associated with potential hyperhidrosis risk factors (smoking, overweight) and disease implications (unemployment, low education level and income).

BackgroundMemory disturbances are frequent in unipolar depression (UD) and bipolar disorder (BD) and may comprise important predisposing and maintaining factors. Previous studies have demonstrated hippocampal abnormalities in UD and BD but there is a lack of studies specifically assessing hippocampus-dependent memory.MethodsWe used a virtual task to assess hippocampus-dependent (allocentric) vs non-hipppocampal (egocentric) spatial memory in remitted and partially remitted patients with UD or BD (N = 22) and a healthy control group (N = 32). Participants also completed a range of standard neuropsychological and functional assessments.ResultsParticipants in the UD/BD group showed selective impairments on high-load hippocampal (allocentric) memory compared to egocentric memory and this effect was independent of residual mood symptoms. Across both samples, both allocentric and egocentric spatial memory correlated with more general measures of memory and other aspects of cognition measured on standard neuropsychological tests but only high-load allocentric memory showed a significant relationship with functional capacity.ConclusionResults show a selective impairment in high-load allocentric spatial memory compared to egocentric memory in the patient group, suggesting impaired hippocampal functioning in patients with remitted UD/BD. BACKGROUND: Memory disturbances are frequent in unipolar depression (UD) and bipolar disorder (BD) and may comprise important predisposing and maintaining factors. Previous studies have demonstrated hippocampal abnormalities in UD and BD but there is a lack of studies specifically assessing hippocampus-dependent memory.METHODS: We used a virtual task to assess hippocampus-dependent (allocentric) vs non-hipppocampal (egocentric) spatial memory in remitted and partially remitted patients with UD or BD (N = 22) and a healthy control group (N = 32). Participants also completed a range of standard neuropsychological and functional assessments.RESULTS: Participants in the UD/BD group showed selective impairments on high-load hippocampal (allocentric) memory compared to egocentric memory and this effect was independent of residual mood symptoms. Across both samples, both allocentric and egocentric spatial memory correlated with more general measures of memory and other aspects of cognition measured on standard neuropsychological tests but only high-load allocentric memory showed a significant relationship with functional capacity.CONCLUSION: Results show a selective impairment in high-load allocentric spatial memory compared to egocentric memory in the patient group, suggesting impaired hippocampal functioning in patients with remitted UD/BD.

Background Allergic rhinitis (AR), allergic conjunctivitis (AC), and asthma composing multiple phenotypes and improved understanding of these phenotypes and their respective risk factors are needed. Objectives The objective of this study was to define the prevalence of AR, AC, and asthma and their association with allergen-specific immunoglobulin E (sIgE) sensitization in a large cohort of blood donors and identify risk factors. Methods From the nationwide population-based Danish Blood Donor Study, 52,976 participants completed an electronic questionnaire including AR, AC, asthma, allergic predisposition, and childhood residence. Of these, 25,257 were additionally tested for sIgE to inhalation allergens (Phadiatop). Results The prevalence of sIgE sensitization, AR, AC, and asthma was 30%, 19%, 15%, and 9%, respectively. The youngest birth cohorts had the highest prevalence of sIgE sensitization and symptoms of asthma, AR, and AC, and for asthma, they apparently experienced symptoms at an earlier age. The sIgE sensitization was positively associated with male sex. The sIgE seroprevalence was higher in participants with both AR and AC (ARC) than in participants with either AR or AC. Allergic predisposition and sIgE sensitization increased the risk of the diseases, while farm upbringing was associated with reduced prevalence of ARC, however, only in sIgE sensitized participants. Conclusion Birth year, childhood residence, sIgE sensitization, and allergic predisposition were associated with asthma, AR, and AC prevalence. Individuals with self-reported ARC represent a primarily sIgE-positive phenotype, while those with either AR or AC represent more diverse phenotypes. Background: Allergic rhinitis (AR), allergic conjunctivitis (AC), and asthma composing multiple phenotypes and improved understanding of these phenotypes and their respective risk factors are needed. Objectives: The objective of this study was to define the prevalence of AR, AC, and asthma and their association with allergen-specific immunoglobulin E (sIgE) sensitization in a large cohort of blood donors and identify risk factors. Methods: From the nationwide population-based Danish Blood Donor Study, 52,976 participants completed an electronic questionnaire including AR, AC, asthma, allergic predisposition, and childhood residence. Of these, 25,257 were additionally tested for sIgE to inhalation allergens (Phadiatop). Results: The prevalence of sIgE sensitization, AR, AC, and asthma was 30%, 19%, 15%, and 9%, respectively. The youngest birth cohorts had the highest prevalence of sIgE sensitization and symptoms of asthma, AR, and AC, and for asthma, they apparently experienced symptoms at an earlier age. The sIgE sensitization was positively associated with male sex. The sIgE seroprevalence was higher in participants with both AR and AC (ARC) than in participants with either AR or AC. Allergic predisposition and sIgE sensitization increased the risk of the diseases, while farm upbringing was associated with reduced prevalence of ARC, however, only in sIgE sensitized participants. Conclusion: Birth year, childhood residence, sIgE sensitization, and allergic predisposition were associated with asthma, AR, and AC prevalence. Individuals with self-reported ARC represent a primarily sIgE-positive phenotype, while those with either AR or AC represent more diverse phenotypes.

BACKGROUND AND OBJECTIVE: Donor selection criteria (DSC) are a vital link in the chain of supply of Substances of Human Origin (SoHO) but are also subject to controversy and differences of opinion. Traditionally, DSC have been based on application of the precautionary principle.MATERIALS AND METHODS: From 2017 to 2020, TRANSPOSE (TRANSfusion and transplantation PrOtection and SElection of donors), a European research project, aimed to identify discrepancies between current DSC by proposing a standardized risk assessment method for all SoHO (solid organs excluded) and all levels of evidence.RESULTS: The current DSC were assessed using a modified risk assessment method based on the Alliance of Blood Operators' Risk-based decision-making framework for blood safety. It was found that with limited or diverging scientific evidence, it was difficult to reach consensus and an international standardized method for decision-making was lacking. Furthermore, participants found it hard to disregard their local guidelines when providing expert opinion, which resulted in substantial influence on the consensus-based decision-making process.CONCLUSIONS: While the field of donation-safety research is expanding rapidly, there is an urgent need to formalize the decision-making process regarding DSC. This includes the need for standardized methods to increase transparency in the international decision-making process and to ensure that this is performed consistently. Our framework provides an easy-to-implement approach for standardizing risk assessments, especially in the context of limited scientific evidence.

Observational evidence suggests that mask wearing mitigates SARS-CoV-2 transmission. It is uncertain if this observed association arises through protection of uninfected wearers (protective effect), via reduced transmission from infected mask wearers (source control), or both. This randomized controlled trial investigates whether recommending surgical mask use when outside the home reduces wearers' risk for SARS-CoV-2 infection in a setting where masks were uncommon and not among recommended public health measures., Visual Abstract. Effectiveness of Mask Recommendation for Preventing SARS-CoV-2 Infection Observational evidence suggests that mask wearing mitigates SARS-CoV-2 transmission. It is uncertain if this observed association arises through protection of uninfected wearers (protective effect), via reduced transmission from infected mask wearers (source control), or both. This randomized controlled trial investigates whether recommending surgical mask use when outside the home reduces wearers' risk for SARS-CoV-2 infection in a setting where masks were uncommon and not among recommended public health measures. Visual Abstract. Effectiveness of Mask Recommendation for Preventing SARS-CoV-2 Infection Observational evidence suggests that mask wearing mitigates SARS-CoV-2 transmission. It is uncertain if this observed association arises through protection of uninfected wearers (protective effect), via reduced transmission from infected mask wearers (source control), or both. This randomized controlled trial investigates whether recommending surgical mask use when outside the home reduces wearers' risk for SARS-CoV-2 infection in a setting where masks were uncommon and not among recommended public health measures., Background: Observational evidence suggests that mask wearing mitigates transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is uncertain if this observed association arises through protection of uninfected wearers (protective effect), via reduced transmission from infected mask wearers (source control), or both. Objective: To assess whether recommending surgical mask use outside the home reduces wearers' risk for SARS-CoV-2 infection in a setting where masks were uncommon and not among recommended public health measures. Design: Randomized controlled trial (DANMASK-19 [Danish Study to Assess Face Masks for the Protection Against COVID-19 Infection]). (ClinicalTrials.gov: NCT04337541) Setting: Denmark, April and May 2020. Participants: Adults spending more than 3 hours per day outside the home without occupational mask use. Intervention: Encouragement to follow social distancing measures for coronavirus disease 2019, plus either no mask recommendation or a recommendation to wear a mask when outside the home among other persons together with a supply of 50 surgical masks and instructions for proper use. Measurements: The primary outcome was SARS-CoV-2 infection in the mask wearer at 1 month by antibody testing, polymerase chain reaction (PCR), or hospital diagnosis. The secondary outcome was PCR positivity for other respiratory viruses. Results: A total of 3030 participants were randomly assigned to the recommendation to wear masks, and 2994 were assigned to control; 4862 completed the study. Infection with SARS-CoV-2 occurred in 42 participants recommended masks (1.8%) and 53 control participants (2.1%). The between-group difference was −0.3 percentage point (95% CI, −1.2 to 0.4 percentage point; P = 0.38) (odds ratio, 0.82 [CI, 0.54 to 1.23]; P = 0.33). Multiple imputation accounting for loss to follow-up yielded similar results. Although the difference observed was not statistically significant, the 95% CIs are compatible with a 46% reduction to a 23% increase in infection. Limitation: Inconclusive results, missing data, variable adherence, patient-reported findings on home tests, no blinding, and no assessment of whether masks could decrease disease transmission from mask wearers to others. Conclusion: The recommendation to wear surgical masks to supplement other public health measures did not reduce the SARS-CoV-2 infection rate among wearers by more than 50% in a community with modest infection rates, some degree of social distancing, and uncommon general mask use. The data were compatible with lesser degrees of self-protection. Primary Funding Source: The Salling Foundations.

Serological SARS-CoV-2 assays are needed to support clinical diagnosis and epidemiological investigations. Recently, assays for the large-volume detection of total antibodies (Ab) and immunoglobulin (Ig) G and M against SARS-CoV-2 antigens have been developed, but there are limited data on the diagnostic accuracy of these assays. This study was organized as a Danish national collaboration and included fifteencommercial and one in-house anti-SARS-CoV-2 assays in sixteen laboratories. Sensitivity was evaluated using 150 serum samples from individuals diagnosed with asymptomatic,mild or moderate nonhospitalized (n=129) or hospitalized (n=31) COVID-19, confirmed bynucleic acid amplification tests, collected 13-73 days from symptom onset. Specificity and cross-reactivity were evaluated in samples collected prior to the SARS-CoV-2 epidemic from > 586 blood donors and patients with autoimmune diseases or CMV or EBV infections. Predefined specificity criteria of ≥ 99% were met by all total-Ab and IgG assays except one (Diasorin/LiaisonXL-IgG 97.2%). The sensitivities in descending order were: Wantai/ELISA total-Ab (96.7%), CUH/NOVO in-house ELISA total-Ab (96.0%), Ortho/Vitros total-Ab (95.3%), YHLO/iFlash-IgG (94.0%), Ortho/Vitros-IgG (93.3%), Siemens/Atellica total-Ab (93.2%), Roche-Elecsys total-Ab (92.7%), Abbott-Architect-IgG (90.0%), Abbott/Alinity-IgG (median 88.0%), Diasorin/LiaisonXL-IgG (84.6%),Siemens/Vista total-Ab (81.0%), Euroimmun/ELISA-IgG (78.0%), and Snibe/Maglumi-IgG (median 78.0%). The IgM results were variable, but one assay (Wantai/ELISA-IgM) hadboth high sensitivity (82.7%) and specificity (99%). The rate of seropositivity increased with time from symptom onset and symptom severity. In conclusion, predefined sensitivity and specificity acceptance criteria of 90%/99%, respectively, for diagnostic use were met in five of six total-Ab and three of seven IgG assays.

BackgroundThe pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has tremendous consequences for our societies. Knowledge of the seroprevalence of SARS-CoV-2 is needed to accurately monitor the spread of the epidemic and also to calculate the infection fatality rate (IFR). These measures may help the authorities to make informed decisions and adjust the current societal interventions. Blood donors comprise approximately 4.7% of the similarly aged population of Denmark and blood is donated in all areas of the country. The objective of this study was to perform real-time seroprevalence surveying among blood donors as a tool to estimate previous SARS-CoV-2 infections and the population based IFR.MethodsAll Danish blood donors aged 17-69 years giving blood April 6 to 17 were tested for SARS-CoV-2 immunoglobulin M and G antibodies using a commercial lateral flow test. Antibody status was compared between areas and an estimate of the IFR was calculated. The seroprevalence was adjusted for assay sensitivity and specificity taking the uncertainties of the test validation into account when reporting the 95% confidence intervals (CI).ResultsThe first 9,496 blood donors were tested and a combined adjusted seroprevalence of 1.7% (CI: 0.9-2.3) was calculated. The seroprevalence differed across areas. Using available data on fatalities and population numbers a combined IFR in patients younger than 70 is estimated at 82 per 100,000 (CI: 59-154) infections.ConclusionsThe IFR was estimated to be slightly lower than previously reported from other countries not using seroprevalence data. The IFR, including only individuals with no comorbidity, is likely several fold lower than the current estimate. This may have implications for risk mitigation. We have initiated real-time nationwide anti-SARS-CoV-2 seroprevalence surveying of blood donations as a tool in monitoring the epidemic.

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. This genome-wide association study (GWAS) of 102,084 migraine cases and 771,257 controls identified 123 loci of which 86 are novel. The loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. A stratification of the risk loci using 29,679 cases with subtype information, of which approximately half have never been used in a GWAS before, indicated three risk variants that appear specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that appear specific for migraine without aura (near SPINK2 and near FECH), and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

BackgroundReports of persistent symptoms after hospitalization with COVID-19 have raised concern of a “long COVID” syndrome. This study aimed at characterizing acute and persistent symptoms in non- hospitalized patients with polymerase chain reaction (PCR) confirmed COVID-19.MethodsCohort study of 445 non-hospitalized participants identified via the Danish Civil Registration System with a SARS-CoV-2-positive PCR-test and available biobank samples for genetic analyses. Participants received a digital questionnaire on demographics and COVID-19-related symptoms. Persistent symptoms: symptoms >four weeks (in sensitivity analyses >12 weeks).Results445 participants were included, of whom 34% were asymptomatic. Most common acute symptoms were fatigue, headache, and sneezing, while fatigue and reduced smell and taste were reported as most severe. Persistent symptoms, most commonly fatigue and memory and concentration difficulties, were reported by 36% of 198 symptomatic participants with follow-up >four weeks. Risk factors for persistent symptoms included female sex (women 44% vs. men 24%, odds ratio 2.7, 95%CI:1.4-5.1, p=0.003) and BMI (odds ratio 1.1, 95%CI:1.0-1.2, p=0.001).ConclusionAmong non-hospitalized PCR-confirmed COVID-19 patients one third were asymptomatic while one third of symptomatic participants had persistent symptoms illustrating the heterogeneity of disease presentation. These findings should be considered in future health care planning and policy making related to COVID-19.

BackgroundKnowledge about the COVID-19 outbreak is still sparse especially in a cross-national setting. COVID-19 is caused by a SARS-CoV-2 infection. The aim of the study is to contribute to the surveillance of the pandemic by bringing new knowledge about SARS-CoV-2 seropositivity among healthcare workers and evaluating whether certain job functions is associated with a higher risk of being infected, and to clarify if such association is mediated by the number of individuals that the employees meet during a workday. Finally, we will investigate regional and national differences in seroprevalence.MethodsA bi-national prospective observational cohort study including 3,272 adults employed at Falck in Sweden and Denmark. Participants were tested for SARS-CoV-2 antibodies every second week for a period of 8 weeks from June 22, 2020 until August 10, 2020. Descriptive statistics as well as multivariable logistic regression analyses were applied.ResultsOf the 3,272 Falck employees participating in this study, 159 (4.9%) tested positive for SARS-CoV-2 antibodies. The seroprevalence was lower among Danish Falck employees than among those from Sweden (2.8% in Denmark and 8.3% in Sweden). We also found that number of customer or patient contacts during a workday was the most prominent predictor for seropositivity, and that ambulance staff was the most vulnerable staff group.ConclusionsOur study presents geographical variations in seroprevalence within the Falck organization and shows evidence that social interaction is one of the biggest risk factors for getting infected with SARS-CoV-2.Key pointsSARS-CoV-2 seroprevalence vary between Denmark and Sweden, between job types and is mostly affected by number of social interactions among Falck healthcare workers

Superficial fungal infections (SFI) are common diseases affecting the skin, hair, nails, and mucosal membranes. They are often caused by dermatophytes and yeasts, e.g. Trichophyton, Candida, and Malassezia1 . Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease of the intertriginous areas associated with minor infections2 , peripheral vascular disease, diabetes, and smoking3 , the last three of which are risk factors for the development of SFI4 . Despite this, and the anatomical overlap between HS and types of SFI e.g. intertriginous candidiasis and tinea cruris, the possibility of an association between HS and SFI has never been investigated.

ObjectiveHaemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.DesignWe conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.ResultsWe demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.ConclusionHEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

ObjectiveAngioedema is a rare, but potentially life-threatening adverse reaction, associated with angiotensin-converting-enzyme inhibitors (ACEi). Identification of potential genetic factors related to this adverse event may help identify at-risk patients.Design, Setting and ParticipantsA genome-wide association study (GWAS) involving patients of European descent, all taking ACEi was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as persons with an angioedema event and a filled prescription for an ACEi 180 days prior to the event. Controls were defined as persons with continuous treatment with ACEi without any history of angioedema. Odds ratios (ORs) and 95 % confidence intervals (95 % CI) were computed for angioedema risk by logistic mixed model regression analysis. Summary statistics from the discovery and the replication cohorts were analyzed with a fixed effects meta-analysis model.ExposureSingle-nucleotide polymorphisms associated with ACEi-associated angioedema.Main outcomeHospital record of angioedema.ResultsThe discovery cohort consisted of 462 cases and 53,391 ACEi-treated controls. The replication cohort consisted of 144 cases and 1,345 ACEi-treated controls. In the discovery cohort, we identified one locus, residing at chromosome 14q32.2, that was associated with angioedema at the genome-wide significance level of P <5 × 10−8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR 1.62; 95 % CI 1.38 to 1.90; P = 4.3 × 10−9). This variant was validated in our replication cohort with similar direction and effect size (OR 1.60; 95 % CI 1.13 to 2.25; P = 7.2 × 10−3). We found that carriers of the risk allele had significantly lower systolic (−0.46 mmHg per T allele; 95 % CI −0.83 to −0.10; P = 0.013) and diastolic blood pressure (−0.26 mmHg per T allele; 95 % CI −0.46 to −0.05; P = 0.013).ConclusionIn this GWAS, involving individuals treated with ACEi, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with ACEi-related angioedema. BDKRB2 genotype-directed therapy may aid in improving safety in evidence-based clinical decision-making.

Hemorrhoidal disease (HEM) affects a large fraction of the population but its etiology including suspected genetic predisposition is poorly understood. We conducted a GWAS meta-analysis of 218,920 HEM patients and 725,213 controls of European ancestry, demonstrating modest heritability and genetic correlation with several other diseases from the gastrointestinal, neuroaffective and cardiovascular domains. HEM polygenic risk scores validated in 180,435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harboring genes whose expression is enriched in blood vessels and gastrointestinal tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses of affected tissue from HEM patients highlighted HEM gene co-expression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organization of the extracellular matrix. We conclude HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

Funder: Scottish Government; doi: https://doi.org/10.13039/100012095, Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289, Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases = 10,257) and a follow up sample of 24,977 (cases = 6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR = 1.25, P = 1.5 × 10−18), rs10068599-T (OR = 1.09, P = 6.9 × 10−10) and rs10769894-A (OR = 0.90, P = 9.4 × 10−14). At four of the 22 RLS loci, cis-eQTL analysis indicates a causal impact on gene expression. Through polygenic risk score for RLS we extended prior epidemiological findings implicating obesity, smoking and high alcohol intake as risk factors for RLS. To improve our understanding, with the purpose of seeking better treatments, more genetics studies yielding deeper insights into the disease biology are needed.

Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental, and developmental factors. While usually benign, in a minority of cases, febrile seizures precede later development of epilepsy. Here, we conducted a genome-wide association study of febrile seizures with 7,635 cases and 93,966 controls identifying and replicating seven new loci, all with P < 5 × 10−10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harbored genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. GABRG2 is a well-established epilepsy gene comprising variants associated with febrile seizures, and overall we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10−4). Finally, a polygenic risk score based on all genome-wide significant loci was associated within patients with number of hospital admissions with febrile seizures and age at first admission, suggesting potential clinical utility of improved genetic understanding of febrile seizure genesis.

Background Ischaemic heart disease (IHD) is a diverse phenotype conventionally characterized by presence of the cardinal symptom, angina pectoris (fig. 1). Evidence of scientific value in electronic health records (EHRs) is accumulating although point of care applications are still limited. In this context, we have curated an EHR database (BTH) containing population-wide medical history of 2,658,323 patients from years 2006–2016 for discovery of new risk stratifying principles, by linkage of phenotypic data from EHRs, genotypes from 107,690 cardiovascular patients and 40 years of population-wide registry data. Purpose To establish a model that defines IHD onset, categorizes IHD patients by degree of disease progression and then discover phenotypic and genetic features that demarcate these patient strata. Features may be combinations of e.g. symptoms, vital signs, diagnosis and genetic variants that reduce or increase risk of disease progression, factor each other out or enhance the effect of one another, interacting non-linearly. Methods In this retrospective cohort study, cases were defined by integrated assessment of The Danish National Patient Registry (NPR) and BTH. Inclusion criteria were patients with an entry in BTH who were: (i) subject to a coronary arteriography (CAG), cardiac CT or MRI where IHD was the action diagnosis or (ii) subject to CAG, cardiac CT or MRI and diagnosed with IHD within one month. EHRs covering the two criteria were available for all cases and facilitated longitudinal alignment of patients with respect to disease onset and progression. IHD was assessed by lookup in NPR of ICD-10 codes I20-I25 and Danish Health Care Classification codes UXAC85, UXCC00A and UXMC80. Vital signs and symptoms were extracted from the free text in EHRs by application of regular expressions (regex) and named entity recognition using controlled vocabularies, respectively. Results In the dataset, 78,896 patients (50,761 males) met the inclusion criteria. The inclusion criteria aligned patients longitudinally facilitating clustering into subgroups displaying different progression patterns. By application of regex to the free text in the EHR, systolic and diastolic blood pressure were identified in 87% of cases. The controlled vocabulary identified about 60,000 patients, who had chest pain recorded in the EHR at time of diagnosis. Ongoing work is centered on optimizing clustering strategies and subsequently performing comorbidity and biochemical enrichment analysis. Genetic enrichment will be performed on 21,994 cases. Conclusion Integrated assessment of various population-wide registries is a promising strategy to curate EHR for obtainment of point of care applications, here exemplified by IHD. We argue that genetically enriched EHRs have potential to be a key element in efforts to obtain a clinical classification system that concertedly reflects etiology and clinically actionable differences in disease progression patterns. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Novo Nordisk Foundation and Innovationsfonden