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OBJECTIVES: There is a gap in knowledge about the effects of smoking on overall infection risk in otherwise healthy populations, possibly leading to underestimation of the dangers of smoking. The present study aimed to examine the association of smoking with the risk of infections in a large cohort of healthy blood donors.METHODS: This cohort study used questionnaire and health register data from 127 831 Danish blood donors. Multivariable Cox proportional hazards analysis was applied to estimate the association of current smoking with the risk of all-cause infection defined as hospital-based treatment for infection or filled prescriptions of antimicrobials stratified for age and adjusted for relevant confounders.RESULTS: Among 18 272 current smokers, 12 272 filled an antimicrobial prescription and 2035 received hospital-based treatment for infections. Among 101 974 non-smokers, 65 117 filled a prescription and 8501 received hospital-based treatment for infections. Smokers had a higher risk of all-cause infection than non-smokers (hazard ratio estimates were 1.27 in males and 1.33 in females for hospital-based treatment and 1.11 in males and up to 1.20 in females for filled prescriptions). Smoking was most strongly associated with an increased incidence of respiratory tract infection, abscesses, skin infection, and prescriptions for these ailments (hazard ratio up to 2.29). Furthermore, smokers' risk of filled prescriptions of broad-spectrum penicillin was increased (hazard ratio up to 1.96).CONCLUSIONS: Current smoking was strongly associated with the risk of hospital-based treatment of infection and filled prescriptions of antimicrobials in a large cohort of healthy individuals. These findings warrant an increased focus on infectious disease risk among smokers.

We report a genome-wide association study of venous thromboembolism (VTE) incorporating 81,190 cases and 1,419,671 controls sampled from six cohorts. We identify 93 risk loci, of which 62 are previously unreported. Many of the identified risk loci are at genes encoding proteins with functions converging on the coagulation cascade or platelet function. A VTE polygenic risk score (PRS) enabled effective identification of both high- and low-risk individuals. Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A (c.*97 G > A) in F2 and p.R534Q in F5. We also document that F2 and F5 mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population. We further show that PRS improved individual risk prediction beyond that of genetic and clinical risk factors. We investigated the extent to which venous and arterial thrombosis share clinical risk factors using Mendelian randomization, finding that some risk factors for arterial thrombosis were directionally concordant with VTE risk (for example, body mass index and smoking) whereas others were discordant (for example, systolic blood pressure and triglyceride levels).

Major Depressive Disorder (MDD) is a heterogeneous disease, which displays sex differences in symptomatology. This study aimed to assess point prevalence of MDD in undiagnosed, healthy adults as well as sex differences in symptomatology and clarify if specific symptoms increased the later need for anti-depressive medication. The study included 51,658 blood donors. Depressive symptoms were assessed according to ICD-10 using the Major Depression Inventory. Demographics, previous MDD, anti-depressive medication were collected from questionnaires and population registers. Descriptive, Logistic and Cox regression analyses were conducted. In total, 1.15% participants met the criteria for MDD. Women were significantly more likely to experience "increased appetite" and less likely to experience "a feeling of life not worth living", compared to men. MDD significantly associated with an increased hazard of later receiving a prescription for anti-depressive medication. The risk increased proportionally with increasing MDD severity. The two symptoms, "feeling that life is not worth living" and "trouble sleeping" were the strongest individual predictive symptoms of future anti-depressive medication in women and men, respectively. The results confirm findings in MDD patient groups. The diagnostic and prognostic value should be investigated further to address their potential as part of the clinical assessment.

Previous studies have reported Blood type O to confer a lower risk of SARS-CoV-2 infection, while secretor status and other blood groups have been suspected to have a similar effect as well.To determine whether any other blood groups influence testing positive for SARS-CoV-2, COVID-19 severity, or prolonged COVID-19, we used a large cohort of 650,156 Danish blood donors with varying available data for secretor status and blood groups ABO, Rh, Colton, Duffy, Diego, Dombrock, Kell, Kidd, Knops, Lewis, Lutheran, MNS, P1PK, Vel, and Yt. Of these, 36,068 tested positive for SARS-CoV-2 whereas 614,088 tested negative between 2020-02-17 and 2021-08-04. Associations between infection and blood groups were assessed using logistic regression models with sex and age as covariates.The Lewis blood group antigen LeThis study uncovers a new association to reduced SARS-CoV-2 susceptibility for Lewis type Le

Purpose: Hyperhidrosis has been associated with a reduced health-related quality of life (HRQoL). The role of common confounding factors of this association such as stress and socioeconomic status, however, remain largely unexplored, and may affect the management strategy for hyperhidrosis. Therefore, the study objective was to compare the HRQoL in individuals with and without hyperhidrosis while adjusting for confounders. Methods: In this retrospective cohort study, data on the HRQoL measured by the short-form-12 questionnaire and self-reported hyperhidrosis were collected from the Danish Blood Donor Study-cohort. Data on international classification of disease-10 codes and redeemed prescriptions were collected from nationwide registries. Linear regression investigated the association between hyperhidrosis and HRQoL. Results: Total 2794 (9.1%) of 30,808 blood donors had self-reported hyperhidrosis and 284 (0.2%) of 122,225 had hospital diagnosed hyperhidrosis. Self-reported hyperhidrosis was associated with a reduced mental HRQoL (adjusted beta coefficient − 1.10; 95% confidence interval − 1.37, − 0.82; p < 0.001) and physical HRQoL (adjusted beta coefficient − 0.90; 95% confidence interval − 1.09, − 0.70; p < 0.001). Hospital diagnosed hyperhidrosis was associated with a reduced mental HRQoL (adjusted beta coefficient − 0.91; 95% confidence interval − 1.82, − 0.04; p = 0.049). Conclusion: Hyperhidrosis is associated with a reduced HRQoL, independently of confounders or mode of diagnosis. This supports an approach primarily targeting hyperhidrosis.

Familial clustering of the skin disease primary hyperhidrosis suggests a genetic component to the disease. The human leucocyte antigen (HLA) is implicated in a range of diseases, including many comorbidities to hyperhidrosis. No study has investigated whether the HLA genes are involved in the pathogenesis of hyperhidrosis. We, therefore, compared HLA alleles in individuals with and without hyperhidrosis in this study of 65 000 blood donors. In this retrospective cohort study, we retrieved information on individuals with and without hyperhidrosis using self-reported questionnaires, the Danish National Patient Registry and the Danish National Prescription Registry on participants recruited to the Danish Blood Donor Study between 2010 and 2019. Association tests using logistic regression were conducted for each HLA allele corrected for sex, age, body mass index, smoking and principal components. Overall, 145 of 65 795 (0.2%) participants had hospital diagnosed hyperhidrosis. Similarly, 1379 of 15 530 (8.9%) participants had moderate-severe self-reported hyperhidrosis, of whom 447 (2.9%) had severe self-reported hyperhidrosis. Altogether, 28 participants had both hospital diagnosed and moderate-severe self-reported hyperhidrosis. Severe self-reported hyperhidrosis was associated with HLA-A*80:01 (adjusted odds ratio 26.97; 95% confidence interval 5.32-136.70; n = 7; P

Hyperhidrosis has been associated with a reduced health-related quality of life (HRQoL). The role of common confounding factors of this association such as stress and socioeconomic status, however, remain largely unexplored, and may affect the management strategy for hyperhidrosis. Therefore, the study objective was to compare the HRQoL in individuals with and without hyperhidrosis while adjusting for confounders.In this retrospective cohort study, data on the HRQoL measured by the short-form-12 questionnaire and self-reported hyperhidrosis were collected from the Danish Blood Donor Study-cohort. Data on international classification of disease-10 codes and redeemed prescriptions were collected from nationwide registries. Linear regression investigated the association between hyperhidrosis and HRQoL.Total 2794 (9.1%) of 30,808 blood donors had self-reported hyperhidrosis and 284 (0.2%) of 122,225 had hospital diagnosed hyperhidrosis. Self-reported hyperhidrosis was associated with a reduced mental HRQoL (adjusted beta coefficient - 1.10; 95% confidence interval - 1.37, - 0.82; p 0.001) and physical HRQoL (adjusted beta coefficient - 0.90; 95% confidence interval - 1.09, - 0.70; p 0.001). Hospital diagnosed hyperhidrosis was associated with a reduced mental HRQoL (adjusted beta coefficient - 0.91; 95% confidence interval - 1.82, - 0.04; p = 0.049).Hyperhidrosis is associated with a reduced HRQoL, independently of confounders or mode of diagnosis. This supports an approach primarily targeting hyperhidrosis.

Background Various conditions with cellular decay are associated with elevated cell-free DNA (cfDNA). This study aimed to investigate if perioperatively measured cfDNA levels were associated with the surgical approach, complications, or recurrence. Methods Plasma was obtained from patients who underwent surgery for colon cancer at admission and at the time of discharge. Quantitative measurement of cfDNA was performed by amplifying two amplicons of 102 base pairs (bp) and 132 bp of Beta-2-Microglobulin (B2M) and Peptidyl-Prolyl cis–trans Isomerase A (PPIA), respectively. Results cfDNA was measured in 48 patients who underwent surgery for colonic cancer. Sixteen patients had recurrence during the follow-up period, fifteen developed a postoperative complication, and seventeen patients developed neither, acting as the control group. Postoperative cfDNA levels were significantly elevated from baseline samples, across all groups, with a median preoperatively B2M level of 48.3 alleles per mL and postoperatively of 220 alleles per mL and a median preoperatively level PPIA of 26.9 alleles per mL and postoperatively of 111.6 alleles per mL (p B2M and p PPIA). Postoperative levels of PPIA, but not B2M, were significantly higher in patients experiencing complications than in the control group (p = 0.036). However, a tendency towards an association between the surgical approach and the changes in cfDNA levels was found for PPIA (p = 0.058), and B2M (p = 0.087). Conclusions Plasma cfDNA was increased after surgery in all patients with colon cancer. Postoperative PPIA levels were significantly higher in patients experiencing surgical complications but not in B2M levels.

PurposeThe aim of Copenhagen Hospital Biobank-Cardiovascular Disease Cohort (CHB-CVDC) is to establish a cohort that can accelerate our understanding of CVD initiation and progression by jointly studying genetics, diagnoses, treatments and risk factors.ParticipantsThe CHB-CVDC is a large genomic cohort of patients with CVD. CHB-CVDC currently includes 96 308 patients. The cohort is part of CHB initiated in 2009 in the Capital Region of Denmark. CHB is continuously growing with ~40 000 samples/year. Patients in CHB were included in CHB-CVDC if they were above 18 years of age and assigned at least one cardiovascular diagnosis. Additionally, up-to 110 000 blood donors can be analysed jointly with CHB-CVDC. Linkage with the Danish National Health Registries, Electronic Patient Records, and Clinical Quality Databases allow up-to 41 years of medical history. All individuals are genotyped using the Infinium Global Screening Array from Illumina and imputed using a reference panel consisting of whole-genome sequence data from 8429 Danes along with 7146 samples from North-Western Europe. Currently, 39 539 of the patients are deceased.Findings to dateHere, we demonstrate the utility of the cohort by showing concordant effects between known variants and selected CVDs, that is, >93% concordance for coronary artery disease, atrial fibrillation, heart failure and cholesterol measurements and 85% concordance for hypertension. Furthermore, we evaluated multiple study designs and the validity of using Danish blood donors as part of CHB-CVDC. Lastly, CHB-CVDC has already made major contributions to studies of sick sinus syndrome and the role of phytosterols in development of atherosclerosis.Future plansIn addition to genetics, electronic patient records, national socioeconomic and health registries extensively characterise each patient in CHB-CVDC and provides a promising framework for improved understanding of risk and protective variants. We aim to include other measurable biomarkers for example, proteins in CHB-CVDC making it a platform for multiomics cardiovascular studies.

The Hippo pathway is important for tissue homeostasis, regulation of organ size and growth in most tissues. The co-transcription factor yes-associated protein 1 (YAP1) serves as a main downstream effector of the Hippo pathway and its dysregulation increases cancer development and blocks colonic tissue repair. Nevertheless, little is known about the transcriptional regulation of YAP1 in intestinal cells. The aim of this study to identify gene control regions in the YAP1 gene and transcription factors important for intestinal expression. Bioinformatic analysis of caudal type homeobox 2 (CDX2) and hepatocyte nuclear factor 4 alpha (HNF4α) chromatin immunoprecipitated DNA from differentiated Caco-2 cells revealed potential intragenic enhancers in the YAP1 gene. Transfection of luciferase-expressing YAP1 promoter-reporter constructs containing the potential enhancer regions validated one potent enhancer of the YAP1 promoter activity in Caco-2 and T84 cells. Two potential CDX2 and one HNF4α binding sites were identified in the enhancer by in silico transcription factor binding site analysis and protein-DNA binding was confirmed in vitro using electrophoretic mobility shift assay. It was found by chromatin immunoprecipitation experiments that CDX2 and HNF4α bind to the YAP1 enhancer in Caco-2 cells. These results reveal a previously unknown enhancer of the YAP1 promoter activity in the YAP1 gene, with importance for high expression levels in intestinal epithelial cells. Additionally, CDX2 and HNF4α binding are important for the YAP1 enhancer activity in intestinal epithelial cells.

Concern of transfusion-transmitted bacterial infections has been the major hurdle to extend shelf life of platelet (PLT) concentrates. We aimed to investigate the association between storage time and risk of positive blood cultures at different times after transfusion.We performed a nationwide cohort study among PLT transfusion recipients in Denmark between 2010 and 2012, as recorded in the Scandinavian Donations and Transfusions (SCANDAT2) database. Linking with a nationwide database on blood cultures (MiBa), we compared the incidence of a positive blood culture among recipients of PLTs stored 6 to 7 days (old) to those receiving fresh PLTs (1-5 days), using Poisson regression models. We considered cumulative exposures in windows of 1, 3, 5, and 7 days.A total of 9776 patients received 66,101 PLT transfusions. The incidence rate ratio (IRR) of a positive blood culture the day after transfusion of at least one old PLT concentrate was 0.77 (95% confidence interval [CI], 0.54-1.09) compared to transfusion of fresh PLT concentrates. The incidence rate of a positive blood culture was lower the day after receiving one old compared to one fresh PLT concentrate (IRR, 0.57; 95% CI, 0.37-0.87). Three, 5, or 7 days after transfusion, storage time was not associated with the risk of a positive blood culture.Storage of buffy coat-derived PLT concentrates in PAS-C up to 7 days seems safe regarding the risk of a positive blood culture. If anything, transfusion of a single old PLT concentrate may decrease this risk the following day.

Genomewide association studies have reported alleles in the ABO locus to be associated with ferritin levels. These studies warrant the investigation of a possible association between the ABO blood group and ferritin levels. We aimed to explore if ABO blood group is associated with iron stores expressed as ferritin levels.Ferritin levels were measured at least once for 30,595 Danish Blood Donor Study participants. Linear regression analyses were performed with the ABO blood group as explanatory variable and adjusted for age, number of donations 3 years before the ferritin measurement, and time since latest donation. In addition, a subanalysis was performed on 15,280 individuals in which further adjustments for body mass index, smoking status, and C-reactive protein levels were possible. Furthermore, logistic regression analyses were performed to determine if ABO blood group was associated with a ferritin level of less than 15 ng/mL.Non-O blood group donors had lower ferritin levels than blood group O donors, regardless of sex. Accordingly, risk of ferritin level of less than 15 ng/mL was increased for individuals with non-O blood group compared with O blood group. In subanalyses similar associations were observed, albeit in women the association between blood group and risk of a ferritin level below 15 ng/mL was no longer significant. ABO blood group was not associated with red blood cell indices such as mean cell volume and mean cell hemoglobin content.Donors with non-O blood group have lower ferritin levels than donors with other blood groups.

Low hemoglobin (Hb) is associated with poor general health and adverse outcomes in a wide range of diseases. However, a link between Hb levels and the risk of infection among healthy individuals has yet to be investigated.Using data from the Scandinavian Donations and Transfusions database, 497,390 donors were followed after 5,458,499 donations in health registers. With 1,339,362 person-years of follow-up, Andersen-Gill Cox regression was used to study the association of Hb levels below deferral thresholds, very low Hb levels (in the lowest 0.1 percentile), and declining Hb levels with the risk of infection as measured by hospital or outpatient contact for infection and filling of prescription for antimicrobials, respectively, within 3 months of donation. Analyses were stratified by sex, menopausal status, and frequency of donation.Hb levels below deferral thresholds were not associated with a risk of hospital contact for infection among premenopausal women (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.95-1.14), postmenopausal women (HR, 0.77; 95% CI, 0.54-1.11), or men (HR, 0.97; 95% CI, 0.81-1.16), nor was there any association with hospital contact for very low Hb levels or patterns of declining Hb levels. However, subthreshold Hb levels were associated with a reduced risk of antimicrobial prescriptions among premenopausal women (HR, 0.92; 95% CI, 0.91-0.93), postmenopausal women (HR, 0.93; 95% CI, 0.89-0.97), and men (HR, 0.91; 95% CI, 0.88-0.94).Neither Hb levels below deferral thresholds nor very low or declining Hb levels were associated with an increased risk of infection. This is reassuring, because blood donation can lead to lower Hb levels.

Many biologic functions depend on sufficient iron levels, and iron deficiency is especially common among blood donors. Genetic variants associated with iron levels have been identified, but the impact of genetic variation on iron levels among blood donors remains unclear.The effect of six single-nucleotide polymorphisms (SNPs) on ferritin levels in 14,126 blood donors were investigated in four genes: in Human Hemochromatosis Protein gene (HFE; rs1800562 and rs179945); in Transmembrane Protease gene, Serine 6 (TMPRSS6-regulating hepcidin; rs855791); in BTB domain containing protein gene (BTBD9-associated with restless legs syndrome; rs9357271); and in the Transferrin gene (TF; rs2280673 and rs1830084). Multiple linear and logistic regression analyses were used to evaluate the effect of each SNP on ferritin levels and the risk of iron deficiency (ferritin15 ng/mL).In HFE, the G-allele of rs1800562 was associated with lower iron stores in both sexes. This was also true for the C-allele of rs179945, but in men only. Also, the T-allele of TMPRSS6 rs855791 was negatively associated with iron stores in men. Homozygocity for C in rs1799945 was associated with iron deficiency in women. Results for all other genetic variants were insignificant.Genetic variants associated with hemochromatosis may protect donors against depleted iron stores. In addition, we showed that presence of the T-allele at rs855791 in TMPRSS6 was associated with lower iron stores in men.

It is well known that blood donors are at increased risk of iron deficiency and subsequent development of iron deficiency anemia. We aimed to investigate the effect of factors influencing hemoglobin (Hb) levels.Initiated in 2010, the Danish Blood Donor Study is a population-based study and biobank. We performed multivariable linear regression analysis to assess the effects of donation activity, physiologic and lifestyle factors, and diet on Hb levels among 15,197 donors. We also performed multivariable logistic regression to evaluate the effects of these factors on the risk of having low Hb (defined as Hb below the 10th percentile among men and women, respectively) and of a decrease in Hb greater than 0.5 mmol/L (0.8 g/dL) between successive donations. All analyses were performed stratified for sex and smoking status. We also tested a previously used model for the prediction of Hb.The strongest predictors of Hb and risk of low Hb were low ferritin (15 ng/mL) and current use of iron supplementation (yes/no). No dietary factors were found to be consistently significant in multivariable models predicting Hb levels, risk of having low Hb, or risk of a decrease in Hb greater than 0.5 mmol/L. We found similar effects to previous studies of factors in the predictive model, with little additional effect of including smoking status and ferritin.As ferritin was the strongest predictor of Hb, this study supports the implementation of regular ferritin measurement as a method of risk assessment among blood donors.

Health-related quality of life (HRQL) represents people's subjective assessment of their mental and physical well-being. HRQL is highly predictive of future health. The effect of iron deficiency without anemia induced by blood donation on HRQL is presently unknown. The aim was to explore the relationship between iron status and self-reported mental component score (MCS; SF-12) and physical component score (PCS; SF-12) in Danish blood donors.Complete relevant data, including the 12-item short-form health survey (SF-12), plasma ferritin levels, age, body mass index, smoking status, C-reactive protein levels, number of donations in the previous 3 years, and PCS and MCS, were available for 8692 men and 7683 women enrolled from March 1, 2010, to December 31, 2010. Multivariable linear and logistic (cutoff at the 10th percentile) regression analyses were used to assess the relationship between iron deficiency (ferritin 15 ng/mL) and MCS and PCS, respectively. Analyses were performed separately for men and women.There was no significant relationship between iron deficiency and self-reported mental or physical health.This study found no association between iron stores and self-reported HRQL among Danish blood donors.