Genetic polymorphisms in IL-2, IL-10 and FOXP3 are associated with autoimmune neutropaenia in early childhood and autoantibody specificity in a Danish cohort.

Autoimmune neutropaenia (AIN) in early childhood is characterized by chronic neutropaenia and positivity for human neutrophil antibodies (HNA), resulting in the excessive destruction of neutrophils. The association between regulatory T cells (Tregs) and AIN has been described, and in this study, we investigated three Treg-associated genes, IL-2, IL-10 and FOXP3. The frequencies of three single nucleotide polymorphisms (SNPs) in IL-2 -330T>G (rs2069762), +114G>T (rs2069763) and IVS3-116 A>G (rs2069772), four SNPs in IL-10 -3575T>A (rs1800890), -1082G>A (rs1800896), -819 C>T (rs1800871) and -592 C>A (rs1800872) and three SNPs in FOXP3 -3499 A>G (rs3761547), -3279 C>A (rs3761548) and -924 A>G (rs2232365) were compared between 166 Danish AIN patients and 358 healthy controls. Disease association was observed for IL-2 IVS3-116 GG (p = 0.0081, OR = 0.35 [0.15-0.80]), IL-10 -3575 TT (p = 0.0078, OR = 1.71 [1.16-2.54]) and IL-10 -1082 AA (p = 0.014, OR = 1.76 [1.14-2.72]) in all patients and FOXP3 -924 (p = 0.0005, A OR = 0.41 [0.25-0.68] and G OR = 2.42 [1.46-4.01]) in male patients. None of the associations were linked to antibody specificity. Disease-associated haplotypes were observed in IL-2 and FOXP3. IL-2 -330T/+114 T/IVS3-116A was associated with anti-FcγRIIIb-positive patients (p = 0.012, OR = 2.07 [1.18-3.62]). FOXP3 -3499A/-3279C/-924A was associated with anti-HNA-1a-positive male patients (p = 0.016, OR = 0.41 [0.20-0.83]), and ACG was associated with female patients, both in the combined group (p = 0.006, OR = NA) and the anti-FcγRIIIb-positive group (p = 0.002, OR = NA). We conclude that our findings reveal a correlation between SNP in Treg-associated genes and AIN, indicating that AIN could be driven by dysfunction of immune homeostatic-evolving Tregs.

Genetic variants associated with syncope implicate neural and autonomic processes.

AIMS: Syncope is a common and clinically challenging condition. In this study, the genetics of syncope were investigated to seek knowledge about its pathophysiology and prognostic implications. METHODS AND RESULTS: This genome-wide association meta-analysis included 56 071 syncope cases and 890 790 controls from deCODE genetics (Iceland), UK Biobank (United Kingdom), and Copenhagen Hospital Biobank Cardiovascular Study/Danish Blood Donor Study (Denmark), with a follow-up assessment of variants in 22 412 cases and 286 003 controls from Intermountain (Utah, USA) and FinnGen (Finland). The study yielded 18 independent syncope variants, 17 of which were novel. One of the variants, p.Ser140Thr in PTPRN2, affected syncope only when maternally inherited. Another variant associated with a vasovagal reaction during blood donation and five others with heart rate and/or blood pressure regulation, with variable directions of effects. None of the 18 associations could be attributed to cardiovascular or other disorders. Annotation with regard to regulatory elements indicated that the syncope variants were preferentially located in neural-specific regulatory regions. Mendelian randomization analysis supported a causal effect of coronary artery disease on syncope. A polygenic score (PGS) for syncope captured genetic correlation with cardiovascular disorders, diabetes, depression, and shortened lifespan. However, a score based solely on the 18 syncope variants performed similarly to the PGS in detecting syncope risk but did not associate with other disorders. CONCLUSION: The results demonstrate that syncope has a distinct genetic architecture that implicates neural regulatory processes and a complex relationship with heart rate and blood pressure regulation. A shared genetic background with poor cardiovascular health was observed, supporting the importance of a thorough assessment of individuals presenting with syncope.

Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement.

OBJECTIVES: Osteoarthritis is a common and severe, multifactorial disease with a well-established genetic component. However, little is known about how genetics affect disease progression, and thereby the need for joint placement. Therefore, we aimed to investigate whether the genetic associations of knee and hip osteoarthritis differ between patients treated with joint replacement and patients without joint replacement. METHODS: We included knee and hip osteoarthritis cases along with healthy controls, altogether counting >700 000 individuals. The cases were divided into two groups based on joint replacement status (surgical vs non-surgical) and included in four genome-wide association meta-analyses: surgical knee osteoarthritis (N = 22 525), non-surgical knee osteoarthritis (N = 38 626), surgical hip osteoarthritis (N = 20 221) and non-surgical hip osteoarthritis (N = 17 847). In addition, we tested for genetic correlation between the osteoarthritis groups and the pain phenotypes intervertebral disc disorder, dorsalgia, fibromyalgia, migraine and joint pain. RESULTS: We identified 52 sequence variants associated with knee osteoarthritis (surgical: 17, non-surgical: 3) or hip osteoarthritis (surgical: 34, non-surgical: 1). For the surgical phenotypes, we identified 10 novel variants, including genes involved in autophagy (rs2447606 in ATG7) and mechanotransduction (rs202127176 in PIEZO1). One variant, rs13107325 in SLC39A8, associated more strongly with non-surgical knee osteoarthritis than surgical knee osteoarthritis. For all other variants, significance and effect sizes were higher for the surgical phenotypes. In contrast, genetic correlations with pain phenotypes tended to be stronger in the non-surgical groups. CONCLUSIONS: Our results indicate differences in genetic associations between knee and hip osteoarthritis depending on joint replacement status.

World human neutrophil antigens investigation survey.

BACKGROUND AND OBJECTIVES: Human neutrophil antigens (HNAs) are categorized into five systems: HNA-1 to HNA-5. Given the importance of neutrophils in immunity, we sought to create awareness of the role of HNA diagnostic services in managing immune neutropenia and transfusion-related acute lung injury. To provide health communities all around the world with access to these services, we conducted a survey to create a directory of these HNA diagnostic services. MATERIALS AND METHODS: An Excel table-based survey was created to capture information on the laboratory's location and was emailed to 55 individuals with known or possible HNA investigation activity. The collected data were then summarized and analysed. RESULTS: Of contacted laboratories, the surveys were returned from 23 (38.2%) laboratories; 17 have already established HNA diagnostic (of them 12 were regular participants of the International Granulocyte Immunobiology Workshop [ISBT-IGIW]), 4 laboratories were in the process of establishing their HNA investigation and the remaining 2 responder laboratories, did not conduct HNA investigations. In established laboratories, investigation for autoimmune neutropenia (infancies and adults) was the most frequently requested, and antibodies against HNA-1a and HNA-1b were the most commonly detected. CONCLUSION: The directory of survey respondents provides a resource for health professionals wanting to access HNA diagnostic services. The present study offers a comprehensive picture of HNA diagnostics (typing and serology), identifying weak points and areas for improvement for the first time. Identifying more laboratories involved in HNA diagnostics with limited access to international societies in the field will globally improve HNA diagnostics.

Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes.

Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 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 harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.

Genetic variations in low-to-medium-affinity Fcγ receptors and autoimmune neutropenia in early childhood in a Danish cohort.

Autoimmune neutropenia (AIN) in early childhood is caused by autoantibodies directed against antigens on the neutrophil membrane and is a frequent cause of neutropenia in children. Association of AIN with Fcγ receptor (FCGR) 3B variants is well described. In this study, we investigate genetic variations in the FCGR locus and copy number variation of FCGR3B. A total of 130 antibody-positive AIN patients, 64 with specific anti-HNA-1a antibodies and 66 with broad-reacting anti-FcγRIIIb antibodies, were genotyped with a multiplex ligation probe assay and compared with healthy controls. Positive findings were confirmed with real-time q-PCR. We determined copy numbers of the FCGR2 and FCGR3 genes and the following SNPs: FCGR2A Q62W (rs201218628), FCGR2A H166R (rs1801274), FCGR2B I232T (rs1050501), FCGR3A V176F (rs396991), haplotypes for FCGR2B/C promoters (rs3219018/rs780467580), FCGR2C STOP/ORF and HNA-1 genotypes in FCGR3B (rs447536, rs448740, rs52820103, rs428888 and rs2290834). Generally, associations were antibody specific, with all associations being representative of the anti-HNA-1a-positive group, while the only association found in the anti-FcγRIIIb group was with the HNA-1 genotype. An increased risk of AIN was observed for patients with one copy of FCGR3B; the HNA genotypes HNA-1a, HNA-1aa or HNA-1aac; the FCGR2A 166H and FCGR2B 232I variations; and no copies of FCGR2B 2B.4. A decreased risk was observed for HNA genotype HNA-1bb; FCGR2A 166R; FCGR2B 232T; and one copy of FCGR2B promoter 2B.4. We conclude that in our Danish cohort, there was a strong association between variation in the FCGR locus and AIN. The findings of different genetic associations between autoantibody groups could indicate the presence of two different disease entities and disease heterogeneity.

ABO, secretor, and Lewis carbohydrate histo-blood groups are associated with autoimmune neutropenia of early childhood in Danish patients.

BACKGROUND: Autoimmune neutropenia of early childhood (AIN) is caused by autoantibodies directed against antigens on the neutrophil membrane. The ABO, secretor, and Lewis histo-blood group systems control the expression of carbohydrate antigens and have previously been linked to autoimmune diseases. We aimed to investigate the association between genotypes and the risk of AIN in Danish patients. STUDY DESIGN AND METHODS: One hundred fifty-four antibody-positive AIN patients were included. Controls (n = 400) were healthy unrelated Danish blood donors. Molecular determination of ABO, secretor (FUT2), and Lewis (FUT3) genotypes were determined using real-time polymerase chain reaction (qPCR) or Sanger sequencing to infer the prevalence of Lewis antigens (Lea and Leb ) and secretor (SeSe or Sese) or nonsecretor (sese) phenotypes. RESULTS: Blood type O was more common in controls (46.8%) than in AIN patients (36.4%) (OR = 0.65; p = 0.028). Secretors of H Leb antigens were less frequent among AIN patients (25.2%) than controls (35.0%) (OR = 0.62; p = 0.037). DISCUSSION: ABO blood group antigens and the secretion of these antigens are associated with a diagnosis of AIN. The mechanism underlying the association between autoimmunity and interaction among ABO, secretor, and Lewis genotypes has not yet been elucidated, but several studies indicate a connection to the gut microbiota.

The Social and Psychological Impact of Acne Treatment: A Cross-Sectional Study of Blood Donors.

BACKGROUND: Acne in adolescence and adulthood is believed to have a long-term impact on socioeconomic status (SES) and health-related quality-of-life (HRQoL) in adults. OBJECTIVE: To estimate the cross-sectional prevalence of medically treated (MedTreAc) and untreated acne (UnTreAc) and to characterize its long-term impact in adults. METHODS: A nationwide cross-sectional study on 17 428 blood donors aged 18-35 was performed. Associations among acne and HRQoL, depressive symptoms, total income, and SES were investigated via linear/logistic/multinomial logistic regression analyses adjusted for relevant covariables. HRQoL was measured by the Short Form-12, and depressive symptoms by the Major Depression Inventory. The data were self-reported. RESULTS: Of the participants, 3591 (20.6%) and 1354 (7.8%) identified as the MedTreAc and UnTreAc phenotype, respectively. Neither phenotype was associated with a long-term impact on total income, but the MedTreAc group was associated with being an apprentice/student (OR = 1.26; 95% CI: 1.12, 1.42; P = 1.3×10-4) or high skill-level employee (OR = 1.22, 95% CI: 1.07; 1.39, P = .0023), while self-employment was more common for those with UnTreAc (OR = 1.53; 95% CI: 1.12, 2.06, P = .0061). Additionally, the UnTreAc group was associated with a lower mental HRQoL (SF-12 mental component summary score -1.05, 95% CI: -1.56, -0.54; P = 1.4×10-9) and increased odds ratio of depressive symptoms (OR = 1.44; 95% CI: 1.00, 2.02, P = .046). CONCLUSION: In this population of blood donors, the cumulative prevalence of MedTreAc and UnTreAc were 20.6% and 7.8%, respectively. Untreated acne had a long-term impact on psychosocial well-being in adulthood. It was associated with lower mental HRQoL and higher occurrence of depressive symptoms. Acne was not associated with a lower salary or SES.

Association between human leukocyte antigens (HLAs) and human neutrophil antigens (HNAs) and autoimmune neutropenia of infancy in Danish patients.

BACKGROUND: Autoimmune neutropenia of infancy (AIN) is a frequent cause of neutropenia in children. The disease is caused by antibodies against epitopes on the immunoglobulin G (IgG) Fc receptor type 3b (FcγIIIb). We investigated the possible association of human neutrophil antigens (HNA), human leukocyte antigen (HLA)-DR, and HLA-DQ alleles with AIN and the association of these genotypes with the presence of autoantibodies. METHODS: Eighty AIN cases with a median age of 13.5 months were included. Controls were healthy unrelated Danish blood donors. Anti-HNA-1a autoantibodies were detected using a flow cytometric granulocyte immunofluorescence test (Flow-GIFT) with phenotyped donor cells for detection of antibody specificity. Molecular determination of HNA genotypes was determined using real-time polymerase chain reaction (q-PCR). High-resolution HLA-DRB1 and HLA-DQB1 were determined by next-generation sequencing. RESULTS: Antibodies against HNA-1a were detected in 51% (n = 41) of AIN patients, and anti-HNA-1b was detected in 3% (n = 2) of cases. In 46% of cases, the antibodies were anti-FcγIIIb-reactive. FCGR3B*01+,*02-,*03- was more common (odds ratio, 6.70; P < .0001), and FCGR3B*01-,*02+,*03- was less common (odds ratio, 0.30; P < .0001) among AIN cases. HNA-1a antibodies were significantly more frequent among AIN cases with the FCGR3B*01+,*02-,*03- genotype (odds ratio, 3.86; P < .007). The HLA-DRB1*14 - HLA-DQB1*05:03 haplotype was significantly more common (odds ratio, 7.44; P < .0001) in AIN patients. CONCLUSION: The HLA haplotype HLA-DRB1*14 - DQB1*05:03 is associated with Danish AIN cases. Among Danish AIN patients, anti-HNA-1a is the most common autoantibody, and the antibody is more common in cases with the FCGR3B*01+,*02-,*03- genotype.

No evidence of transfusion transmitted sporadic Creutzfeldt-Jakob disease: results from a bi-national cohort study.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is an uncommon, invariably fatal, neurodegenerative disorder that presents as progressive dementia with concurrent motor symptoms and myoclonia. The pathophysiology involves prion protein misfolding and spreading in a self-catalyzed manner. It has been shown to be transmissible through tissue transplants. Variant CJD (vCJD), a subtype of the disease is also transmissible through transfusion of blood products. This study aims to corroborate the scarce data that suggest that sporadic CJD (sCJD) is not transmitted via blood transfusion. METHODS AND STUDY DESIGN: A retrospective cohort study was performed, using data from the bi-national Scandinavian Donations and Transfusions (SCANDAT2) database containing data on blood donors, donations, transfusions, and transfused patients in Sweden and Denmark since 1968 and 1982, respectively. Mortality and medical data were collected from nationwide health care and population registries. Donors with subsequent CJD were identified, as well as recipients of blood products from these donors. A second analysis was performed, screening for clustering of CJD cases from donors without a CJD diagnosis. RESULTS: We identified 39 donors with a subsequent diagnosis of sCJD. No cases of CJD occurred among the 883 recipients of blood products from these donors. A total of 89 CJD cases were identified among recipients of transfusions. No clustering of cases from the same donor occurred. DISCUSSION: Using data from a large, bi-national database of transfused patients, we find no evidence of sCJD transmission. Our data adds to the growing body of evidence indicating that sCJD is not transfusion transmitted.

Prevalence and socio-demographic characteristics of persons who have never had a headache among healthy voluntary blood donors - a population-based study.

INTRODUCTION: Headache is an extremely prevalent disorder with a lifetime prevalence of 90-99%. However, a small fraction of people never experiences a headache. Research on people without headache could uncover protective factors in headache, but to our knowledge no study on headache-free individuals has been published. We aim to estimate the prevalence of headache-free individuals among Danish blood donors, and to describe the socio-demographics and health factors of headache-free participants. MATERIALS AND METHODS: In all, 38,557 healthy volunteers were recruited as part of the Danish Blood Donor Study. Headache-free participants were identified based on the question "Have you ever experienced a headache of any kind?". Utilising the Danish registries and self-reported questionnaires, we analysed socio-demographic and lifestyle factors using logistic regression adjusted for age and sex. RESULTS: The prevalence of headache-free individuals was 4.1% (n = 1362) with a female-male ratio of 1:2.2. To be headache free was significantly associated with an employment status as a student, a low level of income and a regular alcohol consumption. DISCUSSION: The prevalence of headache-free individuals was comparable to population-wide studies of headache. To be headache free was not associated with a high socio-economic status. Further studies on people without headache will hopefully reveal protective factors in headache, and this novel approach might be useful in other very prevalent disorders.

Large-scale study of Toxoplasma and Cytomegalovirus shows an association between infection and serious psychiatric disorders.

BACKGROUND: Common infectious pathogens have been associated with psychiatric disorders, self-violence and risk-taking behavior. METHODS: This case-control study reviews register data on 81,912 individuals from the Danish Blood Donor Study to identify individuals who have a psychiatric diagnosis (N = 2591), have attempted or committed suicide (N = 655), or have had traffic accidents (N = 2724). For all cases, controls were frequency matched by age and sex, resulting in 11,546 participants. Plasma samples were analyzed for immunoglobulin G (IgG) antibodies against Toxoplasma gondii and cytomegalovirus (CMV). RESULTS: T. gondii was detected in 25·9% of the population and was associated with schizophrenia (odds ratio [OR], 1·47; 95% confidence interval [CI], 1·03-2·09). Accounting for temporality, with pathogen exposure preceding outcome, the association was even stronger (IRR, 2·78; 95% CI, 1·27-6·09). A very weak association between traffic accident and toxoplasmosis (OR, 1·11; 95% CI, 1·00-1·23, p = 0.054) was found. CMV was detected in 60·8% of the studied population and was associated with any psychiatric disorder (OR, 1·17; 95% CI, 1·06-1·29), but also with a smaller group of neurotic, stress-related, and somatoform disorders (OR, 1·27; 95% CI, 1·12-1·44), and with attempting or committing suicide (OR, 1·31; 95% CI, 1·10-1·56). Accounting for temporality, any psychiatric disorder (IRR, 1·37; 95% CI, 1·08-1·74) and mood disorders (IRR, 1·43; 95% CI, 1·01-2·04) were associated with exposure to CMV. No association between traffic accident and CMV (OR, 1·06; 95% CI, 0·97-1·17) was found. CONCLUSIONS: This large-scale serological study is the first study to examine temporality of pathogen exposure and to provide evidence of a causal relationship between T. gondii and schizophrenia, and between CMV and any psychiatric disorder.

Oral iron supplementation is not associated with short-term risk of infections: results from the Danish Blood Donor Study.

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.

Life events and donor lapse among blood donors in Denmark.

BACKGROUND AND OBJECTIVES: The likelihood of donating blood changes over the life course, with life events shown to influence entry to and exit from the donor population. While these previous findings provide valuable insights for donor management, blood collection agencies need to be cautious about generalizing findings to other countries as blood donor behaviour is context-specific. To examine cross-country variations in donor behaviour, the repeatability of a previous Dutch study on life events and blood donor lapse is examined by using a sample of Danish donors. MATERIALS AND METHODS: Register data from Statistics Denmark was linked to the Scandinavian Donations and Transfusions database (n = 152 887). Logistic regressions were conducted to examine the association between life events in 2009-2012 and blood donor lapse in 2013-2014. RESULTS: Of the total sample, 69 079 (45·2%) donors lapsed. Childbirth and losing a job increased the lapsing risk by 11% and 16%, respectively, while health-related events in the family (i.e. blood transfusion, disease and death) decreased the lapsing risk by 5%, 7% and 9%, respectively. CONCLUSION: Life events are associated with donor lapse of Danish donors. These results are comparable to previous findings from the Netherlands (i.e. childbirth and labour market transitions increased lapsing risk; health-related events decreased lapsing risk), with two thirds of the associations being in the same direction. Differences between study results were mainly related to effect sizes and demographic compositions of the donor pools. We argue contextual factors to be of importance in blood donor studies.

Comorbidity of migraine with ADHD in adults.

BACKGROUND: Migraine and Attention Deficit and Hyperactivity Disorder (ADHD) have been found to be associated in child and adolescent cohorts; however, the association has not been assessed in adults or otherwise healthy population. Assessing the comorbidity between ADHD and migraine may clarify the etiopathology of both diseases. Thus, the objective is to assess whether migraine (with and without visual disturbances) and ADHD are comorbid disorders. METHODS: Participants from the Danish Blood Donor Study (N = 26,456, age 18-65, 46% female) were assessed for migraine and ADHD using the ASRS ver 1.1 clinically validated questionnaire and self-reported migraine in a cross-sectional study. Logistic regression was used to examine the comorbidity between migraine and ADHD, and their associated endophenotypes. RESULTS: Migraine was strongly associated with ADHD (OR = 1.8, 95% CI = 1.5-2.1), (238/6152 vs 690/19,376). There was a significant interaction between age and gender, with comorbidity increasing with age and female sex. Post-hoc analysis showed that migraine with visual disturbance was generally associated with a marginally higher risk of ADHD and this was independent of ADHD endophenotypes. CONCLUSION: Migraine and ADHD were demonstrated to be comorbid disorders; the association with ADHD was most prominent for participants with migraine with visual disturbances. Future studies will elucidate which genetic and environmental factors contribute to migraine-ADHD comorbidity.

Length of Storage of Red Blood Cells and Patient Survival After Blood Transfusion: A Binational Cohort Study.

BACKGROUND: Possible negative effects, including increased mortality, among persons who receive stored red blood cells (RBCs) have recently garnered considerable attention. Despite many studies, including 4 randomized trials, no consensus exists. OBJECTIVE: To study the association between the length of RBC storage and mortality in a large population-based cohort of patients who received transfusions, allowing detection of small yet clinically significant effects. DESIGN: Binational cohort study. SETTING: All transfusion recipients in Sweden and Denmark. PATIENTS: 854 862 adult patients who received transfusions from 2003 to 2012. MEASUREMENTS: Patients were followed from first blood transfusion. Relative and absolute risks for death in 30 days or 1 year in relation to length of RBC storage were assessed by using 3 independent analytic approaches. All analyses were conducted by using Cox proportional hazards regression. RESULTS: Regardless of the analytic approach, no association was found between the length of RBC storage and mortality. The difference in 30-day cumulative mortality between patients receiving blood stored for 30 to 42 days and those receiving blood stored for 10 to 19 days was -0.2% (95% CI, -0.5% to 0.1%). Even among patients who received more than 6 units of RBCs stored for 30 days or longer, the hazard ratio of death was 1.00 (CI, 0.96 to 1.05) compared with those who received no such units. LIMITATION: Observational study; risk of confounding by indication. CONCLUSION: Consistent with previous randomized trials, this study found no association between the length of storage of transfused RBCs and patient mortality. Results were homogeneous, with differences in absolute mortality consistently less than 1% among the most extreme exposure categories. These findings suggest that the current practice of storing RBCs for up to 42 days does not need to be changed. PRIMARY FUNDING SOURCE: The Swedish Research Council, Swedish Heart-Lung Foundation, Swedish Society for Medical Research, Strategic Research Program in Epidemiology at Karolinska Institutet, and Danish Council for Independent Research.

ABO Blood Group and Risk of Thromboembolic and Arterial Disease: A Study of 1.5 Million Blood Donors.

BACKGROUND: ABO blood groups have been shown to be associated with increased risks of venous thromboembolic and arterial disease. However, the reported magnitude of this association is inconsistent and is based on evidence from small-scale studies. METHODS AND RESULTS: We used the SCANDAT2 (Scandinavian Donations and Transfusions) database of blood donors linked with other nationwide health data registers to investigate the association between ABO blood groups and the incidence of first and recurrent venous thromboembolic and arterial events. Blood donors in Denmark and Sweden between 1987 and 2012 were followed up for diagnosis of thromboembolism and arterial events. Poisson regression models were used to estimate incidence rate ratios as measures of relative risk. A total of 9170 venous and 24 653 arterial events occurred in 1 112 072 individuals during 13.6 million person-years of follow-up. Compared with blood group O, non-O blood groups were associated with higher incidence of both venous and arterial thromboembolic events. The highest rate ratios were observed for pregnancy-related venous thromboembolism (incidence rate ratio, 2.22; 95% confidence interval, 1.77-2.79), deep vein thrombosis (incidence rate ratio, 1.92; 95% confidence interval, 1.80-2.05), and pulmonary embolism (incidence rate ratio, 1.80; 95% confidence interval, 1.71-1.88). CONCLUSIONS: In this healthy population of blood donors, non-O blood groups explain >30% of venous thromboembolic events. Although ABO blood groups may potentially be used with available prediction systems for identifying at-risk individuals, its clinical utility requires further comparison with other risk markers.

Epidemiology of Massive Transfusion: A Binational Study From Sweden and Denmark.

OBJECTIVE: There is an increasing focus on massive transfusion, but there is a paucity of comprehensive descriptions of the massively transfused patients and their outcomes. The objective of this study is to describe the incidence rate of massive transfusion, patient characteristics, and the mortality of massively transfused patients. DESIGN: Descriptive cohort study. SETTING: Nationwide study with data from Sweden and Denmark. PATIENTS: The study was based on the Scandinavian Donations and Transfusions database, including all patients receiving 10 or more red cell concentrate transfusions in Sweden from 1987 and in Denmark from 1996. A total of 92,057 patients were included. Patients were followed until the end of 2012. MEASUREMENTS AND MAIN RESULTS: Descriptive statistics were used to characterize the patients and indications. Post transfusion mortality was expressed as crude 30-day mortality and as long-term mortality using the Kaplan-Meier method and using standardized mortality ratios. The incidence of massive transfusion was higher in Denmark (4.5 per 10,000) than in Sweden (2.5 per 10,000). The most common indication for massive transfusion was major surgery (61.2%) followed by trauma (15.4%). Massive transfusion due to obstetrical bleeding constituted only 1.8%. The overall 5-year mortality was very high (54.6%), however with large differences between indication groups, ranging from 91.1% among those transfused for a malignant disease without surgery to 1.7% among patients transfused for obstetrical bleeding. The early standardized mortality ratios were high and decreased thereafter, but remained elevated throughout the time period. CONCLUSIONS: This large-scale study based on nationwide data from Sweden and Denmark describes the complete range of massive transfusion. We report a nonnegligible incidence and both a high absolute mortality and high standardized mortality ratio. The general pattern was similar for Sweden and Denmark, and we believe that similar patterns may be found in other high-resource countries. The study provides a relevant background for clinicians and researchers for designing future studies in this field.

Blood donation and risk of polycythemia vera.

BACKGROUND: It has been suggested that blood donors could have an increased risk of polycythemia vera (PV). However, no study has assessed whether frequent donors have a higher PV risk than less frequent donors. STUDY DESIGN AND METHODS: From the Scandinavian Donations and Transfusions (SCANDAT2) database, we established a cohort of blood donors who had donated whole blood at least once between 1980 and 2012. Within this cohort we first assessed the risk of PV, comparing the donors to the general population using standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CIs). To assess the association between frequency of blood donation and risk of PV we then conducted a case-control study nested within the cohort, where we compared prior donation activity among donors who were diagnosed with PV and matched controls. Here odds ratios (ORs) were used as measures of relative risk comparing donors with different donation frequency. RESULTS: Among 1.4 million donors in the cohort a total of 271 donors developed PV, yielding a SIR of 1.00 (95% CI, 0.89-1.13) compared to the general population. The nested case-control study showed no association between donation frequency and risk of PV. The OR of PV comparing donors who had made at least 33 donations in the period from 3 to 22 years before diagnosis of the case, to donors with one to eight donations in the same period was 1.01 (95% CI, 0.51-1.97). CONCLUSIONS: We find no evidence of excess risk of PV among blood donors or of an association between donation frequency and PV risk.

Flow cytometric measurement of platelet-associated immunoglobulin in children with newly diagnosed Immune Thrombocytopenia.

OBJECTIVE: To explore the clinical utility of measuring platelet-associated immunoglobulin (PAIG) at the time of diagnosis in children with immune thrombocytopenia (ITP). METHODS: PAIG was measured by flow cytometry using fluorescent murine anti-IgG and anti-IgM. In a cohort of 88 children with ITP, the assay was performed within 15 days of diagnosis and before any treatment in 68 cases. We reviewed the results and examined the relation of isotype profile and degree of elevation to clinical manifestations and course of disease. RESULTS: PAIG was elevated in 74%, with raised IgM being more frequent than IgG (63% vs. 44%, P = 0.04) and with isotype profile depending on symptom onset. Platelet counts at presentation were similar in all subgroups, but mucosal bleeding was less frequent in PAIG-negative patients compared to the positive groups (5.5% vs. 34%, P = 0.03). Duration of thrombocytopenia was similar in negative and positive cases, but during follow-up, significant bleeding events occurred less frequently in PAIG-negative patients (0% vs. 14%, P = 0.18). CONCLUSION: Approximately one-quarter of children are PAIG-negative, and these children have milder bleeding tendency at diagnosis and lower morbidity during follow-up. Raised PAIG possibly may cause some degree of platelet dysfunction.