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Comorbid conditions are highly prevalent in chronic lymphocytic leukemia (CLL), nevertheless, detailed information on the association of specific comorbidities with CLL prognosis is missing. Using Danish, nation-wide registers, we followed consecutive patients from CLL-diagnosis in 1997-2018, until death or end of follow-up. Sub-grouping of comorbidities was defined using a modified Charlson comorbidity index. Patients were matched on sex, date of birth (±1 month), and region of residency with up to ten comparators from the general population. In total, 9170 patients with CLL were included in the study, with a median of 5.0 years of follow-up. All comorbid conditions studied were individually associated with increased mortality, and many also with increased cause-specific mortality, related or unrelated to CLL. Comorbidity correlated with increased mortality from infections and cardiovascular disease. CLL patients, particularly older, had a significant loss of lifetime compared with the general population. This study highlights a large subgroup of comorbid CLL patients with an unmet treatment-need and missing efficacy and safety data on treatment, who are under-prioritized in clinical trials. Also, studies assessing interventions that may provide better tolerability of treatment in older or comorbid patients, with cancer in general, and CLL in particular, are warranted.

Objectives To explore the impact of COVID-19 lockdown on premature birth rates in Denmark Design Nationwide register-based prevalence proportion study. Participants 31,180 live singleton infants born in Denmark between March 12, and April 14, from 2015 to 2020 Main outcome measures The Main outcome measure was the odds ratio of premature birth, per preterm category, during the lockdown period compared with the calendar match period in the five previous years. Results A total of 31 180 newborns were included in the study period, of these 58 were born extremely premature (gestational age below 28 weeks). The distribution of gestational ages was significantly different (p = 0.004) during the lockdown period compared to the previous five years. The extremely premature birth rate during the lockdown was significantly lower than the corresponding mean rate for the same dates in the previous years (odds ratio 0.09 [95 % CI 0.01 - 0.04], p < 0.001). No significant difference between the lockdown and previous years was found for other gestational age categories. Conclusions The birth rate of extremely premature infants decreased significantly (~90 % reduction) during the Danish nationwide lockdown from a stable rate in the preceding five years. The reasons for this decrease are unclear. Identification of possible causal mechanisms might stimulate changes in clinical practice. Ideally, some cases of extreme prematurity are preventable which may decrease infant morbidity and mortality.

Introduction: There are conflicting results whether elevated hematocrit is associated with an increased risk of thromboembolic events in individuals without polycythemia vera. To assess the risk of vascular events in relation to hemoglobin concentration, we conducted a large population-based cohort study based on Scandinavian health registers. Materials and methods: We included 1,538,019 Swedish and Danish blood donors between 1987 and 2012. Hazard ratios (HRs) of arterial and venous thrombosis were estimated using Cox regression. Additionally, we fitted person-stratified models where each donor was compared only to him-/herself. Results: The risk of myocardial infarction and ischemic stroke increased with higher hemoglobin concentration in both men and women. The HRs for myocardial infarction and ischemic stroke in men with hemoglobin concentration ≥ 17.5 g/dL were 3.52 (95% confidence interval [CI], 2.85–4.36) and 2.36 (95% CI, 1.63–3.43), respectively, compared to the reference group. The corresponding HRs for women with hemoglobin concentration ≥ 16.0 g/dL were 3.22 (2.12–4.89) and 2.35 (1.37–4.02) for myocardial infarction and ischemic stroke, respectively. The risk of venous thrombosis was highest in men with subnormal hemoglobin concentration (

It has been proposed that children with acute lymphoblastic leukemia (ALL) are born with a dysregulated immune function that together with postnatal environmental exposures causes childhood ALL. Despite its importance for the understanding of ALL etiology, this hypothesis has been inadequately explored. In a population-based case–control study, we measured the concentrations of 10 cytokines and other inflammatory markers on neonatal dried blood spots from 178 children who at ages 1 to 9 years were diagnosed with B-cell precursor ALL and 178 matched controls. Through linkage with Danish nationwide registers, we also assessed whether neonatal inflammatory markers were associated with previously demonstrated risk factors for childhood ALL. Children who developed B-cell precursor ALL had significantly lower neonatal concentrations of IL8, soluble IL6 receptor (sIL6R) α, TGFβ1, monocyte chemotactic protein (MCP)-1, and C-reactive protein (CRP) and higher concentrations of IL6, IL17, and IL18 compared with matched controls. Concentrations of IL10 were below the detection level for both patients and controls. Birth order (IL18 and CRP), gestational age (sIL6Rα, TGFβ1, and CRP), and sex (sIL6Rα, IL8, and CRP), but not maternal age, infections during pregnancy, birth weight nor mode of delivery were significantly associated with the neonatal concentrations of inflammatory markers. Our findings support the hypothesis that children who later develop B-cell precursor ALL are born with a dysregulated immune function. Significance: Children who develop acute lymphoblastic leukemia are immunologically distinct at birth and could potentially react abnormally to infections in early childhood. Cancer Res; 78(18); 5458–63. ©2018 AACR.

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.

Background: Both hepatitis B and C viruses were transmitted through blood transfusion before implementation of donor screening. The existence of additional, yet unknown transfusion transmittable agents causing liver disease could have important public health implications. Methods: Analyses were based on the Scandinavian Donations and Transfusions (SCANDAT2) database. Cox regression models were used to estimate the hazard ratio (HR) of developing chronic liver disease in recipients of blood from donors who later developed any chronic liver disease compared to recipients who received blood transfusion from healthy donors. We also studied whether the risk of liver disease was increased in patients who received units from ‘high-risk’ donors, defined as donors who had a higher than expected occurrence of liver disease amongst their previous recipients. All analyses were stratified before and after 1992 to account for the effect of screening for hepatitis C virus. Results: A total of 1 482 922 transfused patients were included in the analyses. Analyses showed evidence of transfusion transmission of liver diseases before, but not after the implementation of hepatitis C virus screening in 1992, with HRs for any liver disease of 1.38 [95% confidence interval (CI), 1.30–1.46] and 0.99 (95% CI, 0.91–1.07), before and after 1992, respectively. Similarly, blood components from ‘high-risk’ donors conferred increased risks before, but not after 1992. Conclusions: Our data provide no evidence for transfusion transmission of agents causing liver disease after the implementation of screening for hepatitis B and C, and suggest that if such transmission does occur, it is rare.

BACKGROUND 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. STUDY DESIGN AND METHODS 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. RESULTS 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. CONCLUSION 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.

AIMS: This study aimed at quantifying the healthy donor effect by comparing self-perceived mental and physical health between blood donors and non-donors.BACKGROUND: In theory, the selection process known as the healthy donor effect should result in better self-perceived, health-related quality of life in donors than in non-donors.METHODS: The Short Form-12 data from the Danish Twin Registry (DTR) was compared with the data from the Danish Blood Donor Study (DBDS). Data on age, sex and smoking status were included in the analyses. The multivariable linear regression analysis was stratified by sex and age group intervals. Outcome variables were the mental component score (MCS) and the physical component score (PCS).RESULTS: A total of 28 982 and 36 913 participants from the DTR and the DBDS, respectively, were included in this study. Younger donors had higher MCS than non-donors, whereas MCS was only marginally high in older donors compared with non-donors. In contrast, PCS was almost similar for both young donors and non-donors. With the increase in age, non-donors had lower PCS than donors.CONCLUSIONS: Two selection patterns were revealed. Among young individuals, better self-perceived mental health was associated with a blood donor. With the increase in age, better self-perceived physical health was associated with blood donation.

Background It has been proposed that childhood vaccinations protect against acute lymphoblastic leukaemia (ALL) in children by modulation of future responses to common infections in childhood. However, the available studies provide inconsistent findings, and population-based cohort studies with longitudinal information on vaccinations are lacking. Methods In a register-based cohort of all children born in Denmark from 1 January 1990 to 31 December 2008, followed up until age 15 years or 31 December 2009 ( n = 1 225 404), we evaluated exposure to childhood vaccination and risk of childhood ALL, including information on ALL subtypes. Using Cox regression, we estimated hazard ratios (HRs) comparing vaccinated with unvaccinated children. Results Childhood ALL was diagnosed in 490 children during 10 829 194 person-years of follow-up. Neither the total number of vaccine doses received nor exposure to each vaccination given in childhood was associated with altered risk of ALL, including the following: (i) Haemophilus influenzae type b [HR, 1.04; 95% confidence interval (CI), 0.68-1.61]; ii) measles, mumps and rubella (HR, 1.01; 95% CI, 0.76-1.34); iii) whole-cell pertussis (HR, 1.10; 95% CI, 0.51-2.39); and iv) diphtheria, tetanus and inactivated polio (HR, 1.14; 95% CI, 0.42-3.13). Analyses conducted according to ALL subtypes defined by immunopheno- and karyotypes showed no association with childhood vaccination. Conclusions This nationwide cohort study provides no support of the proposed protective effect of childhood vaccination against childhood ALL.

BACKGROUND 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. STUDY DESIGN AND METHODS 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. RESULTS 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). CONCLUSIONS 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.

BACKGROUND Citrate anticoagulation during apheresis induces transient alterations in calcium homeostasis. It is unknown whether the repeated, transient alterations in calcium homeostasis experienced by repeated apheresis donors affects bone turnover to increase fracture risk. Our aim was to investigate the risk of osteoporotic and nonosteoporotic fracture among voluntary, frequent apheresis donors. STUDY DESIGN AND METHODS All apheresis donors were identified from the Scandinavian Donations and Transfusions database (SCANDAT2), which includes information on over 1.6 million blood donors from Sweden and Denmark from the years 1968 and 1981, respectively. Only data from Sweden were used for these analyses. Information on fractures was obtained by linking SCANDAT2 to hospital registers. Poisson regression was used to compute incidence rate ratios of fractures in relation to the cumulative number of apheresis donations, both overall and in fixed time windows. RESULTS In total, 140,289 apheresis donors (67,970 women and 72,319 men) were identified from the SCANDAT2 database and were followed for up to 23 years. We observed no association between the frequency of apheresis donation and the risk of fracture either in the overall study period or during fixed-length time windows. The incidence rate ratio of fractures in donors who had made 100 or more cumulative apheresis donations was 0.99 (95% confidence interval, 0.92-1.06) compared with donors who had made from 9 to 24 donations. The results were similar in analyses stratified by sex and restricted to postmenopausal women. CONCLUSIONS The absence of an association between repeated apheresis donation and fracture risk indicates that apheresis collection is safe with regard to bone health.

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.

Background:\ud Infectious mononucleosis (IM) is a common adverse presentation of primary infection with Epstein-Barr virus (EBV) in adolescence and later, but is rarely recognized in early childhood where primary EBV infection commonly occurs. It is not known what triggers IM, and also not why IM risk upon primary EBV infection (IM attack rate) seemingly varies between children and adolescents. IM symptoms may be severe and persist for a long time. IM also markedly elevates the risk of Hodgkin lymphoma and multiple sclerosis for unknown reasons. The way IM occurrence depends on age and sex is incompletely described and hard to interpret etiologically, because it depends on three quantities that are not readily observable: the prevalence of EBV-naϊve persons, the hazard rate of seroconverting and the attack rate, i.e. the fraction of primary EBV infections that is accompanied by IM. We therefore aimed to provide these quantities indirectly, to obtain epidemiologically interpretable measures of the dynamics of IM occurrence to provide etiological clues.\ud \ud Methods and findings:\ud We used joint modeling of EBV prevalence and IM occurrence data to provide detailed sex- and age-specific EBV infection rates and IM attack rates and derivatives thereof for a target population of all Danes age 0–29 years in 2006–2011. We demonstrate for the first time that IM attack rates increase dramatically rather precisely in conjunction to typical ages of puberty onset. The shape of the seroconversion hazard rate for children and teenagers confirmed a priori expectations and underlined the importance of what happens at age 0–2 years. The cumulative risk of IM before age 30 years was 13.3% for males and 22.4% for females. IM is likely to become more common through delaying EBV infection in years to come.\ud \ud Conclusions:\ud The change in attack rate at typical ages of puberty onset suggests that the immunologic response to EBV drastically changes over a relatively short age-span. We speculate that these changes are an integrated part of normal sexual maturation. Our findings may inform further etiologic research into EBV-related diseases and vaccine design. Our methodology is applicable to the epidemiological study of any infectious agent that establishes a persistent infection in the host and the sequelae thereof.

Identification of individuals at risk of developing disease comorbidities represents an important task in tackling the growing personal and societal burdens associated with chronic diseases. We employed machine learning techniques to investigate to what extent data from longitudinal, nationwide Danish health registers can be used to predict individuals at high risk of developing type 2 diabetes (T2D) comorbidities. Leveraging logistic regression-, random forest- and gradient boosting models and register data spanning hospitalizations, drug prescriptions and contacts with primary care contractors from >200,000 individuals newly diagnosed with T2D, we predicted five-year risk of heart failure (HF), myocardial infarction (MI), stroke (ST), cardiovascular disease (CVD) and chronic kidney disease (CKD). For HF, MI, CVD, and CKD, register-based models outperformed a reference model leveraging canonical individual characteristics by achieving area under the receiver operating characteristic curve improvements of 0.06, 0.03, 0.04, and 0.07, respectively. The top 1,000 patients predicted to be at highest risk exhibited observed incidence ratios exceeding 4.99, 3.52, 1.97 and 4.71 respectively. In summary, prediction of T2D comorbidities utilizing Danish registers led to consistent albeit modest performance improvements over reference models, suggesting that register data could be leveraged to systematically identify individuals at risk of developing disease comorbidities.

Importance Evidence regarding associations of blood donor sex with mortality among red blood cell transfusion recipients is conflicting. Objective To study associations of donor sex and prior pregnancy with mortality of transfusion recipients. Design, Setting, and Participants Data from 3 retrospective cohorts of transfusion recipients (the Kaiser Permanente Northern California [KPNC] and Recipient Epidemiology and Donor Evaluation Study-III [REDS-III] databases of data from January 2013 to December 2016 and the Scandinavian Donations and Transfusions [SCANDAT] database with data from January 2003 to December 2012) were analyzed. Final dates of follow-up were December 31, 2016, for the KPNC and REDS-III cohorts and December 31, 2012, for the SCANDAT cohort. Stratified Cox regression models were used to estimate associations between donor exposure groups with risk of mortality, adjusting for the number of red blood cell unit transfusions. Exposures The number of transfused red blood cell units from female donors, previously pregnant donors, and sex-discordant donors (male donor and female recipient or female donor and male recipient). Main Outcomes and Measures In-hospital mortality. Results The study population included 34 662 patients (mean age, 69 years; 18 652 [54%] women) from the KPNC cohort, 93 724 patients (mean age, 61 years; 48 348 [52%] women) from the REDS-III cohort, and 918 996 patients (mean age, 72 years; 522 239 [57%] women) from the SCANDAT cohort. The median number of red blood cell transfusions per patient was 3 in the KPNC cohort, 2 in the REDS-III cohort, and 3 in the SCANDAT cohort. The percentage of transfusions from previously pregnant or parous donors was 9% in the KPNC cohort, 18% in the REDS-III cohort, and 25% in the SCANDAT cohort. The percentage of transfusions in the 3 cohorts from female donors ranged from 39% to 43%, from previously pregnant or parous donors ranged from 9% to 25%, and from sex-discordant donors ranged from 44% to 50%. There were 3217 in-hospital deaths in the KPNC cohort, 8519 in the REDS-III cohort, and 198 537 in the SCANDAT cohort. There were no statistically significant associations between any of the 3 donor exposures and in-hospital mortality in the 3 cohorts. Hazard ratios for in-hospital mortality per transfused unit from female donors were 0.99 (95% CI, 0.96-1.03) for the KPNC cohort, 1.00 (95% CI, 0.99-1.01) for the REDS-III cohort, and 1.00 (95% CI, 0.99-1.00) for the SCANDAT cohort. For units from previously pregnant or parous female donors, hazard ratios were 1.00 (95% CI, 1.00-1.01) for the KPNC cohort, 1.01 (95% CI, 0.98-1.03) for the REDS-III cohort, and 1.00 (95% CI, 1.00-1.01) for the SCANDAT cohort. For units from sex-discordant transfusions, hazard ratios were 1.02 (95% CI, 0.99-1.05) for the KPNC cohort, 0.99 (95% CI, 0.98-1.00) for the REDS-III cohort, and 1.00 (95% CI, 0.99-1.00) for the SCANDAT cohort. Conclusions and Relevance Among red blood cell transfusion recipients, transfusions from female, previously pregnant, or sex-discordant donors were not significantly associated with increased mortality.

BACKGROUND: Health-Related Quality of Life (HRQL) represent individuals' subjective assessment of their mental and physical well-being, and is highly predictive of future health. C-reactive protein (CRP) is a well-established marker of inflammation. Low-grade inflammation (LGI), defined as slightly increased CRP levels, is associated with increased risk of several diseases. LGI may reflect subclinical pathology, which could affect individual's subjective health assessment. This study aimed to examine whether LGI has an independent impact on self-reported health or rather is a mediator of a confounder in a large population of healthy individuals.METHODS: Plasma CRP levels were measured in 17,024 participants from the Danish Blood Donor Study (DBDS). All participants completed a standard questionnaire including smoking status, and the 12-item short-form health survey (SF-12), which is a widely used scale for HRQL. SF-12 is reported as a mental (MCS) and physical (PCS) score. The relationship between LGI (defined as a plasma CRP level between 3 mg/L and 10 mg/L) and MCS or PCS was explored by mediation analysis and adjusted multivariable linear regression analysis. Multiple imputation modelling was used to remedy missing values. The analyses were stratified according to sex and use of combined oral contraception (OC).RESULTS: In the study, 1,542 (10.3%) participants had LGI. PCS was associated with LGI in all strata, i.e. women using OC: RC = -0.36 points lower PCS in participants with LGI vs no LGI, CI: -0.94 to -0.19, women not using OC: RC = -0.63, CI: -1.05 to -0.21 and men: RC = -0.76, CI: -1.10 to -0.42. But LGI had no impact on MCS. Predictors of lower PCS included obesity, current smoking, and waist circumference in all strata. Physical activity in leisure time was the only factor positively associated with PCS. Age and physical activity in leisure time was associated with increased MCS in all strata whereas current smoking was the only strong predictor of a reduction in MCS. Only a small effect of smoking on PCS was mediated through LGI.CONCLUSION: In this population of healthy individuals, LGI had independent impact on lower self-rated physical health score in HRQL in both sexes, but was not associated with self-rated mental health score. A small and significant effect of smoking on physical health score was mediated through LGI.

Patients with chronic lymphocytic leukemia and unmutated immunoglobulin heavy-chain variable region gene (IGHV) have inferior survival from time of treatment in clinical studies. We assessed real-world outcomes based on mutational status and treatment regimen in a nationwide population-based cohort, comprising all 4,135 patients from the Danish chronic lymphocytic leukemia registry diagnosed between 2008 and 2017. In total, 850 patients with known mutational status received treatment: 42% of patients received intensive chemoimmunotherapy consisting of fludarabine, cyclophosphamide plus rituximab, or bendamustine plus rituximab; 27% received chlorambucil in combination with anti-CD20 antibodies or as monotherapy, and 31% received other, less common treatments. No difference in overall survival from time of first treatment according to mutational status was observed, while treatment-free survival from start of first treatment was inferior for patients with unmutated IGHV. The median treatment-free survival was 2.5 years for patients treated with chlorambucil plus anti-CD20, and 1 year for those who received chlorambucil monotherapy. The 3-year treatment-free survival rates for patients treated with fludarabine, cyclophosphamide plus rituximab, and bendamustine plus rituximab were 90% and 91% for those with mutated IGHV, and 76% and 53% for those with unmutated IGHV, respectively, and the 3-year overall survival rates were similar for the two regimens (86-88%). Thus, it appears that, in the real-world setting, patients progressing after intensive chemoimmunotherapy as first-line therapy can be rescued by subsequent treatment, without jeopardizing their long overall survival. Intensive chemoimmunotherapy remains a legitimate option alongside targeted agents, and part of a personalized treatment landscape in chronic lymphocytic leukemia, while improved supportive care and treatment options are warranted for unfit patients.

BACKGROUND: Due to physiological demands, children and premenopausal women are at risk of developing iron deficiency. In premenopausal women, the risk may be further increased by repeated whole blood donations. Short-term consequences of iron deficiency in infancy include impaired cognitive development and lower IQ scores. This prompts concern that maternal iron deficiency before or during pregnancy may have long-term consequences for the offspring, for example, by affecting scholastic attainment. The aim of this study was to evaluate if prepregnancy donation intensity is associated with offspring scholastic attainment measured as grade averages in standardized national written examinations in Denmark. STUDY DESIGN AND METHODS: By using the Danish personal identification number as key, we obtained information on donation intensity before pregnancy, school grade, year of graduation, age of the students, students' sex, and parental length of education and income from various nationwide registers. Linear regression analyses were performed, with grade average as outcome and maternal donation status as explanatory variable (nondonor, n = 177,078; low-frequency donor, n = 4995 [one to five donations in the 3 years before pregnancy]; high-frequency donor, n = 414 [six or more donations in the 3 years before pregnancy), and further adjusted for the covariates listed above. RESULTS: Adjusted normalized (mean, 0; standard deviation [SD], 1) test scores were statistically significantly higher for children of active female donors compared with children of nondonors (SD, 0.104; 95% confidence interval, 0.079–0.129). We observed no differences in scholastic attainment between children of low-frequency donors and high-frequency donors. CONCLUSION: Prepregnancy donation intensity, as a proxy of iron stores, is not associated with subsequent offspring scholastic attainment.

BACKGROUND AND OBJECTIVES: Chronic red-cell transfusions may be an indispensable part of patient treatment and may require early intervention to avoid adverse transfusion effects. The population of chronic transfusion recipients including common diagnoses and survival remains poorly characterised. Thus, the objective was to examine the complete range of chronic transfusion recipients, including demographic and patient characteristics and survival.MATERIALS AND METHODS: All patients who received their first transfusion in Sweden or Denmark from January 1, 2002 to December 31, 2010 were followed up for subsequent transfusion episodes until December 31, 2012. Data on patient characteristics at time of the first and subsequent transfusions were retrieved from the national registers. We estimated the proportion of transfused patients who experienced 20 or more red-cell transfusion episodes (with an episode defined as all transfusions received 4 days or less apart) and characterised this patient population with respect to diagnoses, demographics and survival.RESULTS: Among 893 117 first time red-cell transfusion recipients, 6157 (0·7%) experienced 20 or more episodes in total. The most common diagnoses among these patients were haematologic malignancies followed by non-haematologic malignancies and non-malignant blood and immune system related diseases. On average, chronically transfused patients had a median survival of less than 1 year following their 20th transfusion episode.CONCLUSION: This study provides an overview of patient characteristics related to repeat red-cell transfusions and of the amount of red-cell transfusion episodes administered during a 10-year period in two countries. Patients who become chronically transfused suffer from diseases with poor prognosis.

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.

The long preclinical phase of rheumatoid arthritis (RA), where some factors involved in RA pathogenesis circulate peripherally, raises concern of RA transmissibility through blood transfusion.1 Specifically, this possibility is suggested by murine RA models in which anticitrullinated peptide/protein antibodies may induce and enhance arthritis, and precursors of the RA-fibroblast-like synoviocyte cells may aggravate and spread the disease between joints.2 3 We used a large Danish–Swedish population-based research donations and transfusions database (SCANDAT2) with health register information on 1.5 million blood donors and 2.1 million recipients of their blood to investigate (1) RA occurrence in recipients of blood from donors who later developed RA and (2) clustering of RA among recipients of blood from individual donors, regardless of the donor’s RA status.4–6 We used two different approaches to analyse RA transmission. First, we identified all donors who developed RA after blood donation. For each of these index donors, we identified up to 10 donors matched on age, sex, county, date of first donation, number of donations and ABO blood group, who were free of RA at the date …

Introduction In chronic lymphocytic leukemia (CLL), few randomized clinical trials include patients who are older or have significant comorbidity, despite constituting a large proportion of the CLL-population. Therefore, detailed data on the association of specific comorbidities with CLL-prognosis are missing and decisions on treatment and follow-up are poorly informed in comorbid patients. We present data on the association of comorbidity with prognostic factors, treatment patterns and causes of death in patients from the world's largest cohort of unselected CLL-patients. Methods All patients diagnosed with CLL in the CLL-registry (2008-2017) or the Danish Cancer Register (1997-2017) were followed through the Civil Registration System from 1 month after CLL-diagnosis until death, emigration or January 2017. Data from Danish nationwide population-based health registers were linked through personal unique identification numbers. Data on comorbidities based on the modified Charlson Comorbidity Index was attained from the Danish National Patient Register, from 20 years prior to the CLL-diagnosis and until 1 month after. Multimorbidity was defined as ≥ 2 comorbidities. Prognostic baseline data such as Binet Stage, IGHV-status, cytogenetics and β2-microglobuline (B2M) level were available through the CLL-registry. Causes of death were ascertained through the National Register of Causes of Death, further sub-categorized as CLL-related (including CLL, all other malignancies and infections) and CLL-unrelated death. Hazard ratios (HR) for mortality were calculated using Cox regression models, adjusting for age, sex, calendar period (5-year intervals) and internally for all other comorbidities. The association between IGHV-status and overall survival (OS) and treatment-free survival (TFS) was assessed by means of Kaplan-Meier and fully adjusted Cox models, stratifying for age and comorbidity-burden. Results The study included 8055 patients with a median follow-up time of 4.2 years; 59 % were male and the median age at diagnosis was 71 years. Overall 2816 patients (35%) were comorbid and 965 (12%) multimorbid. At diagnosis 818 (10%) patients had a history of chronic heart failure or myocardial infarction, 672 (8%) cerebrovascular disease, 626 (8%) diabetes (type 1 or 2), 620 (8%) chronic pulmonary disease, 399 (5%) peripheral vascular disease, 307 (4%) peptic ulcer, 264 (3%) connective tissue disease, 172 (2%) psychiatric disease, 148 (2%) renal disease, 87 (1%) dementia and 86 (1%) hepatic disease. Elevated B2M (>4.0 mg/L) was more common in comorbid (20%) and multimorbid (24%) patients compared with non-comorbid (11%), while Binet Stage B/C, unmutated IGHV-status and del(17p) were evenly distributed across the groups (18-20%, 31-33% and 6-8%, respectively). Among comorbid patients, 56% died during follow-up, compared with 42% among non-comorbid patients. For comorbid patients, death was more commonly caused by cardiovascular disease (14% vs 6%) or other causes (14% vs 10%), while hematological malignancy was less common (25% vs 34%) compared with non-comorbid patients. Other malignancies (11% vs 13%), infection (34% vs 35%) and cerebrovascular disease (2% vs 2%) were equally common causes of death in the two groups. All individual comorbidities were associated with increased all-cause mortality. Except for connective tissue disease, dementia and chronic pulmonary disease, all comorbidities were associated with increased CLL-related mortality (Fig 1A) and as for CLL-unrelated mortality, only ulcer disease, psychiatric disease, renal disease and connective tissue were not associated with an increase. Unmutated IGHV status was associated with inferior TFS for all patients regardless of age and comorbidity burden (range of HRs 1.47-3.70), while IGHV status was associated with inferior OS for non-comorbid patients only (range of HRs 1.43-1.66). Of comorbid patients who died from CLL-related causes, 59% had not received treatment for CLL, compared with 43% among non-comorbid patients. Conclusions All individual types of comorbidity were associated with increased all-cause mortality and most also with higher CLL-related mortality. Improved management is warranted for comorbid CLL-patients, who should be prioritized in clinical trials of agents with high tolerability to further inform treatment guidelines and reduce CLL-related mortality for these patients. Disclosures Curovic Rotbain: Abbvie: Other: Travel Grant; AstraZeneca: Consultancy, Research Funding; Janssen: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; AstraZeneca: Consultancy, Other: Travel Grant, Research Funding; Sunesis: Consultancy; Acerta: Consultancy; CSL Behring: Consultancy; Roche: Other: Travel Grant; Janssen: Consultancy, Other: Travel Grant, Research Funding; Abbvie: Consultancy, Other: Travel Grant, Research Funding; Gilead: Other: Travel Grant. Da Cunha-Bang:Janssen: Consultancy; Abbvie: Consultancy, Other: Travel Grant; AstraZeneca: Consultancy; Roche: Other: Travel Grant. Frederiksen:Gilead: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Novartis: Research Funding; Alexion: Research Funding.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent inflamed nodules. No pathognomonic test is available for HS; hence the diagnosis is based on three clinical criteria.OBJECTIVES: To estimate the cross-sectional prevalence and characterize patients with HS in the Danish Blood Donor Study cohort.METHODS: A questionnaire previously developed containing HS screening questions, the Major Depression Inventory, the Short Form-12, as well as questions about height, weight and drinking habits was answered by 27 765 blood donors.RESULTS: The prevalence of HS was 1·8% [95% confidence interval (CI) 1·6-2·0%] in the cohort of Danish blood donors. Donors with HS were on average 4·7 years younger (P < 0·001), had 1·3 kg m -2 higher mean body mass index (BMI) (P < 0·001) and were significantly more likely to smoke [odds ratio (OR) 1·44, 17·9% vs. 13·1%, P = 0·002] compared with donors without HS. Furthermore, significantly more donors with HS were classified as having moderate depression (3·2% vs. 0·7%, P < 0·001). Also, significantly more patients with HS were apprenticeship educated, received educational support and sickness or cash benefits. CONCLUSIONS: The prevalence of HS in the cohort of blood donors was estimated to 1·8% (95% CI 1·6-2·0%). Donors with HS reported characteristics similar to those reported for hospital-based patients with HS such as higher BMI, smoking rates and lower socioeconomic status than donors without HS.

Background: Hodgkin lymphoma (HL) treatment protocols for children, adolescents and young adults traditionally differ, but the biological and clinical justification for this remains uncertain. Material and methods: We compared age-dependent clinical presentation and treatment and outcome for 1072 classical HL patients 0–24 years diagnosed in Denmark (1990–2010) and Sweden (1992–2009) in pediatric (n = 315, Denmark 2-test and Mantel–Haenszel trend test. The Kaplan–Meier method was used for survival analyses. Hazard ratios (HR) were used to compare the different treatment groups and calculated using Cox regression. Results: Children (0–9 years) less often presented with advanced disease than adolescents (10–17 years) and young adults (18–24 years) (stage IIB-IV: children 32% vs. adolescents 50%, and adults 55%; p

Results from previous investigations have shown associations between the risk of Hodgkin lymphoma (HL) and a history of autoimmune and atopic diseases, but it remains unknown whether these associations apply to all types of HL or only to specific subtypes. We investigated immune diseases and the risk of classical HL in a population-based case-control study that included 585 patients and 3,187 controls recruited from October 1999 through August 2002. We collected information on immune diseases through telephone interviews and performed serological analyses of specific immunoglobulin E reactivity. Tumor Epstein-Barr virus (EBV) status was determined for 498 patients. Odds ratios with 95% confidence intervals were calculated using logistic regression analysis. Rheumatoid arthritis was associated with a higher risk of HL (odds ratio (OR) = 2.63; 95% confidence interval (CI): 1.47, 4.70), especially EBV-positive HL (OR = 3.18; 95% CI: 1.23, 8.17), and with mixed-cellularity HL (OR = 4.25; 95% CI: 1.66, 10.90). HL risk was higher when we used proxies of severe rheumatoid arthritis, such as ever having received daily rheumatoid arthritis medication (OR = 3.98; 95% CI: 2.08, 7.62), rheumatoid arthritis duration of 6-20 years (OR = 3.80; 95% CI: 1.72, 8.41), or ever having been hospitalized for rheumatoid arthritis (OR = 7.36; 95% CI: 2.95, 18.38). Atopic diseases were not associated with the risk of HL. EBV replication induced by chronic inflammation in patients with autoimmune diseases might explain the higher risk of EBV-positive HL.

BACKGROUND: It is well known that obesity complicates the course of several diseases. However, it is unknown whether obesity affects the risk of infection among healthy individuals.METHODS: We included 37,808 healthy participants from the Danish Blood Donor Study, who completed a questionnaire on health-related items. Obesity was defined as a body mass index ≥ 30 kg/m. Infections among participants were identified by relevant ICD-10 codes in the Danish National Patient Register and Anatomical Therapeutic Chemical (ATC) codes in the Danish Prescription Register. Multivariable Cox proportional hazards analysis with age as the underlying timescale was used as the statistical model.RESULTS: During 113,717 person-years of observation, 1,233 participants were treated for infection at a hospital. Similarly, during 58,411 person-years of observation, 15,856 participants filled at least one prescription of antimicrobials. Obesity was associated with risk of hospital-based treatment for infection (women: hazard ratio [HR] = 1.5, 95% confidence interval [CI] = 1.1, 1.9; men: HR = 1.5, 95% CI = 1.2, 1.9). For specific infections, obesity was associated with increased risk of abscesses (both sexes), infections of the skin and subcutaneous tissue (men), and respiratory tract infections and cystitis (women). Similarly, obesity was associated with filled prescriptions of antimicrobials overall (women: HR = 1.22, 95% CI = 1.14, 1.30; men: HR = 1.23, 95% CI: 1.15, 1.33) and particularly with phenoxymethylpenicillin, macrolides, dicloxacillin and flucloxacillin, and broad-spectrum penicillins.CONCLUSIONS: In a large cohort of healthy individuals, obesity was associated with risk of infection. This result warrants further studies of metabolism and the immune response.

BACKGROUND Studies have repeatedly demonstrated that blood donors experience lower mortality than the general population. While this may suggest a beneficial effect of blood donation, it may also r ...

In epidemiological studies, Hodgkin lymphomas (HL) in children younger than 15 years and HL in adolescents and younger adults age 15-35 years has traditionally been studied separately, under the assumption that HL at age 0-14 constitute a homogeneous entity. However, the continued validity of this research practice in affluent settings may be questioned. Specifically, the boundary at age 15 years may not be epidemiologically justified, and therefore also questionable clinically. We therefore updated and further characterised recent HL incidence patterns among Nordic children.We obtained HL incidence data in children aged 0-14 years for the period 1978-2010 from the five nationwide Nordic cancer registries. The data were analysed by log-linear and/or a mixture of Poisson regression models.The analyses showed statistically significantly decreasing and increasing HL incidence rates in children younger and older than eight years, respectively during the study period. Statistical modelling suggested that cases in children age 0-6 years constituted a disease entity of its own, whereas cases in older children were more likely to belong to the younger adult HL entity.Diverging incidence trends and statistical modelling suggest that HL in children age 0-14 years cannot be assumed to constitute a homogeneous disease entity in affluent settings.

BACKGROUND Voluntary blood donation is believed to be mostly motivated by altruism. Because studies have suggested that altruistic personality is determined by both genetic and environmental factors, we speculated that willingness to donate blood could also be governed by constitutional factors. This hypothesis was tested in a study among Danish twins. STUDY DESIGN AND METHODS The nationwide Danish Twin Register, which is virtually complete for all twins born since 1968, was linked with Danish portion of the Scandinavian Donation and Transfusion (SCANDAT) Database, which includes information on all active Danish blood donors from 2002 to 2012, to establish blood donor status for Danish twins, who at age 17 years became eligible for donation in 2002 or later. Casewise concordance in monozygotic (MZ) and dizygotic (DZ) twins were presented and heritability was estimated in Mx by variance component analysis in a liability threshold model. RESULTS A total of 274 MZ and 484 same-sex DZ twins age 17 to 27 years were identified as donors in SCANDAT. There was no difference between MZ and DZ twins with regard to age at first donation or number of donations. Casewise concordance rates were 0.61 (95% confidence interval [CI], 0.56-0.67) and 0.41 (95% CI, 0.36-0.47) in MZ and DZ twin pairs, respectively. Heritability analysis using the ACE model found that additive genetic and shared environmental effects accounted for 0.53 (95% CI, 0.33-0.73) and 0.28 (95% CI, 0.10-0.45) of the variance in the motivation to donate blood, respectively. CONCLUSION Becoming a volunteer blood donor is determined by both genetic and environmental factors shared within families.

Background Risks of transfusion-transmitted disease are currently at a record low in the developed world. Still, available methods for blood surveillance might not be sufficient to detect transmission of diseases with unknown etiologies or with very long incubation periods. Study Design and Methods We have previously created the anonymized Scandinavian Donations and Transfusions (SCANDAT) database, containing data on blood donors, blood transfusions, and transfused patients, with complete follow-up of donors and patients for a range of health outcomes. Here we describe the re-creation of SCANDAT with updated, identifiable data. We collected computerized data on blood donations and transfusions from blood banks covering all of Sweden and Denmark. After data cleaning, two structurally identical databases were created and the entire database was linked with nationwide health outcomes registers to attain complete follow-up for up to 47 years regarding hospital care, cancer, and death. Results After removal of erroneous records, the database contained 25,523,334 donation records, 21,318,794 transfusion records, and 3,692,653 unique persons with valid identification, presently followed over 40 million person-years, with possibility for future extension. Data quality is generally high with 96% of all transfusions being traceable to their respective donation(s) and a very high (>97%) concordance with official statistics on annual number of blood donations and transfusions. Conclusions It is possible to create a binational, nationwide database with almost 50 years of follow-up of blood donors and transfused patients for a range of health outcomes. We aim to use this database for further studies of donor health, transfusion-associated risks, and transfusion-transmitted disease.

The classical Hodgkin lymphoma (cHL) tumor microenvironment shows an ongoing inflammatory response consisting of varying degrees of infiltrating eosinophils, mast cells, macrophages, regulatory T lymphocytes (Tregs), and activated lymphocytes surrounding the malignant cells. Herein, different immune signatures are characterized and correlated with treatment outcome.Tumor-infiltrating leukocytes were phenotyped in biopsies from 459 patients with cHL. Time to progression (TTP) (primary progression, relapse, or death from cHL) and overall survival were analyzed using Cox proportional hazards regression.The leukocyte infiltration in the microenvironment was highly diverse between patients and was categorized in 4 immune signatures (active, anergic, innate, or mixed). A high proportion of Tregs (anergic) resulted in shorter TTP (median 12.9-year follow-up) in age-adjusted analyses (hazard ratio = 1.82; 95% confidence interval 1.05-3-15). Epstein-Barr virus (EBV)-positive cases had higher proportions of macrophages and activated lymphocytes than EBV negative, but neither of those leukocytes predicted prognosis.Abundant Tregs (anergic signature) indicate a shorter TTP, particularly in younger patients. This is probably due to a reduced ability of the immune system to attack the tumor cells. Our data warrant further investigation if these suggested immune signatures could predict outcome of immunotherapy such as immune checkpoint inhibitors.

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.

Transmission of methicillin-resistant Staphylococcus aureus (MRSA) from animals to humans is of great concern due to the implications for human health and the health care system. The objective was to investigate the frequency and duration of MRSA carriage in human volunteers after a short-term exposure in a swine farm. The experimental study included 34 human volunteers staying 1 h in a MRSA-positive swine farm in four trials. In two of the trials, the influence of farm work involving pig contact was studied using a crossover design. The quantities of MRSA in nasal swabs, throat swabs, and air samples were measured at different time points and analyzed in relation to relevant covariates. This investigation showed that, overall, 94% of the volunteers acquired MRSA during the farm visit. Two hours after the volunteers left the stable, the nasal MRSA count had declined to unquantifiable levels in 95% of the samples. After 48 h, 94% of the volunteers were MRSA-negative. Nasal MRSA carriage was positively correlated to personal exposure to airborne MRSA and farm work involving pig contact and negatively correlated to smoking. No association was observed between MRSA carriage and face touching behavior, nasal methicillin-susceptible Staphylococcus aureus (MSSA) carriage, age, or gender. The increase in human MRSA carriage among the volunteers with pig contact seems to be dependent on the increased concentration of airborne MRSA of the surrounding air and not directly on physical contact with pigs. MRSA was not detected in any of the throat samples. IMPORTANCE The experimental approach made it possible to elucidate the contributions of airborne MRSA levels and farm work to nasal MRSA carriage in a swine farm. Short-term exposure to airborne MRSA poses a substantial risk for farm visitors to become nasal carriers, but the carriage is typically cleared within hours to a few days. The risk for short-term visitors to cause secondary transmissions of MRSA is most likely negligible due to the observed decline to unquantifiable levels in 95% of the nasal samples after only 2 h. The MRSA load in the nose was highly correlated to the amount of MRSA in the air and interventions to reduce the level of airborne MRSA or the use of face masks might consequently reduce nasal contamination.

BACKGROUND: Maternal diabetes may be linked to childhood acute lymphoblastic leukaemia (ALL) in the offspring.METHODS: We assessed the association between maternal pregestational or gestational diabetes and offspring risk of childhood ALL in a register-based study, including all singletons born in Denmark during 1996-2015 (n=1 187 482).RESULTS: Adjusted hazard ratios of childhood ALL were 2.91 (95% confidence interval (CI): 1.30-6.51) for maternal pregestational diabetes and 1.75 (95% CI: 1.02-2.98) for maternal gestational diabetes. Paternal diabetes did not alter offspring ALL risk, and we found no association between offspring ALL and later maternal risk of diabetes.CONCLUSIONS: Regardless that absolute ALL risk among offspring of women with diabetes remains low, our findings suggest that characteristics of the diabetic intrauterine environment promote ALL development. This offers a setting for future research into the biological mechanisms underlying childhood ALL.

Natural cytokine-specific autoantibodies (c-aAb) have been measured in healthy and diseased individuals, and have been considered as both endogenous immune-regulators and pathogenic factors. Overall, the etiology and potential pathology of c-aAb are still undefined. To further characterize the sero-prevalence, predictors and consequences of high c-aAb levels, we performed the largest population-based study of c-aAb to date, using participants and epidemiological data from the Danish Blood Donor Study. Using a validated bead-based multiplex assay we assessed plasma levels of IL-1α, IL-6, IL-10, IFNα and GM-CSF-specific c-aAb in 8,972 healthy blood donors. Trace levels of at least one of the investigated c-aAb could be measured in 86% of the participants. The presence of high levels of potentially inhibitory c-aAb was generally associated with increasing age and male or female sex, depending on the c-aAb in question. A negative correlation between high levels of IL-6-specific c-aAb and plasma levels of C-reactive protein was observed, indicating cytokine-neutralizing levels of c-aAb in healthy blood donors. There was no substantial correlation between high levels of the five individual c-aAb investigated in this study. These data suggest that autoimmunity against endogenous cytokines is a relatively common phenomenon in healthy individuals, and that predictive factors for high, potentially neutralizing c-aAb levels vary depending on the cytokine in question, and may differ from predictors of general c-aAb presence.

BACKGROUND: Present understanding of increased risk of Epstein-Barr virus (EBV)-related infectious mononucleosis among children of low birth order or small sibships is mainly based on old and indirect evidence. Societal changes and methodological limitations of previous studies call for new data.METHODS: We used data from the Danish Civil Registration System and the Danish National Hospital Discharge Register to study incidence rates of inpatient hospitalizations for infectious mononucleosis before the age of 20 years in a cohort of 2,543,225 Danes born between 1971 and 2008, taking individual sibship structure into account.RESULTS: A total of 12,872 cases of infectious mononucleosis were observed during 35.3 million person-years of follow-up. Statistical modelling showed that increasing sibship size was associated with a reduced risk of infectious mononucleosis and that younger siblings conferred more protection from infectious mononucleosis than older siblings. In addition to this general association with younger and older siblings, children aged less than 4 years transiently increased their siblings’ infectious mononucleosis risk. Our results were confirmed in an independent sample of blood donors followed up retrospectively for self-reported infectious mononucleosis.CONCLUSIONS: Younger siblings, and to a lesser degree older siblings, seem to be important in the transmission of EBV within families. Apparently the dogma of low birth order in a sibship as being at the highest risk of infectious mononucleosis is no longer valid.

Background. Circumstantial evidence from genome-wide association and family studies of various Epstein-Barr virus–associated diseases suggests a substantial genetic component in infectious mononucleosis (IM) etiology. However, familial aggregation of IM has scarcely been studied. Methods. We used data from the Danish Civil Registration System and the Danish National Hospital Discharge Register to study rate ratios of IM in a cohort of 2 823 583 Danish children born between 1971 and 2011. Specifically, we investigated the risk of IM in twins and in first-, second-, and third-degree relatives of patients with IM. In the analyses, IM was defined as a diagnosis of IM in a hospital contact. Effects of contagion between family members were dealt with by excluding follow-up time the first year after the occurrence of IM in a relative. Results. A total of 16 870 cases of IM were observed during 40.4 million person-years of follow-up from 1977 to 2011. The rate ratios and the associated 95% confidence intervals were 9.3 (3.0–29) in same-sex twins, 3.0 (2.6–3.5) in siblings, 1.9 (1.6–2.2) in children, 1.4 (1.3–1.6) in second-degree relatives, and 1.0 (0.9–1.2) in third-degree relatives of IM patients. The rate ratios were very similar for IM in children (aged 0–6 years) and older children/adolescents (aged 7–19 years). Conclusions. We found evidence of familial aggregation of IM that warrants genome-wide association studies on IM disease etiology, especially to examine commonalities with causal pathways in other Epstein-Barr virus–related diseases.

Background Dietary studies show a relationship between the intake of iron enhancers and inhibitors and iron stores in the general population. However, the impact of dietary factors on the iron stores of blood donors, whose iron status is affected by blood donations, is incompletely understood. Study Design and Methods In the Danish Blood Donor Study, we assessed the effect of blood donation frequency, physiologic factors, lifestyle and supplemental factors, and dietary factors on ferritin levels. We used multiple linear and logistic regression analyses stratified by sex and menopausal status. Results Among high-frequency donors (more than nine donations in the past 3 years), we found iron deficiency (ferritin below 15 ng/mL) in 9, 39, and 22% of men, premenopausal women, and postmenopausal women, respectively. The strongest predictors of iron deficiency were sex, menopausal status, the number of blood donations in a 3-year period, and the time since last donation. Other significant factors included weight, age, intensity of menstruation, iron tablets, vitamin pills, and consumption of meat and wine. Conclusion The study confirms iron deficiency as an important problem, especially among menstruating women donating frequently. The risk of iron depletion was largely explained by sex, menopausal status, and donation frequency. Other factors, including dietary and supplemental iron intake, had a much weaker effect on the risk of iron depletion.

Kamper-Jorgensen, M Rostgaard, K Glaser, S L Zahm, S H Cozen, W Smedby, K E Sanjose, S Chang, E T Zheng, T La Vecchia, C Serraino, D Monnereau, A Kane, E V Miligi, L Vineis, P Spinelli, J J McLaughlin, J R Pahwa, P Dosman, J A Vornanen, M Foretova, L Maynadie, M Staines, A Becker, N Nieters, A Brennan, P Boffetta, P Cocco, P Hjalgrim, H eng 5 ROI CA69269/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England 2013/06/22 06:00 Ann Oncol. 2013 Sep;24(9):2245-55. doi: 10.1093/annonc/mdt218. Epub 2013 Jun 19.; International audience; BACKGROUND: The etiology of Hodgkin lymphoma (HL) remains incompletely characterized. Studies of the association between smoking and HL have yielded ambiguous results, possibly due to differences between HL subtypes. PATIENTS AND METHODS: Through the InterLymph Consortium, 12 case-control studies regarding cigarette smoking and HL were identified. Pooled analyses on the association between smoking and HL stratified by tumor histology and Epstein-Barr virus (EBV) status were conducted using random effects models adjusted for confounders. Analyses included 3335 HL cases and 14 278 controls. RESULTS: Overall, 54.5% of cases and 57.4% of controls were ever cigarette smokers. Compared with never smokers, ever smokers had an odds ratio (OR) of HL of 1.10 [95% confidence interval (CI) 1.01-1.21]. This increased risk reflected associations with mixed cellularity cHL (OR = 1.60, 95% CI 1.29-1.99) and EBV-positive cHL (OR = 1.81, 95% CI 1.27-2.56) among current smokers, whereas risk of nodular sclerosis (OR = 1.09, 95% CI 0.90-1.32) and EBV-negative HL (OR = 1.02, 95% CI 0.72-1.44) was not increased. CONCLUSION: These results support the notion of etiologic heterogeneity between HL subtypes, highlighting the need for HL stratification in future studies. Even if not relevant to all subtypes, our study emphasizes that cigarette smoking should be added to the few modifiable HL risk factors identified.

INTRODUCTION: The aim of this study was to examine whether low-grade inflammation (LGI) is associated with a subsequently increased risk of infection.METHODS: We included 15,754 healthy participants from the Danish Blood Donor Study, who completed a questionnaire on health-related items. LGI was defined as a C-reactive protein level between 3 and 10 mg/L. Infections were identified by ICD-10 codes in the Danish National Patient Register and ATC-codes in the Danish Prescription Register. Multivariable Cox proportional hazard analysis was used as the statistical model.RESULTS: During 53,302 person-years of observation, 571 participants were hospitalized for infection. Similarly, during 26,125 person-years of observation, 7,276 participants filled a prescription of antimicrobials. LGI was associated with increased risk of hospital-based treatment for infection only among men (hazard ratio = 1.60, 95% confidence interval (CI): 1.10-2.34) and specifically infections were abscesses and infections of the skin and subcutaneous tissue. Similarly, LGI was associated with the overall use of antimicrobials among men, and particularly with phenoxymethylpenicillin and broad-spectrum antimicrobials for treatment of urinary tract infections. The difference between men and women was not statistically significant.CONCLUSIONS: In a large cohort of healthy individuals, LGI was associated with an increased risk of infection among healthy male blood donors.

Background: The aggregation of misfolded proteins in the brain occurs in several neurodegenerative disorders. Aberrant protein aggregation is inducible in rodents and primates by intracerebral inoculation. Possible transfusion transmission of neurodegenerative diseases has important public health implications.Objective: To investigate possible transfusion transmission of neurodegenerative disorders.Design: Retrospective cohort study.Setting: Nationwide registers of transfusions in Sweden and Denmark.Participants: 1 465 845 patients who received transfusions between 1968 and 2012.Measurements: Multivariable Cox regression models were used to estimate hazard ratios for dementia of any type, Alzheimer disease, and Parkinson disease in patients receiving blood transfusions from donors who were later diagnosed with any of these diseases versus patients who received blood from healthy donors. Whether excess occurrence of neurodegenerative disease occurred among recipients of blood from a subset of donors was also investigated. As a positive control, transmission of chronic hepatitis before and after implementation of hepatitis C virus screening was assessed.Results: Among included patients, 2.9% received a transfusion from a donor diagnosed with one of the studied neurodegenerative diseases. No evidence of transmission of any of these diseases was found, regardless of approach. The hazard ratio for dementia in recipients of blood from donors with dementia versus recipients of blood from healthy donors was 1.04 (95% CI, 0.99 to 1.09). Corresponding estimates for Alzheimer disease and Parkinson disease were 0.99 (CI, 0.85 to 1.15) and 0.94 (CI, 0.78 to 1.14), respectively. Hepatitis transmission was detected before but not after implementation of hepatitis C virus screening.Limitation: Observational study design, underascertainment of the outcome, and possible insufficient statistical power.Conclusion: The data provide no evidence for the transmission of neurodegenerative diseases and suggest that if transmission does occur, it is rare.Primary Funding Source: Swedish Research Council, Swedish Heart-Lung Foundation, Swedish Society for Medical Research, and Danish Council for Independent Research.

INTRODUCTION: The associations between ABO blood group and cancer risk have been studied repeatedly, but results have been variable. Consistent associations have only been reported for pancreatic and gastric cancers.MATERIALS AND METHODS: We estimated associations between different ABO blood groups and site-specific cancer risk in a large cohort of healthy blood donors from Sweden and Denmark.RESULTS: A total of 1.6 million donors were followed over 27 million person-years (20 million in Sweden and 7 million in Denmark). We observed 119,584 cancer cases. Blood groups A, AB and B were associated either with increased or decreased risk of cancer at 13 anatomical sites (p≤0.05), compared to blood group O. Consistent with assessment using a false discovery rate approach, significant associations with ABO blood group were observed for cancer of the pancreas, breast, and upper gastrointestinal tract (mouth, salivary glands, pharynx, esophageal adenocarcinoma and stomach).DISCUSSION: Our study reconfirms the association between ABO blood group and cancer risk and exact underlying mechanisms involved needs further research.

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.