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Using provisional or opportunistic data, three nationwide studies (The Netherlands, the USA and Denmark) have identified a reduction in preterm or extremely preterm births during periods of COVID-19 restrictions. However, none of the studies accounted for perinatal deaths. To determine whether the reduction in extremely preterm births, observed in Denmark during the COVID-19 lockdown, could be the result of an increase in perinatal deaths and to assess the impact of extended COVID-19 restrictions, we performed a nationwide Danish register-based prevalence proportion study. We examined all singleton pregnancies delivered in Denmark during the COVID-19 strict lockdown calendar periods (March 12–April 14, 2015-2020, N = 31,164 births) and the extended calendar periods of COVID-19 restrictions (February 27–September 30, 2015-2020, N = 214,862 births). The extremely preterm birth rate was reduced (OR 0.27, 95% CI 0.07 to 0.86) during the strict lockdown period in 2020, while perinatal mortality was not significantly different. During the extended period of restrictions in 2020, the extremely preterm birth rate was marginally reduced, and a significant reduction in the stillbirth rate (OR 0.69, 0.50 to 0.95) was observed. No changes in early neonatal mortality rates were found.Conclusion: Stillbirth and extremely preterm birth rates were reduced in Denmark during the period of COVID-19 restrictions and lockdown, respectively, suggesting that aspects of these containment and control measures confer an element of protection. The present observational study does not allow for causal inference; however, the results support the design of studies to ascertain whether behavioural or social changes for pregnant women may improve pregnancy outcomes. What is Known:• The aetiologies of preterm birth and stillbirth are multifaceted and linked to a wide range of socio-demographic, medical, obstetric, foetal, psychosocial and environmental factors.• The COVID-19 lockdown saw a reduction in extremely preterm births in Denmark and other high-income countries. An urgent question is whether this reduction can be explained by increased perinatal mortality. What is New:• The reduction in extremely preterm births during the Danish COVID-19 lockdown was not a consequence of increased perinatal mortality, which remained unchanged during this period.• The stillbirth rate was reduced throughout the extended period of COVID-19 restrictions.

PURPOSE: In pharmacoepidemiology, correctly defining the exposure period of pharmacological treatment is a challenging step when information on the time in treatment is missing or incomplete.METHODS: In this review, we describe several methods for defining exposure to pharmacological treatments using secondary data sources that lack such information.RESULTS AND CONCLUSION: Several methods for assessing the duration of redeemed prescriptions and combining them into temporal sequences are available. We present a set of considerations to make researchers aware of the potentials and pitfalls of these methods that may aid in minimizing biases in research using these methods. Additionally, we highlight that, to date, there is no one-size-fits-all solution. Thus, the choice of method should be based on their area of applicability combined with a careful mapping to the research scenario under investigation.

BACKGROUND: Blood donors report better health-related quality of life (HRQL) than non-donors. Likewise, donors reporting good health are less likely to stop donating and have a higher donation frequency. This is evidence of the healthy donor effect (HDE). This study is the first to investigate the impact of HRQL and depressive symptoms on subsequent donor career.STUDY DESIGN AND METHODS: Prospective cohort study includes 102,065 participants from the Danish Blood Donor Study applying the 12-item short-form health survey (SF-12) measuring a mental (MCS) and a physical component score (PCS) and the Major Depression Inventory (MDI). Poisson and Cox regression models were used to assess the effect of SF-12 and MDI scores on donation frequency and donor cessation. Higher MCS/PCS scores indicate good HRQL, while higher MDI score indicates higher experience of depressive symptoms.RESULTS: For both sexes, MCS was positively correlated with donation frequency for up to 5 years, and similarly for PCS among women. A negative correlation between MDI score and donation frequency in the year following assessment was observed only among men. No correlation was observed among women. An increase in both MCS and PCS was associated with a lower risk of donation cessation in both sexes, while an increase in MDI score was only associated with an increased risk of donation cessation in men.CONCLUSION: MCS, PCS, and MDI score affect donor career. Thus, adjusting for donation frequency may reduce HDE-bias in donor health research. However, because of the small effect sizes, other ways of quantifying HDE may be beneficial.

Background The efficacy of triptans as the main acute treatment strategy for migraine headache at the population-wide level needs to be understood to inform clinical decision-making. We summarise key trends in triptan use using more than 25 years of Danish nationwide data. Methods We conducted a nationwide register-based cohort study based on all Danish residents with access to public healthcare between 1 January 1994 and 31 October 2019 and summarise informative trends of all purchases of triptans in Denmark in the same period. Complete purchase records of Sumatriptan, Naratriptan, Zolmitriptan, Rizatriptan, Almotriptan, Eletriptan, and Frovatriptan were used. Findings Over a 25-year period, triptan use increased from 345 to 945 defined daily doses (DDD) per 1000 inhabitants per year and the yearly prevalence of triptan use increased from 5.17 to 14.57 per 1000 inhabitants. Between 2014 and 2019, 12.3% of the Danish migraine population purchased a triptan. Following their initial purchase, 43% of patients had not repurchased triptans within 5 years. At most, 10% of patients indicating triptan discontinuation tried more than one triptan. The prevalence of triptan overuse, defined as having purchased at least 20 DDDs of triptans per month for 3 consecutive months, increased in parallel with the prevalence of triptan use, prevalent in 56 of every 1000 triptan users every year between 2014 and 2019. Interpretation In a cohort with access to free clinical consultations and low medication costs, we observed low rates of triptan adherence, likely due to disappointing efficacy and/or unpleasant side effects rather than economic considerations. Triptan success continues to be hindered by poor implementation of clinical guidelines and high rates of treatment discontinuance.

Patients with chronic lymphocytic leukaemia (CLL) have an increased risk of new malignancies. However, limited data have been published about the impact of CLL treatment on this risk. Here we followed a Danish population-based cohort of CLL patients for risks of new malignancies. Patients in the Danish CLL registry (2008–2017) were included. Up to 50 CLL-free matched comparators were identified. First-line treatment was categorized into four groups; bendamustine, chlorambucil, fludarabine or other. Patients were followed from CLL diagnosis for individual types of malignancy. Adjusted hazard ratios (HR) for new malignancies and 95% confidence intervals (95% CI) were calculated. Overall, 4286 CLL patients and 214 150 controls developed 594 and 20 565 new malignancies respectively. Risk of new malignancies was increased for CLL patients. Chemotherapy treatment was registered for 1064 (25%) patients with CLL. Chemotherapy was associated with increased HR (1·51, 95% CI: 1·3–1·8) of any new malignancy. Specifically, fludarabine was associated with an increased risk of myelodysplastic syndrome (MDS) (HR 4·93, 95% CI: 1·2–19·8). Patients with CLL are at increased risk of other haematological and solid malignancies compared to the general population. Chemotherapy exposure is associated with increased risk of second malignancies and fludarabine is associated with increased risk of MDS.

Background: Previous studies suggest a 3- to-10-fold increased risk of multiple sclerosis (MS) in offspring of mothers with diabetes mellitus (DM). Objectives: To examine MS risk in offspring of diabetic mothers, overall and according to type of maternal DM, that is, pregestational DM or gestational DM, as well as to examine MS risk among offspring of diabetic fathers. Methods: The study cohort included all 1,633,436 singletons born in Denmark between 1978 and 2008. MS diagnoses were identified in the Danish Multiple Sclerosis Registry, and parental DM diagnoses in the National Patient Register. We used Cox proportional hazards regression analyses to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of parental DM with MS risk in the offspring. Results: MS risk among individuals whose mothers had pregestational DM was 2.3-fold increased compared with that among individuals with nondiabetic mothers (HR = 2.25; 95% CI: 1.35–3.75, n = 15). MS risk was statistically non-significant among offspring of mothers with gestational DM (HR = 1.03 (95% CI: 0.49–2.16), n = 7) and among offspring of diabetic fathers (HR = 1.40 (95% CI: 0.78–2.54), n = 11). Conclusion: Our nationwide cohort study utilizing high-quality register data in Denmark over several decades corroborates the view that offspring of diabetic mothers may be at an elevated risk of developing MS.

Background The two previous versions of the Scandinavian donations and transfusions (SCANDAT) databases, encompassing data on blood donors, blood components, transfusions, and transfused patients linked to national health registers in Sweden and Denmark up until 2012, have been used to study donor health, disease transmission, the role of donor characteristics, and more. Study Design and Methods Here we describe the creation of the Swedish portion of the third iteration of SCANDAT – SCANDAT3‐S – with follow‐up from 1968 to the end of 2017, resulting in up to 50 years of uninterrupted follow‐up for donors and recipients. The database now also includes non‐transfused non‐donors with a blood typing result, increased temporal resolution for transfusions, and linkages to laboratory and drug prescription data. Results After data cleaning, the database contained 23 579 863 donation records, 21 383 317 transfusion records, and 8 071 066 unique persons with valid identification. In total, the database offers 28 638 436 person‐years of follow‐up for donors, 13 582 350 person‐years of follow‐up for transfusion recipients, and 65 613 639 person‐years of follow‐up for non‐recipient non‐donors, with possibility for future extension. Additionally, the database includes 167 820 412 dispense records for prescribed drugs and 316,338,442 laboratory test results. Since the latest update in 2012, >99.9% of all donations were traceable to a donor with valid identification, and >97% of all transfusions to a recipient with valid identification. Conclusion With extended follow‐up and more clinical detail, the Swedish portion of the third and latest iteration of the SCANDAT database should allow for more comprehensive analysis of donation and transfusion‐related research questions.

Chronic lymphocytic leukemia (CLL) is accompanied by increased risk of potentially fatal infections. While this can mostly be attributed to disease-related immune dysfunction, it is not known if CLL patients are also constitutionally susceptible to infections. We linked nation-wide Danish registers to explore this possibility, approximating infection susceptibility by use of antimicrobials. We assessed the incidence of antimicrobials among CLL patients and matched controls from the general population for up to 22 years before index diagnosis, and among children and grandchildren of CLL patients and their matched controls. Our analyses showed that for CLL patients overall antimicrobial use began to increase gradually six years before leukemia diagnosis. Before this time point, CLL patients had used significantly more macrolides (relative risk = 1.15; 95% confidence interval 1.10-1.20), antimycotics (1.18; 1.08-1.30), and antivirals (1.62; 1.45-1.81) than controls for up to 22 years before diagnosis. The same pattern of increased use was found among CLL patients' children and grandchildren. Our study suggests that CLL diagnosis is preceded by decades of increased susceptibility to infections. The duration of this time window is compatible with causal roles of immune dysfunction and/or certain infections in CLL pathogenesis, possibly mediating the association between constitutional infection susceptibility and CLL risk.

Background Patients with hematological malignancies (HM) are known to carry an increased risk of invasive pneumococcal disease (IPD). However, temporal variations in IPD risks following a cancer diagnosis remain poorly characterized. To inform vaccine guidelines and patient management, we assessed the IPD incidence among patients with HM and other malignancies. Methods The study population included all individuals aged ≥15 years during 2000–2016 in Denmark. Variations in incidences of IPD over time and between different types of hematological malignancies and diagnoses were assessed by Poisson regression. Results During 85 002 224 person-years of observation, 13 332 episodes of a first IPD were observed, of which 765 (5.7%) occurred among individuals with HM. Among HM patients, the IPD incidence rate decreased continuously during the study period (rate ratio per year, 0.91; 95% confidence interval, .90–.92). The risk of IPD in patients with HM was up to 39 times higher when compared to the background population and was highest for multiple myeloma, acute lymphoblastic leukemia, and chronic lymphocytic leukemia. Unlike other malignancies, the increased IPD risk did not wane with the time since HM diagnosis. We found a vaccination uptake of only ≤2% in patients with HM and ≤1% for those with other types of malignancies. Conclusions Adults with HM in general and patients with lymphoid malignancies in particular have an increased risk for IPD, compared with patients with other types of cancer and with individuals free of cancer. The pneumococcal vaccination uptake is extremely low in this at risk-population. Efforts to prevent IPD in HM patients are continuously warranted.

BackgroundA large discrepancy between physician-diagnosed and self-reported Hidradenitis suppurativa (HS) exists. Knowledge regarding incidence and remission rates of self-reported HS is missing, but may help bridge the gap in understanding between these two phenotypes.ObjectivesTo determine the incidence and remission rates of self-reported HS, and to what degree these are affected by sex, smoking and BMI.MethodsA prospective cohort of 23 930 Danish blood donors. Information on self-reported HS, symptom-localisation, sex, age, BMI and smoking status was collected at baseline and study termination. Self-reported HS fulfilled clinical obligatory diagnostic criteria. Cox proportional hazards regression analyses were conducted for both incidence and remission rates providing a hazard ratio (HR) of risk for each variable in the regression.ResultsIncidence rate of self-reported HS was 10.8/1000 person-years (95% confidence interval (CI): 9.9–11.7), decreasing as a function of numbers of areas affected. Female BMI points above 25 (HR = 1.11, 95% CI: 1.09–1.13), male BMI points above 25 (HR = 1.07, 95% CI: 1.04–1.11), active smoking (HR = 1.72, 95% CI: 1.15–2.57), male sex (HR = 0.55, 95% CI: 0.45–0.67) and years of age above 25 (HR = 0.97, 95% CI: 0.96–0.97) were all statistically associated with the development of self-reported HS. Remission rate of self-reported HS was 256.7/1000 person-years (95% CI: 223.9–292.6), decreasing as a function of numbers of affected areas. Symptoms in ≥3 areas (HR = 0.54, 95% CI: 0.34–0.85), active smoking (HR = 0.49, 95% CI: 0.32–0.76) and female weight loss (every percentage drop in BMI: HR = 1.07, 95% CI: 1.05–1.11) all significantly affected the remission rate.ConclusionsBoth incidence and remission rates of self-reported HS are high, indicating that many with self-reported HS are unlikely to be diagnosed, as they to a higher degree experience mild transient HS symptoms.

Dry skin or xerosis is a common ailment occurring both as a separate disease entity and as a symptom of other diseases, e.g. it is a cardinal symptom of atopic dermatitis1 . Infections have been described in xerosis associated with dermatitis2 . Whether xerosis without dermatitis is a risk factor for skin infections remains unknown. We therefore tested if individuals with xerosis had a risk of skin infections.

Background The present study aimed to assess whether the widespread concern of inferior cancer survival in adolescents and young adults (AYAs) compared with children and adults holds true in a Nordic setting with important differences in healthcare organisation compared with the United States (e.g. free access to healthcare) and the United Kingdom (e.g. young teenagers are treated in paediatric departments). Methods Five-year relative survival was calculated for 17 diagnostic groups in patients diagnosed in 2000–2013 in three diagnostic age categories: children (0–14 years), AYAs (15–24 years) and adults (25–34 years). Results For 13 out of 17 diagnostic groups examined, there was no difference in survival between AYAs and neighbouring age categories. For acute lymphoblastic leukaemias, astrocytomas, rhabdomyosarcomas and non-rhabdomyosarcoma soft tissue sarcomas we found survival in children to be superior to that in AYAs. For these four diagnostic groups, the rate of survival improvement over three calendar periods (1980–1989, 1990–1999 and 2000–2013) was not particularly low in AYAs compared with neighbouring age categories. Conclusions The present study suggests that in an affluent setting with free access to healthcare, meaningful differences in survival between AYA patients and either childhood or adult patients are a phenomenon of the past for most AYA cancer diagnostic groups.

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

Background and aims Allergic rhinitis (AR), allergic conjunctivitis (AC), and asthma are characterized by activation of the immune system. The aim of this study was to explore the long-term association between AR, AC, asthma, and specific immunoglobulin E (IgE) and blood platelet and leukocyte differential counts. Material and methods In the Danish Blood Donor Study, 14,440 participants from Central Denmark Region had platelet and leukocyte differential counts available and completed a questionnaire regarding AR, AC, and asthma. Of these participants, 8485 were tested for IgE to inhalation allergens. Results The prevalence of AR, AC, asthma, and IgE sensitization was 19%, 15%, 9%, and 29%, respectively. AR, AC, asthma, wheeze, and IgE sensitization was associated with increased blood eosinophil concentration even in IgE sensitized participants who did not report any allergy or asthma. The strongest associations were observed for participants with current disease. We found no differences in eosinophil concentration between months without symptoms and months with symptoms of AR and asthma. Conclusion AR, AC, asthma, wheezing, and IgE sensitization to inhalation allergens are associated with increased eosinophil concentration. This may reflect a persistent inflammation even in periods without symptomatic disease.

ImportanceUsing provisional or opportunistic data, three nationwide studies (The Netherlands, USA, and Denmark) have identified a reduction in preterm or extremely preterm births during periods of COVID-19 restrictions. However, these findings have been challenged as none of the studies accounted for perinatal deaths.ObjectiveTo determine whether the reduction in extremely preterm births, observed in Denmark during the COVID-19 lockdown, could be a result of an increase in number of perinatal deaths; and to assess the impact of extended COVID-19 restrictions on the prevalence of preterm birth and perinatal death.DesignThe study is a nationwide Danish register-based prevalence proportion study using detailed data to capture all births (induced abortions were excluded) throughout Denmark. We assessed the prevalence of stillbirth, preterm birth, and early neonatal death.SettingPopulation-based studyParticipantsAll singleton pregnancies delivered in Denmark, between February 27, and September 30, 2015-2020. COVID-19 lockdown was studied in 31,164 births and the extended period of COVID-19 restrictions in 214,862 births.ExposureCOVID-19 restrictions broadly (February 27, – September 30, 2020) or COVID-19 lockdown specifically (March 12, – April 14, 2020).Main OutcomePrevalence of preterm births, stillbirths and early neonatal deaths across the periods under study.ResultsThe extremely preterm birth rate was reduced (OR 0.27, 95% CI 0.07 to 0.86) during the strict lockdown period, while perinatal mortality was not significantly different. During the extended period of restrictions, the extremely preterm birth rate was marginally reduced, and a significant reduction in the stillbirth rate (OR 0.69, 0.50 to 0.95) was observed. No changes in early neonatal mortality rates were found.Conclusion and RelevanceStillbirth and extremely preterm birth rates were reduced in Denmark during the period of COVID-19 restrictions and lockdown, respectively, suggesting that aspects of these containment and control measures confer an element of protection. The present observational study does not allow for causal inference; however, the results support design of studies to ascertain whether behavioural or social changes for pregnant women may improve pregnancy outcomes.FundingNoneKey pointsQuestionCan changes in stillbirth and early neonatal mortality rates during the COVID-19 lockdown explain the reduction in extremely preterm birth seen in Denmark?FindingsIn this nationwide register-based study that included data pertaining to 245,999 pregnancies, the statistically significant reduction in extremely preterm birth during the COVID-19 lockdown was confirmed. The stillbirth and early neonatal mortality rates were unchanged during lockdown, while the stillbirth rate was reduced over the extended period of COVID-19 restrictions.MeaningThe reduction in extremely preterm births seen during the COVID-19 lockdown in Denmark is not a result of increased stillbirth or early neonatal death.

The peculiar bimodal age distribution of Hodgkin lymphoma (HL), together with other epidemiological findings, inspired the so-called “late infection hypothesis” in the 1970s. Under this model, HL in young adults is caused by delayed infection with a relatively common agent, with HL risk increasing with age at infection. We time-dependently tallied prescriptions filled, for a broad spectrum of antimicrobials, at age 0 to 9 years for all Danish HL patients diagnosed in 1997 to 2015 at age 10 to 25 years (n = 296) and up to 10 controls for each of these, individually matched for sex and birthdate (n = 2688). Antimicrobial use was taken as a proxy for general infectious disease pressure. Analyses were also stratified by the 2 main histological subtypes: nodular sclerosis HL (NSHL) (n = 206) and mixed cellularity HL (MCHL) (n = 47). We compared antimicrobial use at ages 0 to 9 years between cases and comparators using stratified Cox regressions with repeated follow-up for a next prescription, to produce hazard ratios (HRs) of antimicrobial use according to (future) HL status. Reverse causation was mitigated by disregarding risk time

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

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

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.

To explore the impact of COVID-19 lockdown on premature birth rates in Denmark, a nationwide register-based prevalence proportion study was conducted on all 31 180 live singleton infants born in Denmark between 12 March and 14 April during 2015–2020.The distribution of gestational ages (GAs) was significantly different (p=0.004) during the lockdown period compared with the previous 5 years and was driven by a significantly lower rate of extremely premature children during the lockdown compared with the corresponding mean rate for the same dates in the previous years (OR 0.09, 95% CI 0.01 to 0.40, pThe reasons for this decrease are unclear. However, the lockdown has provided a unique opportunity to examine possible factors related to prematurity. Identification of possible causal mechanisms might stimulate changes in clinical practice.

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.