Intervening on the storage time of RBC units and its effects on adverse recipient outcomes using real-world data.

Randomized controlled trials (RCTs) have found no evidence that the storage time of transfused red blood cell (RBC) units affects recipient survival. However, inherent difficulties in conducting RBC transfusion RCTs have prompted critique of their design, analyses, and interpretation. Here, we address these issues by emulating hypothetical randomized trials using large real-world data to further clarify the adverse effects of storage time. We estimated the comparative effect of transfusing exclusively older vs fresher RBC units on the primary outcome of death, and the secondary composite end point of thromboembolic events, or death, using inverse probability weighting. Thresholds were defined as 1, 2, 3, and 4 weeks of storage. A large Danish blood transfusion database from the period 2008 to 2018 comprising >900 000 transfusion events defined the observational data. A total of 89 799 patients receiving >340 000 RBC transfusions during 28 days of follow-up met the eligibility criteria. Treatment with RBC units exclusively fresher than 1, 2, 3, and 4 weeks of storage was found to decrease the 28-day recipient mortality with 2.44 percentage points (pp) (0.86 pp, 4.02 pp), 1.93 pp (0.85 pp, 3.02 pp), 1.06 pp (-0.20 pp, 2.33 pp), and -0.26 pp (-1.78 pp, 1.25 pp) compared with transfusing exclusively older RBC units, respectively. The 28-day risk differences for the composite end point were similar. This study suggests that transfusing exclusively older RBC units stored for >1 or 2 weeks increases the 28-day recipient mortality and risk of thromboembolism or death compared with transfusing fresher RBC units.

Cardiovascular events according to blood pressure thresholds recommended by ACC/AHA.

AIM: The latest guidelines from ACC/AHA define hypertension at systolic blood pressure (SBP) 130-139 mmHg or diastolic blood pressure (DBP) 80-89 mmHg in contrast to guidelines from ESC/ESH defining hypertension at SBP ≥ 140 mmHg or DBP ≥ 90 mmHg. The aim was to determine whether the ACC/AHA definition of hypertension identifies persons at elevated risk for future cardiovascular outcome. METHODS: In a Danish prospective cardiovascular study, 19,721 white men and women aged 20-98 years were examined up to five occasions between 1976 and 2015. The population was followed until December 2018. The ACC/AHA definition of the BP levels were applied: Normal: SBP <120 mmHg and DBP <80 mmHg, Elevated: SBP 120-129 mmHg and DBP <80 mmHg, Stage 1: SBP 130-139 mmHg or DBP 80-89 mmHg, Stage 2: SBP ≥140 mmHg or DBP ≥90 mmHg. Absolute 10-year risk was calculated taking repeated examinations, covariates, and competing risk into account. RESULTS: For all outcomes, the 10-year risk in stage 1 hypertension did not differ significantly from risk in subjects with normal BP: The 10-year risk of cardiovascular events in stage 1 hypertension was 14.1% [95% CI 13.2;15.0] and did not differ significantly from the risk in normal BP at 12.8% [95% CI 11.1;14.5] (p = 0.19). The risk was highest in stage 2 hypertension 19.4% [95% CI 18.9;20.0] and differed significantly from normal BP, elevated BP, and stage 1 hypertension (p < 0.001). The 10-year risk of cardiovascular death was 6.6% [95% CI 5.9;7.4] in stage 1 hypertension and did not differ significantly from the risk in normal BP at 5.7% [95% CI 4.1;7.3] (p = 0.33). CONCLUSIONS: Stage 1 hypertension as defined by the ACC/AHA guidelines has the same risk for future cardiovascular events as normal BP. In contrast, the definition of hypertension as suggested by ESC/ESH identifies patients with elevated risk of cardiovascular events.

Until 2017, there was worldwide agreement on defining hypertension at systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg.In 2017, the American Cardiology Societies (ACC and AHA) lowered the threshold for defining hypertension at SBP 130-139 mmHg or DBP 80-89 mmHg.Lowering the threshold might make healthy persons sick if the thresholds do not identify persons at high risk.Unnecessary medical treatment is associated with high economic cost for the health care systems.We wanted to explore whether applying the American BP definition in a Scandinavian population identified persons with elevated risk for cardiovascular disease.As part of the Copenhagen City Heart study, 19,721 men and women aged 20-98 years were followed from 1976.They went through up to five examinations between 1976 and 2018 including BP measurements.We applied the American BP thresholds and followed the persons until death or 2018.In Denmark all citizens have a unique identification number which is linked to all health care contacts and administrative registers.We used advanced statistical methods and linked the BP measurements with the data for cardiovascular disease and death date from the Danish registries for each person.The results showed that the American definition of hypertension has same risk for future cardiovascular disease as the definition of normal BP.This means that healthy persons will be diagnosed with hypertension if the US guidelines were applied in Denmark.

Analysis of time-to-event for observational studies: Guidance to the use of intensity models.

This paper provides guidance for researchers with some mathematical background on the conduct of time-to-event analysis in observational studies based on intensity (hazard) models. Discussions of basic concepts like time axis, event definition and censoring are given. Hazard models are introduced, with special emphasis on the Cox proportional hazards regression model. We provide check lists that may be useful both when fitting the model and assessing its goodness of fit and when interpreting the results. Special attention is paid to how to avoid problems with immortal time bias by introducing time-dependent covariates. We discuss prediction based on hazard models and difficulties when attempting to draw proper causal conclusions from such models. Finally, we present a series of examples where the methods and check lists are exemplified. Computational details and implementation using the freely available R software are documented in Supplementary Material. The paper was prepared as part of the STRATOS initiative.

Weight trajectories and disordered eating behaviours in 11- to 12-year-olds: A longitudinal study within the Danish National Birth Cohort.

OBJECTIVE: To examine how childhood weight trajectories are associated with disordered eating behaviours (DEBs) in early adolescence. METHODS: Self-reports on DEBs (fasting, purging, and binge eating) were obtained from 18,337 children in the 11-year follow-up of the Danish National Birth Cohort. For this population, birth register information on gestational age and birth weight was categorized into the following: small, appropriate, and large for gestational age. Prospective parent-reported height and weight data at child ages 1 and 7 years were dichotomized using standardized cut-offs into non-overweight and overweight. A 12-category weight trajectory variable was created, and the associations between weight trajectory and DEBs were estimated using logistic regression. RESULTS: In total, 7.0% 11- to 12-year olds reported DEBs. Compared with children born appropriate for gestational age and being non-overweight at age 1 and 7 years, children born small for gestational age and who were overweight at age 1 and 7 years had a very high risk of disordered eating (OR 7.00; CI [2.57, 19.40]). The statistical analyses revealed, however, that overweight at age 7 years was the main contributor and independently of trajectory increased the risk of disordered eating at age 11-12 years significantly (OR 3.16 CI [2.73, 3.65]). CONCLUSION: Overweight not in the first year of life, but at age 7 years was more predictive for DEBs.

Fever and infections in pregnancy and risk of attention deficit/hyperactivity disorder in the offspring.

BACKGROUND: Fever and infections are common events during pregnancy, and have been shown to be associated with neurodevelopmental impairment in the offspring. The evidence in relation to attention deficit/hyperactivity disorder (ADHD) is, however, nonexistent for fever and limited for infections. The aim of this study was therefore to investigate the impact of these exposures on the occurrence of ADHD in the offspring, considering gestational timing as well as intensity of exposure. METHODS: The study was conducted within the Danish National Birth Cohort, using data on 89,146 pregnancies enrolled during 1996-2002. Exposure to fever and infections were assessed prospectively in two computer-assisted telephone interviews during pregnancy and ADHD status in the child was determined using registry information from three nation-wide patient and prescription registers. Stratified Cox regressions were used to calculate adjusted hazard ratios of ADHD occurrence. RESULTS: The analyses revealed no overall association between maternal exposure to fever or infections and ADHD in the offspring [adjusted hazard ratio (aHR): 1.03, 95% confidence interval (CI): 0.93-1.13 and aHR: 1.01, 95% CI: 0.92-1.11]. When the exposures were considered during specific gestational periods, increased rates of ADHD were observed following fever in gestational weeks 9-12 (aHR: 1.33, 95% CI: 1.12-1.58), and genitourinary infections in weeks 33-36 (aHR: 1.60, 95% CI: 1.13-2.26). CONCLUSIONS: Although no overall adverse association between fever and infections in pregnancy and ADHD in the offspring was found, the analyses indicated that exposures during specific time windows of the pregnancy could be associated with increased ADHD occurrence.

Social and ethnic disparities in stillbirth and infant death in Denmark, 2005-2016.

Ethnic disparity in stillbirth and infant death has been demonstrated in Europe. As the relation between migration and health change over time, this population based register study investigated the recent figures and explored if potential differences could be explained by the well-known educational and income inequalities in stillbirth and infant death using a novel approach. Stillbirth and infant mortality varied considerably according to country of origin, with only immigrants from China, Norway, and Poland having an overall lower risk than Danish women. Women of Pakistani, Turkish, and Somali origin had a particularly high risk of both outcomes. Women from recent high conflict areas displayed a pattern with increased stillbirth risk. An observed excess risks across generations was found, which is disturbing and rule out factors related to language barriers or newness. Differences in educational level and household income explained only part of the observed inequalities. Strengthening of the maternity care system to better understand and meet the needs of immigrant women seems needed to mitigate the disparities.

Parkinson's disease and antidepressant drug treatment: a case-register study.

UNLABELLED: We estimated the nationwide prevalence rate of antidepressant drug treatment in Parkinson's disease (PD) patients. BACKGROUND: Very few studies exist on the frequency of antidepressant drug treatment in patients with PD. METHOD: Patients with a PD diagnosis at first hospital contact were identified and followed for up to 6 years. The subsequent probability of antidepressant drug treatment was estimated and compared to a control group of patients with osteoarthritis. RESULTS: The probability of antidepressant drug treatment was 3.98 [95% CI: 3.23-4.91) times higher for PD patients than for controls. CONCLUSION: Patients with PD have higher rates of actual antidepressant drug treatment than a control group with osteoarthritis. Still, however, undertreatment of depressive states may be the case.

Incidence of Depression After Stroke, and Associated Risk Factors and Mortality Outcomes, in a Large Cohort of Danish Patients.

IMPORTANCE: More than 30 million people live with a stroke diagnosis worldwide. Depression after stroke is frequent, and greater knowledge of associated risk factors and outcomes is needed to understand the etiology and implications of this disabling complication. OBJECTIVES: To examine whether the incidence of and risk factors for depression differ between patients with stroke and a reference population without stroke and to assess how depression influences mortality. DESIGN, SETTING, AND PARTICIPANTS: Register-based cohort study in Denmark. Participants were all individuals 15 years or older with a first-time hospitalization for stroke between January 1, 2001, and December 31, 2011 (n = 157 243), and a reference population (n = 160 236) matched on age, sex, and municipality. The data were analyzed between January and March 2016. MAIN OUTCOMES AND MEASURES: The incidence of depression and mortality outcomes of depression (defined by hospital discharge diagnoses or antidepressant medication use) were examined using Cox proportional hazards regression analyses. RESULTS: In total, 34 346 patients (25.4%) with stroke and 11 330 (7.8%) in the reference population experienced depression within 2 years after study entry. Compared with the reference population, patients with stroke had a higher incidence of depression during the first 3 months after hospitalization (hazard ratio for stroke vs the reference population, 8.99; 95% CI, 8.61-9.39), which declined during the second year of follow-up (hazard ratio for stroke vs the reference population, 1.93; 95% CI, 1.85-2.08). Significant risk factors for depression for patients with stroke and the reference population included older age, female sex, single cohabitation status, basic educational attainment, diabetes, high level of somatic comorbidity, history of depression, and stroke severity (in patients with stroke). The associations were strongest for the reference population. In both populations, depressed individuals, especially those with new onset, had increased all-cause mortality (hazard ratio for new-onset depression, 1.89 [95% CI, 1.83-1.95] for patients with stroke and 3.75 [95% CI, 3.51-4.00] for the reference population) after adjustment for confounders. Similar patterns were found for natural and unnatural causes of death. In most models, the depression-related relative mortality was approximately twice as high in the reference population vs the stroke population. CONCLUSIONS AND RELEVANCE: Depression is common in patients with stroke during the first year after diagnosis, and those with prior depression or severe stroke are especially at risk. Because a large number of deaths can be attributable to depression after stroke, clinicians should be aware of this risk.

Diagnostic stability in pediatric bipolar disorder.

BACKGROUND: The diagnostic stability of pediatric bipolar disorder has not been investigated previously. The aim was to investigate the diagnostic stability of the ICD-10 diagnosis of pediatric mania/bipolar disorder. METHODS: All patients below 19 years of age who got a diagnosis of mania/bipolar disorder at least once in a period from 1994 to 2012 at psychiatric inpatient or outpatient contact in Denmark were identified in a nationwide register. RESULTS: Totally, 354 children and adolescents got a diagnosis of mania/bipolar disorder at least once; a minority, 144 patients (40.7%) got the diagnosis at the first contact whereas the remaining patients (210; 59.3%) got the diagnosis at later contacts before age 19. For the latter patients, the median time elapsed from first treatment contact with the psychiatric service system to the first diagnosis with a manic episode/bipolar disorder was nearly 1 year and for 25% of those patients it took more than 2½ years before the diagnosis was made. The most prevalent other diagnoses than bipolar disorder at first contact were depressive disorder (21.4%), acute and transient psychotic disorders or other non-organic psychosis (19.2%), reaction to stress or adjustment disorder (14.8%) and behavioral and emotional disorders with onset during childhood or adolescents (10.9%). Prevalence rates of schizophrenia, personality disorders, anxiety disorder or hyperkinetic disorders (ADHD) were low. LIMITATIONS: Data concern patients who get contact to hospital psychiatry only. CONCLUSIONS: Clinicians should be more observant on manic symptoms in children and adolescents who at first glance present with transient psychosis, reaction to stress/adjustment disorder or with behavioral and emotional disorders with onset during childhood or adolescents (F90-98) and follow these patients more closely over time identifying putable hypomanic and manic symptoms as early as possible.

Genetic and familial environmental effects on suicide attempts: a study of Danish adoptees and their biological and adoptive siblings.

OBJECTIVES: Genetic factors have been found to influence the risk of suicide. It is less clear if this also applies to attempted suicide. We have investigated genetic and familial environmental factors by studying the occurrence of suicide attempts in biological and adoptive siblings of adoptees who attempted suicide compared to siblings of adoptees with no suicide attempts. METHOD: We used a random sample of 1933 adoptees from the Danish Adoption Register, a register of non-familial adoptions of Danish children, i.e. the adoptive parents are biologically unrelated to the adoptee. Analyses were conducted on incidence rates of attempted suicide in biological and adoptive siblings given occurrence of attempted suicide in the adoptees while also taking into account psychiatric disorders. Information about suicidal attempt and history of psychiatric disorder was based on hospital admissions. RESULTS: The rate of attempted suicide in full siblings of adoptees who attempted suicide before age 60 years was higher than in full siblings of adoptees who had not attempted suicide (incidence rate ratios (IRR)=3.45; 95% confidence interval [CI]=0.94-12.7). After adjustment for history of psychiatric admission of siblings the increased rate was statistically significant (IRR=3.88; 95% CI-1.42-10.6). LIMITATIONS: Information on attempted suicide and psychiatric history was limited to that which involved hospitalisation. CONCLUSIONS: Genetic factors influence risk of suicide attempts.

Lifetime alcohol use and overall and cause-specific mortality in the European Prospective Investigation into Cancer and nutrition (EPIC) study.

OBJECTIVES: To investigate the role of factors that modulate the association between alcohol and mortality, and to provide estimates of absolute risk of death. DESIGN: The European Prospective Investigation into Cancer and nutrition (EPIC). SETTING: 23 centres in 10 countries. PARTICIPANTS: 380 395 men and women, free of cancer, diabetes, heart attack or stroke at enrolment, followed up for 12.6 years on average. MAIN OUTCOME MEASURES: 20 453 fatal events, of which 2053 alcohol-related cancers (ARC, including cancers of upper aerodigestive tract, liver, colorectal and female breast), 4187 cardiovascular diseases/coronary heart disease (CVD/CHD), 856 violent deaths and injuries. Lifetime alcohol use was assessed at recruitment. RESULTS: HRs comparing extreme drinkers (≥30 g/day in women and ≥60 g/day in men) to moderate drinkers (0.1-4.9 g/day) were 1.27 (95% CI 1.13 to 1.43) in women and 1.53 (1.39 to 1.68) in men. Strong associations were observed for ARC mortality, in men particularly, and for violent deaths and injuries, in men only. No associations were observed for CVD/CHD mortality among drinkers, whereby HRs were higher in never compared to moderate drinkers. Overall mortality seemed to be more strongly related to beer than wine use, particularly in men. The 10-year risks of overall death for women aged 60 years, drinking more than 30 g/day was 5% and 7%, for never and current smokers, respectively. Corresponding figures in men consuming more than 60 g/day were 11% and 18%, in never and current smokers, respectively. In competing risks analyses, mortality due to CVD/CHD was more pronounced than ARC in men, while CVD/CHD and ARC mortality were of similar magnitude in women. CONCLUSIONS: In this large European cohort, alcohol use was positively associated with overall mortality, ARC and violent death and injuries, but marginally to CVD/CHD. Absolute risks of death observed in EPIC suggest that alcohol is an important determinant of total mortality.