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Preeclampsia and cardiovascular disease (CVD) might share heritable underlying mechanisms. We investigated whether preeclampsia in daughters is associated with CVD in parents. In a register-based cohort study, we used Cox regression to compare rates of CVD (ischemic heart disease, ischemic stroke, myocardial infarction) in parents with ≥ 1 daughters who had preeclampsia and parents whose daughters did not have preeclampsia in Denmark, 1978–2018. Our cohort included 1,299,310 parents, of whom 87,251 had ≥ 1 daughters with preeclampsia and 272,936 developed CVD during 20,252,351 years of follow-up (incidence rate 135/10,000 person-years). Parents with one daughter who had preeclampsia were 1.19 times as likely as parents of daughters without preeclampsia to develop CVD at age Preeclampsia and cardiovascular disease (CVD) might share heritable underlying mechanisms. We investigated whether preeclampsia in daughters is associated with CVD in parents. In a register-based cohort study, we used Cox regression to compare rates of CVD (ischemic heart disease, ischemic stroke, myocardial infarction) in parents with >= 1 daughters who had preeclampsia and parents whose daughters did not have preeclampsia in Denmark, 1978-2018. Our cohort included 1,299,310 parents, of whom 87,251 had >= 1 daughters with preeclampsia and 272,936 developed CVD during 20,252,351 years of follow-up (incidence rate 135/10,000 person-years). Parents with one daughter who had preeclampsia were 1.19 times as likely as parents of daughters without preeclampsia to develop CVD at age < 55 years (hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.13-1.25). Having >= 2 daughters who had preeclampsia yielded an HR of 1.88 (95% CI 1.39-2.53). The corresponding HRs for CVD at >= 55 years of age were 1.13 (95% CI 1.12-1.15) and 1.27 (95% CI 1.16-1.38). Patterns of association were similar for all CVD subtypes. Effect magnitudes did not differ for mothers and fathers (p = 0.52). Analyses by timing of preeclampsia onset in daughters suggested a tendency toward stronger associations with earlier preeclampsia onset, particularly in parents < 55 years. Preeclampsia in daughters was associated with increased risks of CVD in parents. Increasing strength of association with increasing number of affected daughters, equally strong associations for mothers and fathers, and stronger associations for CVD occurring before age 55 years suggest that preeclampsia and CVD share common heritable mechanisms.

Background High parity and extremes of age at first birth have been linked with increased dementia risk in women, with exposure to pregnancy-associated physiological changes proposed as an explanation. However, confounding by socioeconomic and lifestyle factors could also produce such associations, whereby men would share similar patterns of association. We investigated whether these associations hold for both sexes. Methods In a cohort study including all women (N = 2,222,638) and men (N = 2,141,002) ≥ 40 years of age in 1994–2017 in Denmark, we used Cox regression to evaluate associations between number of children, age at first birth, and dementia risk separately for women and men. Results During follow-up, 81,413 women and 53,568 men (median age at diagnosis, 83.3 and 80.3 years, respectively) developed dementia. Compared with having one child, having two or more children was associated with modest decreases in overall dementia risk in both sexes (hazard ratio [HR] range 0.82–0.91, Pdifference men vs. women = 0.07). Although the associations between childlessness and overall dementia risk differed statistically for men and women, the association magnitudes differed only slightly (HRmen 1.04, 95% confidence interval [CI] 1.01–1.06; HRwomen 0.99, 95% CI 0.97–1.01; P = 0.002). Associations between age at becoming a parent and overall dementia were also similar for women and men, with the exception of older (≥ 40 years) first-time parents (HRmen 1.00, 95% CI 0.96–1.05; HRwomen 0.92, 95% CI 0.86–0.98; P = 0.01). With few exceptions, sub-analyses by dementia subtype and timing of onset also revealed similar patterns and effect magnitudes for women and men. Conclusions Associations between number of children, age at becoming a parent, and dementia risk were similar for both sexes. Lifestyle and socioeconomic factors are more likely to explain the observed associations than normal pregnancy-related physiological changes.

The aim of the present study was to describe histopathologic characteristics of synchronous bilateral breast cancer (SBBC), and by comparing SBBC to unilateral breast cancer (UBC), identify possible etiological mechanisms of SBBC. Patients with primary SBBC (diagnosed within 4 months) and UBC diagnosed in Denmark between 1999 and 2015 were included. Detailed data on histopathology were retrieved from the Danish Breast Cancer Group database and the Danish Pathology Register. Associations between bilateral disease and the different histopathologic characteristics were evaluated by odds ratios and estimated by multinomial regression models. 1214 patients with SBBC and 59,221 with UBC were included. Patients with SBBC more often had invasive lobular carcinomas (OR 1.29; 95% CI 1.13–1.47), a clinically distinct subtype of breast cancer, than UBC patients. Further, they were older than UBC patients, more often had multifocal cancer (OR 1.13; 95% CI 1.01–1.26), and a less aggressive subtype than UBC patients. Invasive lobular carcinoma was associated with having multiple tumors in breast tissue—both in the form of bilateral disease and multifocal disease, and this association was independent of laterality. No similar pattern was observed for other tumor characteristics. We identified two etiological mechanisms that could explain some of the occurrence of SBBC. The high proportion of less aggressive carcinomas and higher age of SBBC compared to UBC patients suggests that many are diagnosed at a subclinical stage as slow-growing tumors have a higher probability of simultaneous diagnosis. The high proportion of invasive lobular carcinoma observed in bilateral and multifocal disease, being independent of laterality, suggests that these patients have an increased propensity to malignant tumor formation in breast tissue.

BackgroundInfantile hypertrophic pyloric stenosis (IHPS) is caused by hypertrophy of the pyloric sphincter smooth muscle. Building on a previously reported association between IHPS and lipid metabolism, we aimed to (1) investigate associations between IHPS and a wide array of lipid-centric targeted metabolites in newborns, and (2) address causality of the associations by integrating genetic data.MethodsDried blood spots were taken from 267 pairs of IHPS cases and controls matched by sex and day of birth. A mixed effects linear regression model was used to evaluate associations between Biocrates p400 Kit selected 148 metabolites and IHPS in a matched case-control design.ResultsSeven metabolites showed significantly lower levels in IHPS cases. Levels of the top associated metabolite, phosphatidylcholine PC(38:4), were significantly correlated with levels of the remaining six metabolites (P−12). Associations were driven by case-control pairs with older age at sampling. IHPS cases had more diagnoses for neonatal difficulty in feeding at breast (P = 6.15 ⨯ 10−3). Genetic variants explaining a large proportion of variance in the levels of PC(38:4) did not associate with IHPS.ConclusionsWe detected lower levels of certain metabolites in IHPS, possibly reflecting different feeding patterns in the first days of life.Key points–Our previous GWAS of IHPS identified genetic associations between lipid metabolism and IHPS.–Building on that finding, this study investigated associations between a wide array of lipid-centric metabolites in newborns and IHPS.–Newborns who later developed IHPS had lower levels of certain metabolites. The associations were driven by individuals born at a later age at sampling, suggesting different feeding patterns after birth.

As the population ages, cognitive decline is becoming a worldwide threat to older adults’ independence and quality of life. Cognitive decline involves problems with memory, language, thinking and judgement, thus severely compromising multiple aspects of people’s everyday life. Diagnosis of cognitive disorders is currently performed through clinical questionnaire-based assessments, which are typically conducted by medical experts once symptoms appear. Digital technologies can help providing more immediate, pervasive and seamless assessment, which could, in turn, allow for much earlier diagnosis of cognitive disorders and decline. In this work, we present MobileCogniTracker, a digital tool for facilitating momentary, seamless and ubiquitous clinically-validated cognitive measurements. The proposed tool develops digital cognitive tests in the form of multimedia experience sampling questionnaires, which can run on a smartphone and can be scheduled and assessed remotely. The tool further integrates the digital cognitive experience sampling with passive smartphone sensor data streams that may be used to study the interplay of cognition and physical, social and emotional behaviours. The Mini-Mental State Examination test, a clinical questionnaire extensively used to measure cognitive disorders, has been particularly implemented here to showcase the possibilities offered by our tool. A usability test showed the tool to be usable for performing digital cognitive examinations, and that cognitively unimpaired persons in the relevant age-group are capable of performing such digital examination. A qualitative expert-driven validation also shows a high inter-reliability between the digital and pencil-and-paper version of the test.

Background: Mitochondrial mutations are commonly reported in tumours, but it is unclear whether impaired mitochondrial function per se is a cause or consequence of cancer. To elucidate this, we examined the risk of cancer in a nationwide cohort of patients with mitochondrial dysfunction. Methods: We used nationwide results on genetic testing for mitochondrial disease and the Danish Civil Registration System, to construct a cohort of 311 patients with mitochondrial dysfunction. A total of 177 cohort members were identified from genetic testing and 134 genetically untested cohort members were matrilineal relatives to a cohort member with a genetically confirmed maternally inherited mDNA mutation. Information on cancer was obtained by linkage to the Danish Cancer Register. Standardised incidence ratios (SIRs) were used to assess the relative risk of cancer. Results: During 7334 person-years of follow-up, 19 subjects developed a primary cancer. The corresponding SIR for any primary cancer was 1.06 (95% confidence interval 0.68–1.63). Subgroup analyses according to mutational subtype yielded similar results, for example, a SIR of 0.94 (95% CI 0.53 to 1.67) for the m.3243A>G maternally inherited mDNA mutation, cases=13. Conclusions: Patients with mitochondrial dysfunction do not appear to be at increased risk of cancer compared with the general population.

Background: Approximately 10% of gastric carcinomas are associated with Epstein–Barr virus (EBV). The Inuit in Greenland have a high incidence of EBV-associated nasopharyngeal carcinoma. Methods: We conducted a population-based case–control study comparing gastric carcinomas in Greenland and in Denmark. Results: The prevalence rate of EBV-associated gastric carcinomas was 8.5% in both populations. Conclusion: The findings of this study argue against a general susceptibility to EBV-associated carcinomas among the Inuit.

Childcare in the first 2 years of life reduces the risk of childhood acute lymphoblastic leukemia

Reproductive patterns have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL) in women, and fathering patterns in relation to NHL risk have not been studied. The authors conducted a register-based cohort study of 4.1 million Danes to investigate associations of livebirths with subsequent NHL incidence (85 million person-years, 3819 NHL cases). The impact of induced abortions, ectopic pregnancies, spontaneous abortions, missed abortions, stillbirths, and hydatidiform moles on subsequent NHL incidence was studied in a subcohort of 1.2 million women. Ratios of NHL incidence rates, accompanying trend tests and two-sided p-values were calculated by log-linear Poisson regression analyses. Pregnancies, whether ending in livebirths or not, were unrelated to NHL incidence in women. The only statistically significant finding in women was that, among parous women, age at first child-birth was inversely associated with NHL incidence (p-trend = 0.001). In men, there was no overall difference in NHL incidence between fathers and non-fathers. However, in men with children, NHL risk declined with increasing number of children (p-trend = 0.02) and increased with time since birth of the most recent child (p-trend < 0.001). Pregnancies have limited impact, if any, on subsequent NHL risk in women. Our findings in men need replication, but, if verified, they may reflect lymphomagenesis-associated male subfertility prior to NHL diagnosis.

Objective: The increased risk of breast cancer in women with family history of breast cancer (FHBC) might be reduced by early childbirths. However, childbirth induces a transient increase in risk in the first 5–10 years, which coincides with the relatively increased risk of family cases at a young age. The objective was to investigate this short-term change in risk according to FHBC. Methods: We used a population-based cohort of 1.5 million Danish women. Between 1968 and 1990, 2770 incident cases of breast cancer below 40 years of age were identified in the Danish Cancer Register, of whom 276 (10%) had a FHBC. Results: The first 5 years after a birth the short-term increase in risk was 30% (3–64%) larger in women with FHBC than without FHBC. After the first 5 years we observed no difference in the effect of a birth between women with and without FHBC. Conclusions: The adverse short-term effect of childbirth is stronger in women with FHBC.

Introduction Digoxin use is associated with increased incidence of breast and uterus cancers. We postulated that digoxin use might affect tumor characteristics and increase relapse risk in women with breast cancer. Methods Incident breast cancer cases in Danish women (n = 49,312; 1995 to 2008) were identified. Analyses were conducted in women 20 to 74 years old. Relapse hazard ratios (HR) were compared in women using and not using digoxin, adjusting for age, calendar period, protocol, tumor size, nodal involvement, histology grade, estrogen-receptor (ER) status, and anti-estrogen therapy in Cox regression models. Results At diagnosis, tumors in digoxin users were more likely ER+ (85.4% vs. 78.6%: P = 0.002) and have grade 1 ductal histology (37.2% vs. 25.7%; P = 0.004), compared to non-users. 45 relapses occurred in women already using digoxin at breast cancer diagnosis (1,487 person-years); 24 relapses occurred in women later starting digoxin (384 person-years). Overall relapse risk HR in digoxin users was 1.13 (95% confidence interval: 0.88, 1.46) compared to non-users. Relapse risk in digoxin users was significantly increased in the first year (2.19; 1.26, 3.78) but not thereafter (0.99; 0.74, 1.32) (P = 0.02 for difference in HRs). First-year relapse hazard was high in digoxin-using women with ER+ tumors (2.51; 1.39, 4.55) but not ER- tumors (0.72; 0.10, 5.27). Recurrence hazard was not significantly changed among digoxin-using women also using tamoxifen. Conclusions Breast cancers arising in digoxin-using women had better prognostic features. After adjustment for markers, overall breast cancer relapse risk in digoxin users was not increased significantly, although recurrence hazards for ER+ tumors were higher in the first year following diagnosis.

Gender of offspring is influenced by maternal hormonal level during pregnancy, which is blieved to influence the subsequent maternal breast cancer risk. However, analysing national birth and cancer registrations in a cohort of 998 499 women, we found no association between gender of offspring and subsequent breast cancer risk. © 2000 Cancer Research Campaign

The aim of this study was to evaluate new and previously hypothesised non-genetic risk factors for serologic subtypes of rheumatoid arthritis (RA) defined by the presence or absence of auto-antibodies to cyclic citrullinated peptides (CCP). In a national case-control study, we included 515 patients recently diagnosed with RA according to the American College of Rheumatology 1987 classification criteria and 769 gender- and age-matched population controls. Telephone interviews provided information about non-genetic exposures, and serum samples for patients were tested for anti-CCP-antibodies. Associations between exposure variables and risk of anti-CCP-positive and anti-CCP-negative RA were evaluated using logistic regression. A series of RA subtype-specific risk factors were identified. Tobacco smoking (odds ratio [OR] = 1.65; 95% confidence interval: 1.03–2.64, for >20 versus 0 pack-years) was selectively associated with risk of anti-CCP-positive RA, whereas alcohol consumption exhibited an inverse dose-response association with this RA subtype (OR = 1.98, 1.22–3.19, for 0 versus >0–5 drinks per week). Furthermore, coffee consumption (OR = 2.18; 1.07–4.42, for >10 versus 0 cups per day), ever use of oral contraceptives (OR = 1.65; 1.06–2.57) and having a first-degree relative with schizophrenia (OR = 4.18; 1.54–11.3) appeared more strongly associated with risk of anti-CCP-positive RA. Obesity was selectively associated with risk of anti-CCP-negative RA, with obese individuals being at more than 3-fold increased risk of this subtype compared with normal-weight individuals (OR = 3.45; 1.73–6.87). Age at menarche was the only examined factor that was significantly associated with both serologic subtypes of RA (p-trends = 0.01); women with menarche at age ≥ 15 years had about twice the risk of either RA subtype compared with women with menarche at age ≤ 12 years. Major differences in risk factor profiles suggest distinct etiologies for anti-CCP-positive and anti-CCP-negative RA.