BackgroundAdherence to antihypertensive medication, alongside lifestyle modifications, is fundamental to managing hypertension and reducing the risk of cardiovascular disease. Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder associated with a range of cardiovascular diseases, including hypertension. ADHD medication has also been associated with hypertension. However, the influence of ADHD and ADHD medication on discontinuation and adherence to antihypertensive treatments is unknown.MethodsWe conducted a multinational cohort study using electronic health databases from seven countries, which included adults who initiated antihypertensive medication between 2010 and 2020. ADHD was identified by a diagnosis of ADHD or dispensation of ADHD medications. The outcomes were (1) time to the first discontinuation of antihypertensive medication and (2) poor adherence, defined as the proportion of days covered (PDC) below 80% during 1-, 2-, and 5-year follow-up periods. We used Cox proportional hazards models and logistic regression to estimate associations, adjusting for age, sex, and calendar year of antihypertensive medication initiation. We pooled results from different countries via random-effects meta-analysis.ResultsWe identified 12,174,321 adults who initiated antihypertensive medication during the study period, including 320,691 (2.6%) with ADHD. In the pooled analysis across all countries, ADHD was associated with an increased rate of discontinuation in 5-year follow-up of antihypertensive medication (hazard ratio [HR] 1.14; 95% CI, 1.02-1.27). In age-stratified analyses, ADHD was associated with a higher rate of antihypertensive medication discontinuation in middle-aged (HR, 1.11; 95% CI, 1.01-1.23) and older adults (HR, 1.14; 95% CI, 1.01-1.29), but not in young adults. Individuals with ADHD also had higher odds of poor adherence across 1 year after treatment initiation (odds ratio [OR] 1.45, 95% CI 1.26-1.67) to 5 years (OR 1.64, 95% CI 1.34-2.00). Among those with ADHD, use of ADHD medications was associated with lower odds of poor adherence (1 year OR 0.66, 95% CI 0.60-0.73; 5 years OR 0.58, 95% CI 0.46-0.72).ConclusionsAdults with ADHD are more likely to discontinue antihypertensive treatment and exhibit poor medication adherence. However, ADHD medication use appears to be associated with better adherence among individuals with ADHD.

Background:Psychiatric disorders represent a significant global health burden with complex etiologies involving both genetic and environmental factors. However, while the main effects of genetic and environmental factors are frequently studied, their interplay in shaping psychiatric disorder risk remains poorly understood. This study investigates the interaction between polygenic scores (PGS) as proxies for genetic risk and environmental factors in the risk of psychiatric disorders. Method:This study utilized the iPSYCH case-cohort sample (n = 141,265). Environmental factors, including region, urbanicity, parental socioeconomic status, parental age, parental psychiatric history and early-life exposures: autoimmune disease, brain injury, and central nervous system (CNS) infections, were obtained from Danish nationwide registers. Logistic regression was used to examine the effects of targeted disorder-specific PGSs, environmental factors and their interactions on psychiatric disorders. Analyses were adjusted for age, sex and ancestral principal components to account for population stratification. Results:Both PGS and environmental factors were associated with psychiatric disorders. We found limited evidence of gene-environment interactions across the investigated psychiatric disorders. Most interaction terms were small and not statistically significant, but a few remained significant. These included a smaller PGS association with attention deficit hyperactivity disorder in Southern Denmark compared with the Capital Region, a reduced PGS association with bipolar disorder in the medium and lowest parental income groups compared with the highest income group, and a weaker PGS association with major depressive disorder in individuals with parental psychiatric history compared with those without such history. In contrast, a larger PGS association with schizophrenia was observed in the paternal age group 31-35 years compared with the 26-30 years reference group, and a stronger PGS association with anorexia nervosa in North Denmark compared with the Capital Region. Conclusion:Genetic liability for psychiatric disorders, captured through PGS, was associated with mental disorder risk across environmental contexts. Only a few gene-environment interactions were significant, and these were modest and mental disorder-specific. Overall, the findings highlight the difficulty of detecting robust gene-environment interactions and the need for studies of sufficient scale and statistical power to identify subtle gene-environment effects and improve understanding of psychiatric disorder etiology.

BACKGROUND:Involuntary treatment for patients with anorexia nervosa is common and lifesaving, but also highly intrusive. Understanding how morbidity patterns relate to involuntary treatment can help minimise its use. AIM:We estimate the relative risk of involuntary treatment according to morbidity profiles in patients with anorexia nervosa. METHOD:This register-based cohort study included all individuals diagnosed with anorexia nervosa (ICD-10: F50.0, F50.1) between 1 January 2000 and 31 December 2016 in Denmark. Individuals were grouped by prior morbidities using latent class analysis (LCA). Cox proportional hazards regression estimated the relative risk of first involuntary treatment (e.g. involuntary admission, detention, locked wards) after a diagnosis with anorexia nervosa, regardless of the associated diagnosis. The relative risk of involuntary treatment was estimated with latent classes and the number of morbidities as exposure. RESULTS:A total of 9892 individuals with anorexia nervosa were included (93.3% female), of which 821 (8.3%) individuals experienced at least one involuntary treatment event. The LCA produced six classes, with distinct morbidity profiles. The highest hazard ratio was observed for a group characterised by personality disorders, self-harm and substance misuse (hazard ratio 4.46, 95% CI: 3.43-5.79) followed by a high burden group with somatic and psychiatric disorders (hazard ratio 3.96, 95% CI: 2.81-5.59) and a group with developmental and behavioural disorders (hazard ratio 3.61, 95% CI: 2.54-5.11). The relative risk of involuntary treatment increased primarily with the number of psychiatric morbidities. CONCLUSIONS:Specific morbidity groups are associated with highly elevated risk of involuntary treatment among patients with anorexia nervosa. Targeting preventive interventions to high-risk groups may help reduce the need for involuntary treatment.

Prenatal antidepressant exposure has been associated with lower gestational age and birthweight. Yet, unmeasured residual confounding may inflate this association. We explored if maternal genetic liability for major depression explains part of the association of antidepressant use in pregnancy with lower gestational age and birthweight. We employed the maternal polygenic score (PGS) for major depression as a measure of genetic liability. We used generalised linear models to estimate the differences in gestational age and birthweight at each PGS quintile between children whose mothers continued antidepressant use during pregnancy (continuation group), children whose mothers discontinued antidepressant use during pregnancy (discontinuation group) and unexposed children. After adjusting for confounders, we found significant differences in birthweight between PGS quintiles in the continuation and unexposed group. Yet, this relationship was not linear. Furthermore, at the lowest and highest PGS quintiles, the continuation group had significantly reduced mean gestational ages (adjusted β ranges: 1.7–4.5 days, p  < 0.001–0.008) and lower mean birthweights (adjusted β ranges: 58.6–165.4 g, p  = 0.001–0.008) than the discontinuation and unexposed groups. We confirmed that antidepressant use in pregnancy was associated with small reductions in gestational age and birthweight but found that genetic liability for depression was not linearly associated with this risk. The causality of the observed associations could not be established due to the observational nature of the study. Residual confounding linked to the underlying disease was likely still present.

OBJECTIVE:Anorexia nervosa (AN) is associated with increased risk of mortality, but little is known about the risk of inpatient admissions and mortality outcomes in individuals with diagnoses of both AN and other psychiatric and somatic conditions. We aimed to investigate the inpatient admissions and mortality among people with AN and other diagnosed conditions using Danish national registers. METHOD:This retrospective cohort study included individuals diagnosed with AN in Denmark, born 1977-2010. We identified other mental and somatic conditions in this population. We used Cox proportional hazards regression to estimate the risk of inpatient admission and mortality, focusing on (i) the number of other diagnosed conditions, and (ii) specific combinations of conditions diagnosed prior to the AN diagnosis. Categories of inpatient admissions considered were due to: (i) AN, (ii) any psychiatric disorder, and (iii) any somatic disorder. Additionally, competing risks survival analysis was used to calculate the cumulative incidence of inpatient admission and all-cause mortality over the follow-up period. RESULTS:The study population included 11,489 individuals. The most common conditions individuals had prior to their AN diagnosis were other eating disorders (34.5%) and anxiety disorders (32.7%). During the follow-up, 3184 (27.7%), 4604 (40.1%), and 6636 (57.8%) individuals were admitted for AN, any psychiatric disorder, and any somatic disorder, respectively; and in total 106 (0.9%) died. The risk of all outcomes was highest among those who had received a higher number of other diagnoses. For most combinations, the risks of admission and mortality were increased. DISCUSSION:Our study presents the prevalence of other conditions in patients with AN in Denmark and elucidates their association with higher rates of inpatient admission and mortality. Our findings highlight the need for comprehensive, multidisciplinary care of patients with AN considering the spectrum of other diagnosed conditions to improve health outcomes.

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981-2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD or ASD diagnosis. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44%-100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal half sibling with ASD had increased risk of AN compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk whereas a negative association was found between AN-PGS and ADHD. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and genetic associations between ASD-PGS and AN and between AN-PGS and ADHD were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

The association between antidepressant continuation during pregnancy and postpartum mental health in women with obsessive-compulsive disorder (OCD) is uncertain. We identified 1317 women with live-birth singleton pregnancies and having outpatient/inpatient visits for OCD in the 4 years pre-pregnancy from the Danish registries. We defined three groups based on antidepressant prescriptions filled in the 2 years before pregnancy to delivery: (i) unexposed (n = 449); (ii) discontinuers (n = 346), i.e., with pre-pregnancy antidepressant fills only; (iii) continuers (n = 522), i.e., with antidepressant fills before and during pregnancy. We estimated crude and propensity score weighted hazard ratio (HRs) of postpartum visit for OCD and mood/anxiety disorders using Cox proportional hazard models. In weighted analyses, we found no difference in the probability of a postpartum visit for OCD or MADs with antidepressant continuation compared to unexposed and discontinuers. The likelihood of a postpartum OCD visit was higher in pregnancies having only one prescription fill during pregnancy compared to unexposed (HR = 3.44, 95% CI: 1.24, 9.54) or discontinuers (HR = 2.49, 95% CI: 0.91, 6.83). Continuers in pregnancy without antidepressant fill in the first three months postpartum had higher probability for postpartum visit for mood/anxiety disorders compared to discontinuers (HR = 3.84, 95% CI: 1.49, 9.92). Among pregnant women with pre-existing OCD, we found similar probabilities of a postpartum visit for OCD or mood/anxiety disorders in antidepressant continuers compared to unexposed and discontinuers. Continuers with a single prescription fill during pregnancy or no fill postpartum may have higher risks for these outcomes. Our findings highlight the importance of continuity of treatment throughout the perinatal period.

Anorexia nervosa (AN) is a serious eating disorder with high morbidity and mortality. In line with clinical and epidemiological studies that have established comorbidity to be the norm in psychiatric disorders, psychiatric as well as medical comorbidities have been shown to be frequent among individuals with AN. Notably, a recent Danish epidemiological study has identified comorbidity burden to be associated with increased risk of readmission and mortality in AN, highlighting the need to further examine the etiology and burden of comorbidity. The objective of the present study is to examine the genetic underpinnings of psychiatric and medical comorbidity burden in patient with AN using Danish population registers. The study population consists of individuals born in Denmark between May 1, 1981 and December 31, 2009 who received an AN diagnosis (ICD-10: F50.0 and F50.1) by December 31, 2016, followed up until the end of 2018. Information on comorbidities was obtained from the Danish National Patient Register and the Danish Psychiatric Central Research Register. In our ongoing analysis, the Danish subcohort of Anorexia Nervosa Genetics Initiative and Eating Disorders Genetics Initiative serves as our target cohort, comprising ∼7,000 AN cases with genotype data. Using Cox regression models adjusted for birth year and genomic principal components, polygenic risk scores (PRS) calculated using LDpred2-auto and meta-PRS for 422 phenotypes across 44 categories are used as predictors of psychiatric and medical comorbidity burden in AN cases. We will also present our findings on whether certain PRS categories predict specific combinations of comorbidities within AN patients. Additional sensitivity analyses will focus on ancestral diversity and other clinically relevant variables such as sex assigned at birth. To our knowledge, this is the largest and most detailed genomic examination of psychiatric and medical comorbidities in AN to date. Our findings have the potential to serve as a crucial step toward identifying distinct clinically relevant phenotypes within AN as assessed by polygenic burden to a large variety of complex traits and diseases in a data-driven approach, elucidating the biological mechanisms associated with AN outcome based on comorbidities, as well as developing risk prediction models toward personalized precision medicine.

OBJECTIVE:To determine the association between continued antidepressant use in pregnancy and postpartum psychiatric visits for eating (ED) or mood/anxiety disorders in women with preexisting ED.METHOD:Using Danish health registry data (1998-2015), we identified 3529 pregnancies in women with ED prepregnancy: (i) 564 with continued antidepressant use before and during pregnancy; (ii) 778 with discontinued antidepressants before pregnancy; (iii) 2137 unexposed. Outpatient and inpatient postpartum visits for an ED or a mood/anxiety disorder constituted the outcome measures. We estimated hazard ratios (HRs) and 95% confidence intervals (CI) using Cox regression with inverse probability of treatment weighting, and performed stratified analyses by antidepressant prescription filling in the first 3 months postpartum.RESULTS:The weighted cumulative incidence for an ED visit at end of follow-up was 4.5% (continued) and 4.8% (discontinued). We found no association between continued antidepressant and postpartum ED visit, relative to discontinued (HR: 0.89, 95% CI: 0.52-1.52). The HR for postpartum mood/anxiety disorder visit was 1.27 (95% CI: 0.68-2.36) with continued antidepressants versus discontinued but decreased if more than two antidepressant prescriptions were refilled. Continued antidepressant use was associated with a 57% reduced likelihood of a postpartum ED visit versus discontinued use in pregnancies with antidepressant prescription refills in the early postpartum.CONCLUSION:Among women with preexisting ED, there was no association between continued antidepressant use during pregnancy and the likelihood of postpartum psychiatric visits, relative to discontinued antidepressants before pregnancy. Continuation of treatment into the early postpartum is associated with reduced likelihood of postpartum ED visit.PUBLIC SIGNIFICANCE:Based on data from the Danish registries, we identified 3529 pregnancies among women with preexisting eating disorders before pregnancy. Women with continued antidepressant treatment both before and during pregnancy did not have a lower probability of having postpartum psychiatric visits for an eating disorder or for mood/anxiety disorders (often coexisting with eating disorders), relative to those who discontinued antidepressants before pregnancy. Further continuation of antidepressant treatment into the early postpartum is associated with improved maternal postpartum outcomes. However, residual confounding by disease severity limits confidence in this conclusion.

BACKGROUND:There is limited evidence that nitrate, a common contaminant in drinking water, increases the risk of childhood cancers. Our objective was to examine this association in Denmark. METHODS:We conducted a nationwide case-control study based on all singletons liveborn to Danish-born parents from 1991 to 2015 (N = 1,219,140) that included 596 leukemias, 180 lymphomas, and 310 central nervous system cancers (CNC) who were ≤15 years of age at diagnosis and were identified from the Danish Cancer Registry. Approximately 100 controls were randomly selected and matched to each case on date of birth and sex. Nitrate measurements in public water systems were linked with an address registry to estimate individual average nitrate concentrations during preconception, prenatal, and postnatal periods. Odd ratios (OR) and 95% confidence intervals (95%CI) were estimated using conditional logistic regression controlling for the matching variables, and birth order, birthweight, urbanicity, maternal education, employment, income and smoking, and parental age. RESULTS:There was no evidence of an association of nitrate with leukemia or lymphoma. An association between CNC and the highest category of nitrate exposure (>25 mg/L nitrate) was observed for preconception (OR = 1.82, 95%CI:1.09 to 3.04), prenatal (OR = 1.65, 95%CI:0.97 to 2.81), and postnatal exposure (OR = 1.48, 95%CI:0.82 to 2.68) in fully adjusted models. There was also some evidence of an exposure-response in models of continuous nitrate exposure and CNC. CONCLUSIONS:Our findings provide some evidence that exposure to nitrate from drinking water may increase the risk of childhood CNC cancer, but not leukemia or lymphoma.

Asynchronous cellular automata (ACAs) are cellular automata (CAs) that allow cells to undergo state transitions independently and randomly. Notwithstanding the unpredictable update timings of each cell, universal computation can be carried out on ACAs via the embedding of logic circuits into cell spaces, like the ACA with von Neumann neighborhood that uses 5 cell states and 55 transition rules (Lee et al. (2003)). Recently, the complexity in terms of the numbers of cell states and rules has been reduced via the use of local configurations representing signals that may fluctuate between moving forward and backward in the cell space. This forms the basis for the implementation of simple circuit elements in ACAs that can exploit signal fluctuations. Nevertheless, universal ACA still appears much more complex than the best synchronous CAs found to date, e.g., the 2-state and 3-rule CA (Banks 1970). This paper aims to propel the fluctuation-based scheme further, by proposing a novel ACA with von Neumann neighborhood which requires merely 3 cell states and 10 rules. The universality of our ACA is shown by implementing a new set of circuit elements that are able to exploit fluctuations, as well as a special circuitry to conduct the crossing of signals in the two-dimensional cell space. The further reduction in the numbers of both cell states and rules demonstrates that random fluctuations may play an important role in pursuing the minimal complexity of universal ACAs.

Collagen fibre diffraction patterns are typically interpreted assuming a monotonous, average triple helical conformation for the collagen molecule. Two different helical symmetries have been proposed: seven residues in two turns versus 10 residues in three turns. Collagen model peptides show predominantly the 7-fold symmetry but provide evidence for local changes in the helical twist, which are related to some extent to the local sequence of the peptides but also to the lattice interactions in the crystal. Thus, it is difficult to determine precisely to what degree the amino acid sequence dictates the fine details of collagen conformation. A new method is presented here in which an internal triple helical twist is defined. This method takes into consideration all three chains simultaneously, and facilitates investigating the sequence dependence of helical twist variation, the conformational consequences of collagen interruptions, and the effects on collagen conformation introduced upon receptor or ligand-binding. Analysis of the crystal structures of model peptides suggests that collagen varies gradually and continuously its helical twist according to the local distribution of imino acid residues, with the 7-fold and 10-fold symmetries representing the limits of this variation for the cases of imino acid saturation or absence, respectively.