Maternal Epilepsy and Long-term Offspring Mortality: A Nationwide Cohort Study.

OBJECTIVE: We examined how maternal epilepsy and use of antiseizure medications in pregnancy was associated with offspring mortality. METHODS: This population-based cohort study included all live- and stillborn singletons in Denmark between 1981 and 2016. We used nation-wide registers to retrieve information on pregnancy characteristics, epilepsy diagnoses, use of antiseizure medications, and mortality. Adjusted mortality rate ratios (MRR) were estimated using log-linear Poisson regression. RESULTS: The cohort consisted of 1,862,474 children. In total, 12,026 live-born children died during follow-up, of whom 170 (1.4%) were offspring of mothers with epilepsy. Overall mortality was increased in offspring of mothers with epilepsy compared to offspring of mothers without epilepsy (MRR = 1.46, 95% CI: 1.23-1.71), driven by an excess mortality only in the first year of life. Mortality was increased for natural deaths (MRR = 1.50, 95% CI: 1.25-1.78) but not from unnatural deaths (MRR = 1.38, 95% CI: 0.84-2.14), and only in offspring of women with epilepsy who used antiseizure medications during pregnancy (MRR = 1.51, 95% CI: 1.00-2.17), but not in offspring of women with epilepsy who did not use antiseizure medications while pregnant (MRR = 0.97, 95% CI: 0.69-1.31). When analyses were restricted to children born from 2000 and onwards, the excess mortality that was observed in the first year of life among children of mothers with epilepsy, was no longer evident. INTERPRETATION: During the 1981 to 1999 epoch, offspring of women with epilepsy were at increased risk of dying in the first year of life. However, this risk did not extend to children born after 2000. Future retrospective studies of the effects of maternal epilepsy on the health of the offspring should take this difference into account. ANN NEUROL 2022;91:455-465.

The complexities of suicide: a multilevel survival analysis examining individual, familial and neighbourhood determinants of suicide risk using Danish register-based data.

BACKGROUND: Suicide risk is complex and nuanced, and how place impacts suicide risk when considered alongside detailed individual risk factors remains uncertain. We aimed to examine suicide risk in Denmark with both individual and neighbourhood level risk factors. METHODS: We used Danish register-based data to identify individuals born in Denmark from 1972, with full parental information and psychiatric diagnosis history. We fitted a two-level survival model to estimate individual and neighbourhood determinants on suicide risk. RESULTS: We identified 1723 cases of suicide in Denmark during the follow-up period from 1982 to 2015. Suicide risk was explained mainly by individual determinants. Parental comorbidities, particularly maternal schizophrenia [incidence rate ratio (IRR): 2.29, 95% CI 1.56-3.16] and paternal death (2.29, 95% CI 1.31-3.72) partly explained suicide risk when adjusted for all other determinants. The general contextual effect of suicide risk across neighbourhoods showed a median incidence rate ratio (MRR) of 1.13 (1.01-1.28), which was further reduced with full adjustment. Suicide risk increased in neighbourhoods with a higher proportion of manual workers (IRR: 1.08; 1.03-1.14), and decreased with a higher population density (IRR: 0.89; 0.83-0.96). CONCLUSION: Suicide risk varies mainly between individuals, with parental comorbidities having the largest effect on suicide risk. Suicide risk was less impacted by neighbourhood, though, albeit to a lesser extent than individual determinants, some characteristics were associated with suicide risk. Suicide prevention policies might consider targeting interventions towards individuals more vulnerable due to particular parental comorbidities, whilst taking into account that some neighbourhood characteristics might exacerbate this risk further.

Schizophrenia spectrum disorders in Denmark between 2000 and 2018: Incidence and early diagnostic transition.

BACKGROUND: Schizophrenia spectrum disorders (SSD) comprise a group of related mental disorders, which share clinical features and common genetic disposition, but it is unknown if there is a diagnostic transition between these disorders over time. We aimed to study the incidence at the first SSD diagnosis between 2000 and 2018, defined as schizophrenia, schizotypal or schizoaffective disorder, and the early diagnostic transition between these disorders. METHODS: Using Danish nationwide healthcare registers, we identified all individuals aged 15-64 years during the period from 2000 to 2018 in Denmark and calculated the yearly incidence rates for the specific SSDs. We studied the diagnostic pathways from the first ever diagnosis of an SSD across the subsequent two treatment courses with an SSD diagnosis to evaluate early diagnostic stability, and explore potential changes over time. RESULTS: Among 21,538 patients, yearly incidence rates per 10,000 individuals were similar during the observation period for schizophrenia (2000: 1.8; 2018: 1.6), lower for schizoaffective disorder (2000: 0.3; 2018: 0.1) and increasing for schizotypal disorder (2000: 0.7; 2018: 1.3). Among the subgroup of 13,417 individuals with three separate treatment courses, early diagnostic stability was present among 89.9% which differed between the disorders (schizophrenia: 95.4%; schizotypal disorder: 78.0%; schizoaffective disorder: 80.5%). Among 1352 (10.1%) experiencing an early diagnostic transition, 398 (3.0%) were diagnosed with schizotypal disorder after a schizophrenia or schizoaffective disorder diagnosis. CONCLUSION: This study provides comprehensive incidence rates for SSDs. The majority of patients experienced early diagnostic stability, but sizable proportions of people with initial schizophrenia or schizoaffective disorder are subsequently diagnosed with schizotypal disorder.

Towards more comprehensive nationwide familial aggregation studies in Denmark: The Danish Civil Registration System versus the lite Danish Multi-Generation Register.

AIM: Linking information on family members in the Danish Civil Registration System (CRS) with information in Danish national registers provides unique possibilities for research on familial aggregation of diseases, health patterns, social factors and demography. However, the CRS is limited in the number of generations that it can identify. To allow more complete familial linkages, we introduce the lite Danish Multi-Generation Register (lite MGR) and the future full Danish MGR that is currently being developed. METHODS: We generated the lite MGR by linking the current version of the CRS with historical versions stored by the Danish National Archives in the early 1970s, which contain familial links not saved in the current CRS. We describe and compare the completeness of familial links in the lite MGR and the current version of the CRS. We also describe planned procedures for generating the full MGR by linking the current CRS with scanned archived records from Parish Registers. RESULTS: Among people born in Denmark in 1960 or later, the current CRS contains information on both parents. However, it has limited parental information for people born earlier. Among the 732,232 people born in Denmark during 1950-1959, 444,084 (60.65%) had information on both parents in the CRS. In the lite MGR, it was 560,594 (76.56%). CONCLUSIONS: The lite MGR offers more complete information on familial relationships than the current CRS. The lite and full MGR will offer an infrastructure tying together existing research infrastructures, registers and biobanks, raising their joint research value to an unparalleled level.

School performance and genetic propensities for educational attainment and depression in the etiology of self-harm: a Danish population-based study.

BACKGROUND: Poor school performance is linked to higher risks of self-harm. The association might be explained through genetic liabilities for depression or educational attainment. We investigated the association between school performance and self-harm in a population-based sample while assessing the potential influence of polygenic risk scores (PRSs) for depression (PRSMDD) and for educational attainment (PRSEDU). METHOD: We conducted a follow-up study of individuals born 1987-98 and followed from age 18 until 2016. The total sample consisted of a case group (23,779 diagnosed with mental disorders; schizophrenia, bipolar disorder, depression, autism, and attention deficit hyperactivity disorder (ADHD) and a randomly sampled comparison group (n = 10,925). Genome-wide data were obtained from the Neonatal Screening Biobank and information on school performance, family psychiatric history, and socioeconomic status from national administrative registers. RESULTS: Individuals in the top PRSMDD decile were at higher self-harm risk in the case group (IRR: 1.30; 95% CI 1.15-1.46), whereas individuals in the top PRSEDU decile were at lower self-harm risk (IRR: 0.63; 95% CI: 0.55-0.74). Poorer school performance was associated with higher self-harm risk in persons diagnosed with any mental disorder (IRR: 1.69; 95% CI: 1.44-1.99) and among the comparison group (IRR: 7.93; 95% CI: 4.47-15.18). Observed effects of PRSMDD and PRSEDU on self-harm risk were strongest for individuals with poor school performance. CONCLUSION: Associations between PRSMDD and self-harm risk and between PRSEDU and self-harm risk were found. Nevertheless, these polygenic scores seem currently of limited clinical utility for identifying individuals at high self-harm risk.

Environmental pollution is associated with increased risk of psychiatric disorders in the US and Denmark.

The search for the genetic factors underlying complex neuropsychiatric disorders has proceeded apace in the past decade. Despite some advances in identifying genetic variants associated with psychiatric disorders, most variants have small individual contributions to risk. By contrast, disease risk increase appears to be less subtle for disease-predisposing environmental insults. In this study, we sought to identify associations between environmental pollution and risk of neuropsychiatric disorders. We present exploratory analyses of 2 independent, very large datasets: 151 million unique individuals, represented in a United States insurance claims dataset, and 1.4 million unique individuals documented in Danish national treatment registers. Environmental Protection Agency (EPA) county-level environmental quality indices (EQIs) in the US and individual-level exposure to air pollution in Denmark were used to assess the association between pollution exposure and the risk of neuropsychiatric disorders. These results show that air pollution is significantly associated with increased risk of psychiatric disorders. We hypothesize that pollutants affect the human brain via neuroinflammatory pathways that have also been shown to cause depression-like phenotypes in animal studies.

Exposure to ambient air pollution during childhood and subsequent risk of self-harm: A national cohort study.

A growing body of evidence indicates that exposure to air pollution not only impacts on physical health but is also linked with a deterioration in mental health. We conducted the first study to investigate exposure to ambient particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) and nitrogen dioxide (NO2) during childhood and subsequent self-harm risk. The study cohort included persons born in Denmark between January 1, 1979 and December 31, 2006 (N = 1,424,670), with information on daily exposures to PM2.5 and NO2 at residence from birth to 10th birthday. Follow-up began from 10th birthday until first hospital-presenting self-harm episode, death, or December 31, 2016, whichever came first. Incidence rate ratios estimated by Poisson regression models revealed a dose relationship between increasing PM2.5 exposure and rising self-harm risk. Exposure to 17-19 µg/m3 of PM2.5 on average per day from birth to 10th birthday was associated with a 1.45 fold (95% CI 1.37-1.53) subsequently elevated self-harm risk compared with a mean daily exposure of <13 µg/m3, whilst those exposed to 19 µg/m3 or above on average per day had a 1.59 times (1.45-1.75) elevated risk. Higher mean daily exposure to NO2 during childhood was also linked with increased self-harm risk, but the dose-response relationship observed was less evident than for PM2.5. Covariate adjustment attenuated the associations, but risk remained independently elevated. Although causality cannot be assumed, these novel findings indicate a potential etiological involvement of ambient air pollution in the development of mental ill health.

Temporal trends in incidence of hospital-treated self-harm among adolescents in Denmark: national register-based study.

BACKGROUND: Studies conducted in the UK and in Ireland have reported increased rates of self-harm in adolescent females from around the time of the 2008 economic recession and through periods of subsequent national austerity programme implementation. It is not known if incidence rates have increased similarly in other Western European countries during this period. METHODS: Data from interlinked national administrative registers were extracted for individuals born in Denmark during 1981-2006. We estimated gender- and age-specific incidence rates (IRs) per 10,000 person-years at risk for hospital-treated non-fatal self-harm during 2000-2016 at ages 10-19 years. RESULTS: Incidence of self-harm peaked in 2007 (IR 25.1) and then decreased consistently year on year to 13.8 in 2016. This pattern was found in all age groups, in both males and females and in each parental income tertile. During the last 6 years of the observation period, 2011-2016, girls aged 13-16 had the highest incidence rates whereas, among boys, incidence was highest among 17-19 year olds throughout. CONCLUSIONS: The temporal increases in incidence rates of self-harm among adolescents observed in some Western European countries experiencing major economic recession were not observed in Denmark. Restrictions to sales of analgesics, access to dedicated suicide prevention clinics, higher levels of social spending and a stronger welfare system may have protected potentially vulnerable adolescents from the increases seen in other countries. A better understanding of the specific mechanisms behind the temporal patterns in self-harm incidence in Denmark is needed to help inform suicide prevention in other nations.

Trauma, comorbidity, and mortality following diagnoses of severe stress and adjustment disorders: a nationwide cohort study.

Longitudinal outcomes following stress or trauma diagnoses are receiving attention, yet population-based studies are few. The aims of the present cohort study were to examine the cumulative incidence of traumatic events and psychiatric diagnoses following diagnoses of severe stress and adjustment disorders categorized using International Classification of Diseases, Tenth Revision, codes and to examine associations of these diagnoses with all-cause mortality and suicide. Data came from a longitudinal cohort of all Danes who received a diagnosis of reaction to severe stress or adjustment disorders (International Classification of Diseases, Tenth Revision, code F43.x) between 1995 and 2011, and they were compared with data from a general-population cohort. Cumulative incidence curves were plotted to examine traumatic experiences and psychiatric diagnoses during the study period. A Cox proportional hazards regression model was used to examine the associations of the disorders with mortality and suicide. Participants with stress diagnoses had a higher incidence of traumatic events and psychiatric diagnoses than did the comparison group. Each disorder was associated with a higher rate of all-cause mortality than that seen in the comparison cohort, and strong associations with suicide were found after adjustment. This study provides a comprehensive assessment of the associations of stress disorders with a variety of outcomes, and we found that stress diagnoses may have long-lasting and potentially severe consequences.

National cohort study of absolute risk and age-specific incidence of multiple adverse outcomes between adolescence and early middle age.

BACKGROUND: Psychiatric illness, substance misuse, suicidality, criminality and premature death represent major public health challenges that afflict a sizeable proportion of young people. However, studies of multiple adverse outcomes in the same cohort at risk are rare. In a national Danish cohort we estimated sex- and age-specific incidence rates and absolute risks of these outcomes between adolescence and early middle age. METHODS: Using interlinked registers, persons born in Denmark 1966-1996 were followed from their 15(th) until 40(th) birthday or December 2011 (N = 2,070,904). We estimated sex- and age-specific incidence rates of nine adverse outcomes, in three main categories: Premature mortality (all-causes, suicide, accident); Psychiatric morbidity (any mental illness diagnosis, suicide attempt, alcohol or drug misuse disorder); Criminality (violent offending, receiving custodial sentence, driving under influence of alcohol or drugs). Cumulative incidences were also calculated using competing risk survival analyses. RESULTS: For cohort members alive on their 15(th) birthday, the absolute risks of dying by age 40 were 1.99 % for males [95 % confidence interval (CI) 1.95-2.03 %] and 0.85 % for females (95 % CI 0.83-0.88 %). The risks of substance misuse and criminality were also much higher for males, especially younger males, than for females. Specifically, the risk of a first conviction for a violent offence was highest amongst males aged below 20. Females, however, were more likely than males to have a hospital-treated psychiatric disorder. By age 40, 13.25 % of females (95 % CI 13.16-13.33 %) and 9.98 % of males (95 % CI 9.91-10.06 %) had been treated. Women aged below 25 were also more likely than men to first attempt suicide, but this pattern was reversed beyond this age. The greatest gender differentials in incidence rates were in criminality outcomes. CONCLUSIONS: This is the first comprehensive assessment of the incidence rates and absolute risks of these multiple adverse outcomes. Approximately 1 in 50 males and 1 in 120 females who are alive on their 15th birthday will die by age 40. By examining the same cohort at risk, we compared risks for multiple outcomes without differential inter-cohort biases. These epidemiological profiles will inform further research into the pathways leading to these adverse events and future preventive strategies.

Severe stress and adjustment disorder diagnoses in the population of Denmark.

We created a registry of Danish-born citizens of Denmark with incident International Classification of Diseases (10th ed.; ICD-10) severe stress and adjustment disorder diagnoses between 1995 and 2011. A unique personal identifier was used to retrieve and merge data on demographic characteristics and diagnoses (ICD-10 codes F43.x). Here we report on the incidence of these disorders and the demographic characteristics of the subset of the Danish population who have received 1 of these diagnoses: 111,844 adults and children received a first diagnosis between 1995 and 2011. More women than men (60.1% vs. 39.9%) received a diagnosis. Diagnoses increased during the late teens through early 30s. Adjustment disorder was the most common diagnosis (65.7% of adults and 64% of children). Reaction to severe stress unspecified was the second most common (19.8% of adults and 23.8% of children), and there was a large increase in both, as well as acute stress reaction diagnoses, in 2007 (3,717-5,141, 1,248-2,520, and 348-1,024 in 2006 to 2007, respectively). Findings regarding gender and age of onset are similar to other westernized countries. This registry can be used for future research programs, contributing to the study of stress and trauma.

Changing Neighborhood Income Deprivation Over Time, Moving in Childhood, and Adult Risk of Depression.

Importance: Complex biological, socioeconomic, and psychological variables combine to cause mental illnesses, with mounting evidence that early-life experiences are associated with adulthood mental health. Objective: To evaluate whether changing neighborhood income deprivation and residential moves during childhood are associated with the risk of receiving a diagnosis of depression in adulthood. Design, Setting, and Participants: This cohort study included the whole population of 1 096 916 people born in Denmark from January 1, 1982, to December 31, 2003, who resided in the country during their first 15 years of life. Individuals were followed up from 15 years of age until either death, emigration, depression diagnosis, or December 31, 2018. Longitudinal data on residential location was obtained by linking all individuals to the Danish longitudinal population register. Statistical analysis was performed from June 2022 to January 2024. Exposures: Exposures included a neighborhood income deprivation index at place of residence for each year from birth to 15 years of age and a mean income deprivation index for the entire childhood (aged ≤15 years). Residential moves were considered by defining "stayers" as individuals who lived in the same data zone during their entire childhood and "movers" as those who did not. Main Outcomes and Measures: Multilevel survival analysis determined associations between neighborhood-level income deprivation and depression incidence rates after adjustment for individual factors. Results were reported as incidence rate ratios (IRRs) with 95% credible intervals (95% CrIs). The hypotheses were formulated before data collection. Results: A total of 1 096 916 individuals (563 864 male participants [51.4%]) were followed up from 15 years of age. During follow-up, 35 098 individuals (23 728 female participants [67.6%]) received a diagnosis of depression. People living in deprived areas during childhood had an increased risk of depression (IRR, 1.10 [95% CrI, 1.08-1.12]). After full individual-level adjustment, the risk was attenuated (IRR, 1.02 [95% CrI, 1.01-1.04]), indicating an increase of 2% in depression incidence for each 1-SD increase in income deprivation. Moving during childhood, independent of neighborhood deprivation status, was associated with significantly higher rates of depression in adulthood compared with not moving (IRR, 1.61 [95% CrI, 1.52-1.70] for 2 or more moves after full adjustment). Conclusions and Relevance: This study suggests that, rather than just high or changing neighborhood income deprivation trajectories in childhood being associated with adulthood depression, a settled home environment in childhood may have a protective association against depression. Policies that enable and support settled childhoods should be promoted.

Exposure to air pollution and risk of respiratory tract infections in the adult Danish population-a nationwide study.

OBJECTIVES: The association between air pollution and risk of respiratory tract infection (RTI) in adults needs to be clarified in settings with low to moderate levels of air pollution. We investigated this in the Danish population between 2004 and 2016. METHODS: We included 3 653 490 persons aged 18-64 years in a nested case-control study. Exposure was defined as the average daily concentration at the individual's residential address of CO, NOX, NO2, O3, SO2, NH3, PPM2.5, black carbon, organic carbon, mineral dust, sea salt, secondary inorganic aerosols, SO42-, NO3-, NH4+, secondary organic aerosols, PM2.5, and PM10 during a 3-month exposure window. RTIs were defined by hospitalization for RTIs. Incidence rate ratios (IRRs) and 95% CIs were estimated comparing highest with lowest decile of exposure using conditional logistic regression models. RESULTS: In total, 188 439 incident cases of RTI were identified. Exposure to most air pollutants was positively associated with risk of RTI. For example, NO2 showed an IRR of 1.52 (CI: 1.48-1.55), and PM2.5 showed an IRR of 1.45 (CI: 1.40-1.50). In contrast, exposure to sea salt, PM10, NH3, and O3 was negatively associated with a risk of RTIs. DISCUSSION: In this nationwide study comprising adults, exposure to air pollution was associated with risk of RTIs and subgroups hereof. Sea salt, PM10, NH3, and O3 may be proxies for rural areas, as the levels of these species in Denmark are higher near the western coastlines and/or in rural areas with fewer combustion sources.

Parental history of lupus and rheumatoid arthritis and risk in offspring in a nationwide cohort study: does sex matter?

OBJECTIVES: To examine the familial risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), including juvenile rheumatoid/idiopathic arthritis (JRA), in a population-based setting; and to determine whether patterns of transmission differ according to the sex of the parent or offspring, in order to provide insight into the potential impact of X-chromosomal factors on sex disparities in these autoimmune diseases. METHODS: A population-based cohort of parent-offspring triads from Denmark (1977-2010) was established. SLE and RA incidence rates among offspring were calculated, and Cox regression was performed to assess the sex-specific risk of disease in offspring according to maternal or paternal disease history. RESULTS: Among 3 513 817 parent-offspring triads, there were 1258 SLE cases among offspring (1095 female, 163 male) and 9118 cases of RA/JRA (6086 female, 3032 male). Among female offspring, SLE risk was nearly the same according to maternal (HR 14.1) or paternal (HR 14.5) history (p=NS); likewise among male offspring, risk according to maternal (HR 5.5) and paternal (no cases) history were similar (p=NS). For RA, all risk estimates were similar, regardless of the sex of the offspring or parent (HR 2.6-2.9; p=NS). CONCLUSIONS: The authors quantified the familial risk of SLE and RA in a nationwide cohort study. For both diseases, transmission was comparable among both female and male offspring of maternal and paternal cases. These data provide evidence at the population level that X-chromosomal factors do not play a major role in sex disparities associated with the risk of SLE and RA.

Multilevel interactions between family and neighbourhood socioeconomic indices in childhood and later risks of self-harm and violent criminality in Denmark: a national cohort study.

BACKGROUND: A socioeconomically disadvantaged childhood has been associated with elevated self-harm and violent criminality risks during adolescence and young adulthood. However, whether these risks are modified by a neighbourhood's socioeconomic profile is unclear. The aim of our study was to compare risks among disadvantaged young people residing in deprived areas versus risks among similarly disadvantaged individuals residing in affluent areas. METHODS: We did a national cohort study, using Danish interlinked national registers, from which we delineated a longitudinal cohort of people born in Denmark between Jan 1, 1981, and Dec 31, 2001, with two Danish-born parents, who were alive and residing in the country when they were aged 15 years, who were followed up for a hospital-treated self-harm episode or violent crime conviction. A neighbourhood affluence indicator was derived based on nationwide income quartiles, with parental income and educational attainment indicating the socioeconomic position of each cohort member's family. Bayesian multilevel survival analyses were done to examine the moderating influences of neighbourhood affluence on associations between family socioeconomic position and sex-specific risks for the two adverse outcomes. FINDINGS: 1 084 047 cohort members were followed up for 12·8 million person-years in aggregate. Individuals of a low socioeconomic position residing in deprived neighbourhoods had a higher incidence of both self-harm and violent criminality compared with equivalently disadvantaged peers residing in affluent areas. Women from a low-income background residing in affluent areas had, on average, 95 (highest density interval 76-118) fewer self-harm episodes and 25 (15-41) fewer violent crime convictions per 10 000 person-years compared with women of an equally low income residing in deprived areas, whereas men of a low income residing in affluent areas had 61 (39-81) fewer self-harm episodes and 88 (56-191) fewer violent crime convictions per 10 000 person-years than men of a low income residing in deprived areas. INTERPRETATION: Even in a high-income European country with comprehensive social welfare and low levels of poverty and inequality, individuals residing in affluent neighbourhoods have lower risks of self-harm and violent criminality compared with individuals residing in deprived neighbourhoods. More research is needed to explore the potential of neighbourhood policies and interventions to reduce the harmful effects of growing up in socioeconomically deprived circumstances on later risk of self-harm and violent crime convictions. FUNDING: European Research Council, Lundbeck Foundation Initiative for Integrative Psychiatric Research, and BERTHA, the Danish Big Data Centre for Environment and Health funded by the Novo Nordisk Foundation Challenge Programme.

PM2.5 air pollution components and mortality in Denmark.

BACKGROUND: Ambient fine particulate matter (PM2.5) causes millions of deaths every year worldwide. Identification of the most harmful types of PM2.5 would facilitate efficient prevention strategies. OBJECTIVES: The aim of this study was to investigate associations between components of PM2.5 and mortality in a nation-wide Danish population. METHODS: Our study base was Danes born 1921-1985 and aged 30-85 years, who were followed up for mortality from 1991 to 2015. We included 678,465 natural cause mortality cases and selected five age, sex and calendar time matched controls to each case from the study base. We retrieved the address history of the study population from Danish registries and assessed five-year average concentrations of eight PM2.5 components using deterministic Chemistry-Transport Models air pollution models. We estimated mortality rate ratios (MRRs) by conditional logistic regression and adjusted for socio-demographical factors at individual and neighborhood level. RESULTS: Single pollutant models showed the strongest associations between natural cause mortality and an interquartile increase in sulfate particles (SO4--) (MRR: 1.123; 95 % CI: 1.100-1.147 per 1.5 µg/m3) and secondary organic aerosol (SOA) (MRR: 1.054; 95 % CI: 1.048-1.061 per 0.050 µg/m3). Two-pollutant models showed robust associations between SO4-- and SOA and natural cause mortality. Elemental carbon and mineral dust showed robust associations with higher respiratory and lung cancer mortality. CONCLUSION: This nation-wide study found robust associations between natural cause mortality and SO4-- particles and SOA, which is in line with the results of previous studies. Elemental carbon and mineral dust showed robust associations with higher respiratory and lung cancer mortality.

Urban-Rural Differences in Schizophrenia Risk: Multilevel Survival Analyses of Individual- and Neighborhood-Level Indicators, Urbanicity and Population Density in a Danish National Cohort Study.

Background: Urban-rural differences in schizophrenia risk have been widely evidenced across Western countries. However, explanation of these differences is lacking. We aimed to identify contextual risk factors for schizophrenia that explain urban-rural differences in schizophrenia risk. Methods: Utilizing Danish population-based registers, we partitioned Denmark into 1885 geographic "neighborhoods" homogeneously sized in terms of population. Information on the entire Danish population from 1981 to 2016 was used to quantify a spectrum of neighborhood-level domains. We subsequently conducted multilevel survival analyses following persons born in Denmark from 1971 to 1982 for the development of schizophrenia allowing for clustering of people within neighborhoods. We used this method to tease apart the effects of individual, specific, and general contextual risk factors for schizophrenia. Results: A significant general contextual effect in schizophrenia risk across neighborhoods was estimated (Medium Incidence Rate Ratio (MRR):1.41; 95% CI:1.35-1.48). Most of the specific contextual factors examined were associated with schizophrenia risk. For instance, neighborhood-level proportion of lone adult households (Incidence Rate Ratios (IRR):1.53; 95% CI:1.44-1.63) had largest risk estimate. Adjustment for all individual-level and specific contextual constructs reduced the IRR for urbanicity from 1.98 (95% CI:1.77-2.22) to 1.30 (95% CI:1.11-1.51). Conclusions: In the largest prospective multilevel survival analyses of schizophrenia risk conducted to date, multiple neighborhood-level characteristics were associated with raised schizophrenia risk, with these contextual factors explaining most of the elevated risk linked with urbanicity. However, the unexplained heterogeneity that was evident in our multilevel models indicates that our understanding of the role of urbanicity in schizophrenia's etiology remains incomplete.

Adverse Childhood Experiences and Risk of Subsequently Engaging in Self-Harm and Violence towards Other People-"Dual Harm".

The etiology of "dual harm" (the co-occurrence of self-harm and externalized violence in the same individual) is under-researched. Risk factors have mostly been investigated for each behavior separately. We aimed to examine adversities experienced between birth and age 15 years among adolescents and young adults with histories of self-harm and violent criminality, with a specific focus on dual harm. Three nested case-control studies were delineated using national interlinked Danish registers; 58,409 cases in total aged 15-35 were identified: 28,956 with a history of violent criminality (but not self-harm), 25,826 with a history of self-harm (but not violent criminality), and 3987 with dual-harm history. Each case was matched by date of birth and gender to 20 controls who had not engaged in either behavior. We estimated exposure prevalence for cases versus controls for each of the three behavior groups, and incidence rate ratios (IRRs). Experiencing five or more childhood adversities was more prevalent among individuals with dual-harm history (19.3%; 95% CI 18.0, 20.8%) versus self-harm (10.9%; 10.5, 11.3%) and violence (11.4%; 11.0%, 11.8%) histories. The highest IRRs for dual harm were linked with parental unemployment (5.15; 95% CI 4.71, 5.64), parental hospitalization following self-harm (4.91; 4.40, 5.48) or assault (5.90; 5.07, 6.86), and parental violent criminality (6.11; 5.57, 6.70). Growing up in environments that are characterized by poverty, violence, and substance misuse, and experiencing multiple adversities in childhood, appear to be especially strongly linked with elevated dual-harm risk. These novel findings indicate potential etiologic pathways to dual harm.

Long-term exposure to air pollution and mortality in the Danish population a nationwide study.

BACKGROUND: Studies have shown higher mortality in association with exposure to air pollution. We investigated this association with focus on differences between socioeconomic groups. METHODS: We included all Danes born between 1921 and 1985 aged 30-85 years from 1991 to 2015 (N = 4,401,348). We applied a nested case-control design and identified those who died during follow-up and selected five controls per case. We modelled NO2, fine particulate matter (PM2·5), black carbon (BC) particles, and ozone (O3) as five-year average concentrations at the residential addresses of 672,895 all natural cause mortality cases and 3,426,533 controls in conditional logistic regression with adjustment for individual and neighbourhood level socio-demographic variables. FINDINGS: In single pollutant models, a 10 µg/m3 (BC: 1 µg/m3) increase in NO2, PM2·5, BC, and O3 was associated with natural cause mortality rate ratios (MRR) of 1·05 (95% confidence interval 1·04-1·06), 1·08 (1·04-1·13), 1·05 (1·02-1·08), and 0·96 (0·95-0·97), respectively. The patterns were similar for respiratory disease and lung cancer mortality. O3 was associated with higher risk of CVD mortality. The rate differences for a unit increase in PM2·5, NO2, and BC were largest among those with the lowest income; this pattern was not detected when considering the relative risk measure, MRR. INTERPRETATION: Long-term concentration of air pollution at the residence was associated with higher natural cause mortality in the Danish population and the strength of the association differed by socioeconomic group. We recommend that future studies express socioeconomic differences in absolute rather than relative risk.

Exposure to air pollution during childhood and risk of developing schizophrenia: a national cohort study.

BACKGROUND: Ambient air pollution affects neurological function, but its association with schizophrenia risk is unclear. We investigated exposure to nitrogen oxides (NOX) as a whole and nitrogen dioxide (NO2) specifically, as well as PM10, and PM2·5, during childhood and subsequent schizophrenia risk. METHODS: People born in Denmark from 1980 to 1984 (N=230 844), who were residing in the country on their tenth birthday, and who had two Danish-born parents were followed-up from their tenth birthday until schizophrenia diagnosis or Dec 31, 2016. Mean daily exposure to each pollutant (NO2, NOX, PM10, and PM2·5) at all of an individual's residential addresses from birth to their tenth birthday was modelled. Incidence rate ratios, cumulative incidence, and population attributable risks were calculated using survival analysis techniques. FINDINGS: We analysed data between Aug 1, 2018, and Nov 15, 2019. Of 230 844 individuals included, 2189 cohort members were diagnosed with schizophrenia during follow-up. Higher concentrations of residential NO2 and NOX exposure during childhood were associated with subsequent elevated schizophrenia risk. People exposed to daily mean concentrations of more than 26·5 µg/m3 NO2 had a 1·62 (95% CI 1·41-1·87) times increased risk compared with people exposed to a mean daily concentration of less than 14·5 µg/m3. The absolute risks of developing schizophrenia by the age of 37 years when exposed to daily mean concentrations of more than 26·5 µg/m3 NO2 between birth and 10 years were 1·45% (95% CI 1·30-1·62%) for men and 1·03% (0·90-1·17) for women, whereas when exposed to a mean daily concentration of less than 14·5 µg/m3, the risk was 0·80% (95% CI 0·69-0·92%) for men and 0·67% (0·57-0·79) for women. Associations between exposure to PM2·5 or PM10 and schizophrenia risk were less consistent. INTERPRETATION: If the association between air pollution and schizophrenia is causal, reducing ambient air pollution including NO2 and NOX could have a potentially considerable effect on lowering schizophrenia incidence at the population level. Further investigations are necessary to establish a causal relationship. FUNDING: Lundbeck Foundation, Stanley Medical Research Institute, European Research Council, NordForsk, Novo Nordisk Foundation, National Health and Medical Research Council, Danish National Research Foundation.