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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.

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). 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. 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. 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.

BackgroundA 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.MethodsWe 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.Findings1 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.InterpretationEven 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.FundingEuropean 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.

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.

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.

Ambient fine particulate matter (PMThe aim of this study was to investigate associations between components of PMOur 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 PMSingle pollutant models showed the strongest associations between natural cause mortality and an interquartile increase in sulfate particles (SOThis nation-wide study found robust associations between natural cause mortality and SO

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.

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

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.

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.

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.

BackgroundAdverse health and social outcomes are known to occur more frequently following parental death during childhood, but evidence is lacking for comparing long-term risks of internalised v. externalised harm.MethodsThis national register-based cohort study consisted of Danish persons born 1970–2000. The Civil Registration System and National Causes of Death Register were linked to ascertain parental deaths by cause before cohort members' 15th birthdays. From age 15 years, hospital-treated self-harm episodes were ascertained through linkage to the National Patient Register and the Psychiatric Central Research Register, and violent crimes were identified via linkage to the National Crime Register. Hazard ratio and cumulative incidence values were estimated.ResultsSelf-harm and violent criminality risks were elevated following parental death during childhood. Covariate adjustment for gender, birth year and first-degree relatives' mental illnesses attenuated these associations, although significantly heightened risks persisted. The estimated hazard ratios did not differ greatly according to which parent died, but losing both parents conferred particularly large risk increases. Risks for both adverse outcomes were higher in relation to unnatural v. natural parental death; violent criminality risk was especially raised among individuals exposed to parental death by unnatural causes other than suicide. The association was strongest when pre-school age children experienced parental death.ConclusionsEffective early intervention is needed to help youngsters who have experienced the death of one or both parents to develop immediate and sustained coping strategies. Enhanced cooperation between health and social services and criminal justice agencies may mitigate risks for these two destructive behaviours.

Aim of database: The aim of DANARREST is to collect data on processes of care and outcomes for patients with in-hospital cardiac arrest in Denmark, and thereby facilitate and monitor quality and quality improvement initiatives. Study population: In-hospital cardiac arrest patients with a clinical indication for cardiopulmonary resuscitation in Denmark. Main variables: DANARREST includes a number of descriptive variables as well as seven quality of care indicators; four related to processes of care and three related to clinical outcomes. The four process measures are related to whether the cardiac arrest was witnessed, whether the cardiac arrest was ECG-monitored, the timing of cardiopulmonary resuscitation, and the timing of the first rhythm analysis. The three outcomes measures include return of spontaneous circulation, 30-day survival, and 1-year survival. Database status: DANARREST started in 2013, and the coverage has increased steadily since. As of 2017, 95% of relevant hospitals are reporting data with an estimated coverage rate of approximately 80%. Conclusion: DANARREST is a relatively new national registry of in-hospital cardiac arrests in Denmark, with a high coverage rate. The registry provides an opportunity to monitor and improve quality of care for patients with in-hospital cardiac arrest.

The etiology of &ldquo, dual harm&rdquo, (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&ndash, 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.

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 vs. controls for each of the three behavior groups, and incidence rate ratios (IRRs). Experiencing 5 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.

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.

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

BACKGROUND: Discharged psychiatric inpatients are at elevated risk of serious adverse outcomes, but no previous study has comprehensively examined an array of multiple risks in a single cohort.METHODS: We used data from the Danish Civil Registration System to delineate a cohort of all individuals born in Denmark in 1967-2000, who were alive and residing in Denmark on their 15th birthday, and who had been discharged from their first inpatient psychiatric episode at age 15 years or older. Each individual in the discharged cohort was matched on age and sex with 25 comparators without a history of psychiatric admission. Data linked to each individual were also obtained from the Psychiatric Central Research Register, Register of Causes of Death, National Patient Register, and the National Crime Register. We used survival analysis techniques to estimate absolute and relative risks of all-cause mortality, suicide, accidental death, homicide victimisation, homicide perpetration, non-fatal self-harm, violent criminality, and hospitalisation following violence, until Dec 31, 2015.FINDINGS: We included 62 922 individuals in the discharged cohort, and 1 573 050 matched comparators. Risks for each of all eight outcomes examined were markedly elevated in the discharged cohort relative to the comparators. Within 10 years of first discharge, the cumulative incidence of death, self-harm, committing a violent crime, or hospitalisation due to interpersonal violence was 32·0% (95% CI 31·6-32·5) in the discharged cohort (37·1% [36·5-37·8] in men and 27·2% [26·7-27·8] in women). Absolute risk of at least one adverse outcome occurring within this timeframe were highest in people diagnosed with a psychoactive substance use disorder at first discharge (cumulative incidence 49·4% [48·4-50·4]), and lowest in those diagnosed with a mood disorder (24·4% [23·6-25·2]). For suicide and non-fatal self-harm, risks were especially high during the first 3 months post-discharge, whereas risks for accidental death, violent criminality, and hospitalisation due to violence were more constant throughout the 10-year follow-up.INTERPRETATION: People discharged from inpatient psychiatric care are at higher risk than the rest of the population for a range of serious fatal and non-fatal adverse outcomes. Improved inter-agency liaison, intensive follow-up immediately after discharge, and longer-term social support are indicated.FUNDING: Medical Research Council, European Research Council, and Wellcome Trust.

BACKGROUND: Self-harm and violent criminality have overlapping causes, but people who engage in these behaviours are typically studied as two discrete populations. In this study, we aimed to examine the risk of unnatural death (ie, death from external causes such as accidents, suicide, and undetermined causes) among people with a history of self-harm and violent crime, focusing specifically on those with co-occurring behaviours.METHODS: For this population-based nested case-control study, we used national interlinked Danish registers. Individuals aged 35 years or younger, who were alive and residing in the country on their 15th birthday, and who died from external causes (cases) were matched by age and gender to living people (controls). We compared risks of suicide, accidental death, and any death by external causes among those with a history of hospital-treated self-harm, violent criminality, or both behaviours with those in individuals without histories of either behaviour. We estimated incidence rate ratios (IRRs), adjusted for age and gender, to compare risks.FINDINGS: We identified 2246 individuals who died from external causes, whom we matched to 44 920 living controls. 1499 (66·7%) of 2246 individuals died from accidental causes and 604 (26·9%) died by suicide. The risk of unnatural death was elevated for individuals with a history of violence (IRR 5·19, 95% CI 4·45-6·06) or self-harm (12·65, 10·84-14·77), but the greatest risk increase was among those with histories of both behaviours (29·37, 23·08-37·38). Substance misuse disorders, particularly multiple drug use, was more prevalent among individuals with co-occurring self-harm and violence than among those engaging in just one of these behaviours. Psychiatric disorders seemed to account for some of the excess risk of unnatural death among people with dual-harm histories, but excess risk, particularly of accidental death, persisted in the multivariable models.INTERPRETATION: Among individuals with co-occurring self-harm and violence, the risk of accidental death, particularly accidental self-poisoning, should be considered to be as important as the risk of suicide. People with a history of both behaviours who also have a substance misuse disorder are at particularly high risk of dying from external causes. Strategies should be designed to be accessible for people facing turbulent lives with multiple problems. Individuals in this group with both behaviours are likely to be treated by health-care services for self-harm and have contact with criminal justice services, providing multiple opportunities for proactive intervention.FUNDING: European Research Council.

OBJECTIVE: Persons discharged from inpatient psychiatric units are at greatly elevated risk of dying unnaturally. We conducted a comprehensive examination of specific causes of unnatural death post-discharge in a national register-based cohort.METHOD: A cohort of 1,683,645 Danish residents born 1967-1996 was followed from their 15th birthday until death, emigration, or December 31, 2011, whichever came first. Survival analysis techniques were used to estimate incidence rate ratios (IRRs) comparing risk for persons with and without psychiatric admission history in relation to (a) suicide method, (b) accidental death type, (c) fatal poisoning type, and (d) homicide.RESULTS: More than half (52.5%, n = 711) of all unnatural deaths post-discharge were fatal poisonings, compared with less than a fifth (17.0%, n = 1,012) among persons in the general population not admitted. Just 6.8% (n = 92) of all unnatural deaths post-discharge were due to transport accidents-the most common unnatural death type in the general population (53.4%, n = 3,184). Suicide risk was 32 times higher among discharged patients (IRR 32.3; 95% CI, 29.2-35.8) and was even higher during the first year post-discharge (IRR 70.4; 95% CI, 59.7-83.0). Among the suicide methods examined, relative risk values were significantly larger for intentional self-poisoning (IRR 40.8; 95% CI, 33.9-49.1) than for "violent" suicide methods (IRR 29.4; 95% CI, 26.1-33.2). The greatest relative risk observed was for fatal poisoning (irrespective of intent) by psychotropic medication (IRR 93.7; 95% CI, 62.5-140.5). The highest post-discharge mortality rate was for accidental self-poisoning among persons diagnosed with a psychoactive substance abuse disorder: 290.1 per 100,000 person-years.CONCLUSIONS: Closer liaison between inpatient services and community care, more effective early treatment for comorbid substance abuse, enhanced psychosocial assessment following self-harm, and tighter medication surveillance could decrease risk of unnatural death post-discharge.

IntroductionSeparation from a parent during childhood has been linked with heightened longer-term violence risk, but it remains unclear how this relationship varies by gender, separation subgroup, and age at separation. This phenomenon was investigated by examining a wide array of child–parent separation scenarios.MethodsNational cohort study including individuals born in Denmark, 1971–1997 (N=1,346,772). Child–parent separation status was ascertained each year from birth to 15th birthday, using residential addresses from the Danish register. Members were followed up from their 15th birthday until the date of first violent offense conviction, or December 31, 2012. Incidence rate ratios were estimated using survival analyses techniques. Analyses were conducted during 2016–2017.ResultsSeparation from a parent during childhood was associated with elevated risk for subsequent violent offending versus those who lived continuously with both parents. These links were attenuated but persisted after adjustment for parental SES. Associations were stronger for paternal than for maternal separation at least up until mid-childhood and rose with the number of separations. Separation from a father for the first time at a younger age was associated with higher risks than if paternal separation first occurred at an older age, but there was little variation in risk associated with age at first maternal separation. Increasing risks were linked with rising age at first separation from both parents.ConclusionsViolence prevention should include strategies to tackle a range of correlated familial adversities, with promoting a stable home environment being one salient aspect.

This Danish population-based cohort study uses national registry data to evaluate the association of exposure to nitrogen dioxide in childhood and genetic liability for schizophrenia with the risk of developing schizophrenia., Key Points Question How is the combination of childhood exposure to nitrogen dioxide and genetic liability for schizophrenia (as measured by a polygenic risk score based on variation in multiple genetic loci and their associated weight for schizophrenia) associated with the risk of developing schizophrenia? Findings In this Danish population-based cohort study of 23 355 individuals, increasing polygenic risk score for schizophrenia was correlated with higher childhood nitrogen dioxide exposure. Polygenic risk score for schizophrenia could not fully explain the association between childhood nitrogen dioxide exposure and schizophrenia, and both were independently associated with elevated schizophrenia risk. Meaning This study’s findings suggest that schizophrenia risk may be heightened with increasing levels of childhood nitrogen dioxide exposure, but the pathogenic association between these variables remains unclear., Importance Schizophrenia is a highly heritable psychiatric disorder, and recent studies have suggested that exposure to nitrogen dioxide (NO2) during childhood is associated with an elevated risk of subsequently developing schizophrenia. However, it is not known whether the increased risk associated with NO2 exposure is owing to a greater genetic liability among those exposed to highest NO2 levels. Objective To examine the associations between childhood NO2 exposure and genetic liability for schizophrenia (as measured by a polygenic risk score), and risk of developing schizophrenia. Design, Setting, and Participants Population-based cohort study including individuals with schizophrenia (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code F20) and a randomly selected subcohort. Using national registry data, all individuals born in Denmark between May 1, 1981, and December 31, 2002, were followed up from their 10th birthday until the first occurrence of schizophrenia, emigration, death, or December 31, 2012, whichever came first. Statistical analyses were conducted between October 24, 2018, and June 17, 2019. Exposures Individual exposure to NO2 during childhood estimated as mean daily exposure to NO2 at residential addresses from birth to the 10th birthday. Polygenic risk scores were calculated as the weighted sum of risk alleles at selected single-nucleotide polymorphisms based on genetic material obtained from dried blood spot samples from the Danish Newborn Screening Biobank and on the Psychiatric Genomics Consortium genome-wide association study summary statistics file. Main Outcomes and Measures The main outcome was schizophrenia. Weighted Cox proportional hazards regression models were fitted to estimate adjusted hazard ratios (AHRs) for schizophrenia with 95% CIs according to the exposures. Results Of a total of 23 355 individuals, 11 976 (51.3%) were male and all had Danish-born parents. During the period of the study, 3531 were diagnosed with schizophrenia. Higher polygenic risk scores were correlated with higher childhood NO2 exposure (ρ = 0.0782; 95% CI, 0.065-0.091; P

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.

BACKGROUND/OBJECTIVE: Prenatal exposure to antibacterials may permanently dysregulate fetal metabolic patterns via epigenetic pathways or by altering maternal microbiota. We examined the association of prenatal exposure to systemic antibacterials with overweight and obesity in schoolchildren.SUBJECTS/METHODS: We conducted a prevalence study among Danish schoolchildren aged 7 to 16 years using data from routine school anthropometric evaluations conducted during 2002-2013. Prenatal exposure to antibacterials was ascertained by using maternal prescription dispensations and infection-related hospital admissions during pregnancy. We defined overweight and obesity among the children using standard age- and sex-specific cut-offs. We computed sex-specific adjusted prevalence ratios (aPR) of overweight and obesity associated with exposure to prenatal antibacterials, adjusting for maternal age at delivery, marital status, smoking in pregnancy, and multiple gestation; we also stratified the analyses by birth weight.RESULTS: Among 9 886 schoolchildren, 3 280 (33%) had prenatal exposure to antibacterials. Adjusted PRs associated with the exposure were 1.26 (95% confidence interval [CI]: 1.10-1.45) for overweight and 1.29 (95% CI: 1.03-1.62) for obesity. Among girls, aPRs were 1.16 (95% CI: 0.95-1.42) for overweight, and 1.27 (95% CI: 0.89 to 1.82) for obesity. Among boys, aPRs were 1.37 (95% CI: 1.13-1.66) for overweight, and 1.29 (95% CI: 0.96-1.73) for obesity. The aPR for overweight was higher among schoolchildren with birth weight CONCLUSIONS: Prenatal exposure to systemic antibacterials is associated with an increased risk of overweight and obesity at school age, and this association varies by birth weight.International Journal of Obesity accepted article preview online, 16 July 2015. doi:10.1038/ijo.2015.129.

Background Epidemiological research has reported strong links between trauma-related hospitalisation and future risks of fatal and nonfatal adverse outcomes. However, some important research questions remain unanswered, including association with hospitalisation occurring specifically during childhood, longer-term follow-up from mid-adolescence through the earlier stages of adulthood, assessment of self-harm versus violence risks in the same study population, and absolute risk estimation. To reduce risk in young people, clinicians and public health experts require a better knowledge of subsequent pathways for individuals who experience trauma-related hospitalisation during childhood. Methods This national cohort study examined n=1,087,672 persons born in Denmark 1977–1997 with complete linkage to national psychiatric, general hospital and crime registers. Survival analyses (© SAS Institute Inc.) was used to estimate incidence rate ratios (IRRs) for self-harm, violent criminality, interpersonal violence injury, and all-cause mortality between 15th and 35th birthdays among cohort members with and without trauma-related hospitalisation prior to 15th birthday. Accounting for competing risks, cumulative incidence percentage values were estimated to age 35. Estimates were stratified by gender and by reason for hospitalisation during childhood: self-harm, interpersonal violence or accident. Results Risk for each adverse outcome assessed was raised among young persons who experienced trauma-related hospitalisation at least once during childhood. Confounding by parental socioeconomic status, measured according to income, educational attainment and employment status, explained little of these risk elevations. Individuals hospitalised during childhood following self-harm or interpersonal violence had much higher risks for self-harm and violent criminality aged 15–35 years. Some particularly high cumulative incidence values were observed: subsequent violent offending in males hospitalised following interpersonal violence during childhood, 25.0% (95% CI 21.2–28.9); later self-harm in females hospitalised following interpersonal violence, 18.3% (95% CI 13.5–23.6) and following self-harm during childhood, 21.4% (95% CI 19.8–23.1). More frequent trauma-related hospitalisations, and hospitalisations for multiple trauma types at such an early age, conferred marked risk elevations through young adulthood. Conclusion Although not all episodes of self-harm and interpersonal violence in the community are routinely captured via hospital records, trauma-related hospitalisation during upbringing may be a clinically useful marker for familial dysfunction and childhood distress that subsequently predicts internalised and externalised destructive behaviours among youths and young adults. Comprehensive national guidelines are needed to tackle the multifaceted vulnerabilities of children hospitalised for injuries or poisonings.Healthcare, social services and educational workers must provide particularly robust support to children hospitalised following self-harm or interpersonal violence, and those who experience multiple trauma-related hospitalisations during upbringing.

Background Childhood poverty is associated with later elevated risks for self-directed and interpersonal violence. However, changes in parental income during upbringing on the risk of these outcomes remain unclear. We aimed to investigate fluctuations in parental income levels during childhood and subsequent risk of self-harm and violent criminality; in particular, to examine the associations by: 1) parental income in the year of birth, in early and middle childhood, and adolescence; 2) time spent in financially disadvantaged versus affluent conditions; 3) changes in parental income between the year of birth and age 15 years. Methods Using interlinked Danish national registers, we constructed a nested case-control study of all first registered episodes of self-harm (n=16,915) and all first violent crime convictions (n=19,579) during 1997–2012 at ages 15–30 years. Twenty five unaffected controls were matched to each case on sex and age using incidence density sampling. Parental income was assessed in the year of birth, and at ages 5, 10 and 15 years. Incidence rate ratios (IRRs) were estimated using conditional logistic regression in Stata 13.1. Results For both outcomes, the lower the income the higher the risk. The associations were stronger for violent offending than for self-harm, with those from the lowest income quintile showing disproportionately higher risks. The longer a child lived in poorer circumstances the higher the risk, and vice versa for time spent in more affluent conditions. For example, compared with those whose parental income was consistently at the highest quintile at all 4 age points, those whose parental income remained in the lowest quintile were at 7 and 10 times elevated risk for self-harm (IRR=6.9, 95% CI 6.4–7.4) and violent offending (IRR=10.3, 9.6–11.0), respectively. Compared with parental income being in the highest quintile at birth and also at age 15 years, all other income trajectories between these two ages were associated with elevated risks for both outcomes. In general, however, regardless of the parental income at birth, being upwardly mobile was associated with smaller elevations in risk compared with being downwardly mobile. Conclusion Family income dynamics are strongly linked with later risks of self-harm and violent criminality. Although income is a marker for an array of familial circumstances and causal inferences could not be drawn, our findings suggest that reducing poverty at any stage during children’s development and promoting upward socio-economic mobility could ameliorate such risks, and have a marked cumulative societal benefit.

BACKGROUND: Development of a better understanding of subsequent pathways for individuals who experienced trauma during childhood might usefully inform clinicians and public health professionals regarding the causes of self-harm and interpersonal violence. We aimed to examine these risks during late adolescence and early adulthood among people admitted to hospital following injuries or poisonings during their childhood.METHODS: This national cohort study included Danish people born between Jan 1, 1977, and Dec 31, 1997, and was linked to the National Patient Register and Psychiatric Central Research Register to identify all people exposed to hospital admissions for injuries or poisonings due to self-harm, interpersonal violence, or accidents before their 15th birthday. Linkage to these two registers and to the National Crime Register enabled ascertainment of self-harm and violent offending, respectively, as adverse outcomes at ages 15-35 years. Sex-specific incidence rate ratios (IRRs; relative risks) and cumulative incidence percentage values (absolute risks) were estimated. The confounding influence of parental socioeconomic status was also explored.FINDINGS: 1 087 672 Danish people were included in this study. The prevalence of any trauma-related hospital admission was 10% (105 753 per 1 087 672; males: 64 454 [11%]; females: 44 299 [8%]) and for both sexes, accident was by far the most prevalent of the categories assessed (males: 59 011 [11%]; females: 40 756 [8%]). Similar patterns of increased risk for self-harm and violent criminality were observed in both sexes, although the IRRs were consistently and significantly larger in women (self-harm: IRR 1·94 [95% CI 1·85-2·02]; violent criminality: 2·16 [1·97-2·36]) than in men (self-harm: 1·61 [1·53-1·69]; violent criminality: 1·58 [1·53-1·63]). Confounding by parental socioeconomic status explained little of the increased risks observed. For young adult men, the highest absolute risk observed was for violent offending among individuals admitted to hospital for interpersonal violence injury during childhood (cumulative incidence 25·0% [95% CI 21·2-28·9]). For young adult women, absolute risk was highest for repeat self-harm among those admitted to hospital following self-harm during childhood (cumulative incidence 21·4% [95% CI 19·8-23·1]). More frequent trauma-related hospital admissions in childhood, and being admitted multiple times for more than one reason, conferred substantial risk increases among young people, with especially steep gradients of this nature observed among women.INTERPRETATION: Trauma-related hospital admission early in life could be a useful marker for childhood distress that subsequently predicts internalised and externalised destructive behaviours among youths and young adults and might provide a timely opportunity for initiating family-oriented interventions.FUNDING: European Research Council.

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.

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.

Importance: Self-directed and interpersonal violence share some common risk factors such as a parental history of mental illness. However, relationships between the full spectrum of parental psychiatric disease and these 2 related outcomes are unclear.Objective: To examine associations between the full spectrum of parental psychiatric disease and risks of attempted suicide and violent offending among offspring.Design, Setting, and Participants: Population-based cohort study of all persons born in Denmark 1967 through 1997, followed up from their 15th birthday until occurrence of adverse outcome or December 31, 2012, whichever came first.Exposures: Array of parental psychiatric disorders and parental suicide attempt, delineated from records of secondary care treatments.Main Outcomes and Measures: Using survival analyses techniques, incidence rate ratios were estimated for offspring suicide attempt and violent offending.Results: We examined 1 743 525 cohort members (48.7% female; total follow-up, 27.2 million person-years). Risks for offspring suicide attempt and violent offending were elevated across virtually the full spectrum of parental psychiatric disease. Incidence rate ratios were the most elevated for parental diagnoses of antisocial personality disorder (suicide attempt, 3.96; 95% CI, 3.72-4.21; violent offending, 3.62; 95% CI, 3.41-3.84) and cannabis misuse (suicide attempt, 3.57; 95% CI, 3.25-3.92; violent offending, 4.05; 95% CI, 3.72-4.39), and for parental suicide attempt (suicide attempt, 3.42; 95% CI, 3.29-3.55; violent offending, 3.31; 95% CI, 3.19-3.44). Parental mood disorders (and bipolar disorder in particular) conferred more modest risk increases. A history of mental illness or suicide attempt in both parents was associated with double the risks compared with having just 1 affected parent. Associations between parental psychiatric disease and offspring violent offending were stronger for female than for male offspring, whereas little sex difference in risk was found for offspring suicide attempt.Conclusions and Relevance: The similarities in risk patterns observed between the 2 outcomes may evidence a shared etiology. Early interventions to tackle parental mental disorders may be beneficial to both parents and children.

Background: Immigrant populations in Western European countries have grown in their size and diversity, but little is known about risks of self-directed and externalised violence among second-generation immigrants. Aims: To compare risks for attempted suicides and violent offending among second-generation immigrants to Denmark according to parental region of origin versus the native Danish population. Methods: Data from interlinked national Danish registers were used ( N = 1,973,614). Parental origin outside Denmark was categorised thus: Asia, Africa, Middle East, Greenland, other Scandinavian countries, elsewhere in Europe and all other regions. We estimated gender-specific cumulative incidence and incidence rate ratios (IRRs) versus native Danes. Results: In virtually all subgroups of second-generation immigrants, risk was elevated for the two adverse outcomes in both genders. Females generally had greater elevations in attempted suicide risk, and males had greater elevations in violent offending risk. For attempted suicide, especially large IRRs were observed for males and females whose parents emigrated from Greenland; for violent offending, risks were particularly raised for males and females of Middle Eastern, Greenlandic and African origin. Adjustment for socioeconomic status partially explained these associations. Conclusion: Western European nations should develop preventive programmes tailored towards specific second-generation immigrant populations, with integrated approaches jointly tackling suicidality and violence.

Background Urban-rural differences in schizophrenia incidence have been reported from numerous published studies. Though as yet unknown, the underlying causes responsible for these differences have been postulated to include urban-rural differences in pollution, diet, infections, stress, or selective migration. Exposure to the air pollutant nitrogen dioxide (NO2) has been linked with increased rates of mortality, lung cancer, and psychotropic medication prescribing. However, no study to date has examined whether NO2 exposure during early childhood is associated with schizophrenia risk. Methods Utilizing individual-level information in the rich Danish population-based registers enriched with longitudinal information on residential exposure to air pollution, we investigated the putative link between NO2 exposure during childhood and schizophrenia risk. For each cohort member, exposure to NO2 was estimated longitudinally from birth to 10th birthday, expressed as mean of daily exposures at residence across the first 10 years of life. Incidence rate ratios per 10μg/m3 increase in mean NO2 exposure were estimated using survival analysis techniques. Air pollutant exposures were modelled using the UBM model in 1*1km grids covering Denmark from 1979 onwards. Results We observed a dose response relationship between childhood NO2 exposure and elevated risk for developing schizophrenia. Risk increased 1.36 fold (95%CI: 1.31–1.41) per 10μg/m3 increase in mean NO2 exposure during childhood. This association remained materially unaltered when adjusted for potential confounders such as family socioeconomic position and history of severe mental disorders. In absolute risk terms, at age 35 a person exposed to more than 25μg/m3 mean NO2 faced a 1.4% risk of schizophrenia whereas persons exposed to less than 10μg/m3 per day faced a 0.8% risk. Discussion This is the first population-based study demonstrating that exposure to NO2 during childhood is linked with elevated schizophrenia risk. The potential mechanism of NO2 on the risk of schizophrenia remains to be identified, however, if causality is proven this finding offers great potential for prevention of some cases of schizophrenia.

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.

OBJECTIVE: Surgery is the only potentially curable treatment for colorectal cancer (CRC), but it is hampered by high mortality. Human serum albumin (HSA) below 35 g/L is associated with poor overall prognosis in patients with CRC, but evidence regarding the impact on postoperative mortality is sparse.METHODS: We performed a population-based cohort study including patients undergoing CRC surgery in North and Central Denmark (1997-2011). We categorised patients according to HSA concentration measured 1-30 days prior to surgery date. We used the Kaplan-Meier method to compute 30-day mortality and Cox regression model to compute HRs as measures of the relative risk of death, controlling for potential confounders. We further stratified patients by preoperative conditions, including cancer stage, comorbidity level, and C reactive protein concentration.RESULTS: Of the 9339 patients undergoing first-time CRC surgery with preoperative HSA measurement, 26.4% (n=2464) had HSA below 35 g/L. 30-day mortality increased from 4.9% among patients with HSA 36-40 g/L to 26.9% among patients with HSA equal to or below 25 g/L, compared with 2.0% among patients with HSA above 40 g/L. The corresponding adjusted HRs increased from 1.75 (95% CI 1.25 to 2.45) among patients with HSA 36-40 g/L to 7.59 (95% CI 4.95 to 11.64) among patients with HSA equal to or below 25 g/L, compared with patients with HSA above 40 g/L. The negative impact associated with a decrement of HSA was found in all subgroups.CONCLUSIONS: A decrement in preoperative HSA concentration was associated with substantial concentration-dependent increased 30-day mortality following CRC surgery.

BACKGROUND: Immigrant populations in western societies have grown in their size and diversity yet evidence is incomplete for their risks of suicidality and criminal violence. We examined these correlated harmful behaviours in a national cohort.AIMS: (i) Compare absolute risk between first and second generation immigrants, foreign-born adoptees and native Danes by plotting cumulative incidence curves to onset of early middle age; (ii) estimate sex-specific relative risks for these immigrant type subgroups vs. native Danes; (iii) examine effect modification by higher vs. lower socio-economic status.METHODS: In a cohort of over two million persons, attempted suicides and violent crimes were investigated using data from multiple interlinked registers. We plotted sex-specific cumulative incidence curves and estimated incidence rate ratios.RESULTS: In the whole study cohort, 1414 people died by suicide, 46,943 attempted suicide, and 51,344 were convicted of committing a violent crime. Among all immigrant subgroups combined, compared with native Danes, relative risk of attempted suicide was greater in female immigrants (incidence rate ratio, 1.59; 95% confidence interval: CI 1.54-1.64) than in male immigrants (1.26; CI 1.20-1.32), and vice versa for relative risk of violent offending in male immigrants (2.36; CI 2.31-2.42) than in female immigrants (1.74; CI 1.62-1.87). Risk for both adverse outcomes was significantly elevated in virtually every gender-specific immigrant type subgroup examined. Violent crime risk was markedly raised in first generation immigrant males and in the Danish born male children of two immigrant parents. However, male immigrants of lower social status had lower risk of attempted suicide than their native Danish peers.CONCLUSION: Young immigrants of both first and second generation status face serious challenges and vulnerabilities that western societies need to urgently address. Relative risk patterns for these adverse outcomes vary greatly between the genders and also by socioeconomic status. This high degree of heterogeneity points to the existence of modifiable factors that are amenable to positive change and a potential for effective intervention.

Kimberly M Shea,1,2 Timothy L Lash,3,4 Sussie Antonsen,4 Susan S Jick,1,5 Henrik T Sørensen1,41Department of Epidemiology, Boston University School of Public Health, 2Department of Pediatrics, Boston University School of Medicine, Boston, MA, 3Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 5Boston Collaborative Drug Surveillance Program, Boston University, Boston, MA, USABackground: Although asthma has recently been established as a risk factor for pneumococcal disease (PD), few studies have specifically evaluated this association in children.Methods: We conducted a nation-wide population-based cohort study of the effect of asthma on childhood PD among all singleton live births in Denmark from 1994 to 2007, before the introduction of the 7-valent pneumococcal conjugate vaccine. All data were abstracted from Danish medical registries. Because underlying comorbidity substantially increases the PD risk in children, standard methods were used to assess the evidence of biologic interaction between comorbidity and asthma on the risk of PD.Results: There were 2,253 cases of childhood PD among 888,655 children born in Denmark from 1994 to 2007. The adjusted incidence rate ratio of the effect of asthma on childhood PD was 2.2 (95% confidence interval [CI]: 2.0, 2.5). Age-stratified incidence rate ratios were 2.1 (95% CI: 1.8, 2.9) in children 6 months to

Deirdre P Cronin-Fenton,1 Sussie Antonsen,1 Karynsa Cetin,2 John Acquavella,2 Andre Daniels,3 Timothy L Lash1,4 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Center for Observational Research, Amgen Incorporated, Thousand Oaks, CA, USA; 3Global Regulatory Affairs and Safety, Amgen Incorporated, Thousand Oaks, CA, USA; 4Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA Objectives: We describe several methodological issues that were addressed in conducting a Danish population-based matched cohort study comparing rates of new primary cancers (NPCs) in men with and without prostate cancer (PC). Methods: We matched 30,220 men with PC to 151,100 men without PC (comparators) on age (±2 years) and PC diagnosis/index date. We focused on several methodological issues: 1) to address survival differences between the cohorts we compared rates with and without censoring comparators on the date their matched PC patient died or was censored; 2) to address diagnostic bias, we excluded men with a history of cancer from the comparator cohort; 3) to address prostate cancer immunity, we graphed the hazard of NPC in both cohorts, with and without prostate cancer as an outcome; 4) we used empirical Bayes methods to explore the effect of adjusting for multiple comparisons. Results: After 18 months of follow-up, cumulative person-time was lower in the PC than comparator cohort due to higher mortality among PC patients. Terminating person-time in comparators at the matched PC patient's death or loss to follow-up resulted in comparable person-time up to 30 months of follow-up and lower person-time among comparators thereafter. The hazard of NPC was lower among men with PC than comparators throughout follow-up. There was little difference in rates beyond the first four years of follow-up after removing PC as an outcome. Empirical Bayes adjustment for multiple comparisons had little effect on the estimates. Conclusion: Addressing the issues of competing risks, treatment interference or diagnostic bias, prostate cancer immunity due to radical prostatectomy, and multiple comparisons lowered the deficit rate of NPCs among men with a history of PC compared with those without PC. However, the differing rates of NPCs may also be due to risk factor differences between the cohorts. Keywords: prostate cancer, cohort study, cancer epidemiology, new primary cancer, incidence rate, competing risks, multiple comparisons

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.

Background : Osteonecrosis of the jaw (ONJ) is an important adverse event associated with therapies suppressing bone turnover, especially in patients with high-dose regimens of antiresorptive therapy, such as cancer patients. Danish health registries are an important resource for monitoring side effects of drugs. The International Classification of Diseases , 10th revision (ICD-10), currently used in Denmark, does not have a specific code for ONJ, making it difficult to monitor its occurrence. Objectives : To estimate the positive predictive value (PPV) for ONJ of currently used ICD-10 codes, suggested by Danish oral and maxillofacial surgeons, in order to assess feasibility of identification of ONJ cases among cancer patients in the Danish National Registry of Patients (DNRP). Methods : This study was conducted in northern Denmark (1.8 million inhabitants) among patients with a history of cancer. In Denmark ONJ cases are referred to hospital-based departments of oral and maxillofacial surgery (DOMS). In the DNRP, we identified patients with potential ONJ diagnosed at DOMS (as suggested by a series of ICD-10 codes) from 1 January 2005 to 31 December 2009. To confirm or rule out ONJ, we reviewed hospital records of these patients originating from DOMS. A confirmed ONJ case was defined by the presence of exposed maxillofacial bone for 8 weeks or more, in the absence of previous craniofacial radiation therapy. The PPV was the proportion of confirmed cases among all potential cases. Results : Among 85,910 eligible cancer patients, we identified 91 (0.11%) potential cases of ONJ, of which 18 were confirmed. The overall PPV was 20% (95% CI: 12–29%), ranging from 0% to50% for individual ICD-10 codes. Conclusions : A majority of cases identified by the suggested ICD-10 codes did not fulfill the criteria for ONJ, even though the potential cases were identified at DOMS. Therefore, reliance on ICD-10 codes, without hospital chart review, will lead to an overestimation of the occurrence of ONJ among cancer patients.