Multiple adverse outcomes associated with antipsychotic use in people with dementia: population based matched cohort study.

OBJECTIVE: To investigate risks of multiple adverse outcomes associated with use of antipsychotics in people with dementia. DESIGN: Population based matched cohort study. SETTING: Linked primary care, hospital and mortality data from Clinical Practice Research Datalink (CPRD), England. POPULATION: Adults (≥50 years) with a diagnosis of dementia between 1 January 1998 and 31 May 2018 (n=173 910, 63.0% women). Each new antipsychotic user (n=35 339, 62.5% women) was matched with up to 15 non-users using incidence density sampling. MAIN OUTCOME MEASURES: The main outcomes were stroke, venous thromboembolism, myocardial infarction, heart failure, ventricular arrhythmia, fracture, pneumonia, and acute kidney injury, stratified by periods of antipsychotic use, with absolute risks calculated using cumulative incidence in antipsychotic users versus matched comparators. An unrelated (negative control) outcome of appendicitis and cholecystitis combined was also investigated to detect potential unmeasured confounding. RESULTS: Compared with non-use, any antipsychotic use was associated with increased risks of all outcomes, except ventricular arrhythmia. Current use (90 days after a prescription) was associated with elevated risks of pneumonia (hazard ratio 2.19, 95% confidence interval (CI) 2.10 to 2.28), acute kidney injury (1.72, 1.61 to 1.84), venous thromboembolism (1.62, 1.46 to 1.80), stroke (1.61, 1.52 to 1.71), fracture (1.43, 1.35 to 1.52), myocardial infarction (1.28, 1.15 to 1.42), and heart failure (1.27, 1.18 to 1.37). No increased risks were observed for the negative control outcome (appendicitis and cholecystitis). In the 90 days after drug initiation, the cumulative incidence of pneumonia among antipsychotic users was 4.48% (4.26% to 4.71%) versus 1.49% (1.45% to 1.53%) in the matched cohort of non-users (difference 2.99%, 95% CI 2.77% to 3.22%). CONCLUSIONS: Antipsychotic use compared with non-use in adults with dementia was associated with increased risks of stroke, venous thromboembolism, myocardial infarction, heart failure, fracture, pneumonia, and acute kidney injury, but not ventricular arrhythmia. The range of adverse outcomes was wider than previously highlighted in regulatory alerts, with the highest risks soon after initiation of treatment.

Temporal trends in eating disorder and self-harm incidence rates among adolescents and young adults in the UK in the 2 years since onset of the COVID-19 pandemic: a population-based study.

BACKGROUND: Self-harm and eating disorders share multiple risk factors, with onset typically during adolescence or early adulthood. We aimed to examine the incidence rates of these psychopathologies among young people in the UK in the 2 years following onset of the COVID-19 pandemic. METHODS: We conducted a population-based study using the primary care electronic health records of patients aged 10-24 years in the UK Clinical Practice Research Datalink (CPRD). The observation period was from Jan 1, 2010, to March 31, 2022. We calculated the monthly incidence rates of eating disorders and self-harm according to the first record of each outcome. On the basis of antecedent trends between January, 2010, and February, 2020, negative binomial regression models were fitted to predict monthly incidence rates after the pandemic began in March, 2020. Percentage differences between observed and expected incidence were calculated to indicate changes since the onset of the pandemic, with stratification by sex, age, and deprivation quintile. FINDINGS: The primary care health records of 9 184 712 patients aged 10-24 years (4 836 226 [52·7%] female patients and 4 348 486 [47·3%] male patients; n=1881 general practices) were included for analysis. The incidence rates of eating disorders and self-harm among girls were higher than expected between March 1, 2020, and March 31, 2022. The observed incidence of eating disorders was 42·4% (95% CI 25·7-61·3) higher than expected for girls aged 13-16 years, and 32·0% (13·3-53·8) higher than expected for girls aged 17-19 years, whereas other age groups showed little difference between observed and expected incidence. Similarly, the increase in self-harm incidence was driven by girls aged 13-16 years, for whom the observed incidence was 38·4% (20·7-58·5) higher than expected. By contrast, among boys in all age groups, the incidence rates of eating disorders and self-harm were lower than, or close to, the expected rates. Among boys, the observed incidence of eating disorders was 22·8% (9·2-34·4) lower than expected, and the observed incidence of self-harm was 11·5% (3·6-18·7) lower than expected. The estimated increases in eating disorder and self-harm incidence among girls aged 13-16 years were largely attributable to increases within less deprived communities. INTERPRETATION: Although causes are uncertain, increased incidence of eating disorder diagnoses and self-harm among teenage girls in the UK during the first 2 years of the COVID-19 pandemic highlight an urgent need for intervention. Early identification of mental health difficulties by primary care clinicians is necessary. Timely access to treatments and sufficient support from general practitioners and mental health services needs to be available to manage presenting problems and to prevent exacerbations of conditions. FUNDING: National Institute for Health and Care Research.

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.

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.

Extended Work Shifts and Neurobehavioral Performance in Resident-Physicians.

OBJECTIVES: Extended-duration work rosters (EDWRs) with shifts of 24+ hours impair performance compared with rapid cycling work rosters (RCWRs) that limit shifts to 16 hours in postgraduate year (PGY) 1 resident-physicians. We examined the impact of a RCWR on PGY 2 and PGY 3 resident-physicians. METHODS: Data from 294 resident-physicians were analyzed from a multicenter clinical trial of 6 US PICUs. Resident-physicians worked 4-week EDWRs with shifts of 24+ hours every third or fourth shift, or an RCWR in which most shifts were ≤16 consecutive hours. Participants completed a daily sleep and work log and the 10-minute Psychomotor Vigilance Task and Karolinska Sleepiness Scale 2 to 5 times per shift approximately once per week as operational demands allowed. RESULTS: Overall, the mean (± SE) number of attentional failures was significantly higher (P =.01) on the EDWR (6.8 ± 1.0) compared with RCWR (2.9 ± 0.7). Reaction time and subjective alertness were also significantly higher, by ∼18% and ∼9%, respectively (both P <.0001). These differences were sustained across the 4-week rotation. Moreover, attentional failures were associated with resident-physician-related serious medical errors (SMEs) (P =.04). Although a higher rate of SMEs was observed under the RCWR, after adjusting for workload, RCWR had a protective effect on the rate of SMEs (rate ratio 0.48 [95% confidence interval: 0.30-0.77]). CONCLUSIONS: Performance impairment due to EDWR is improved by limiting shift duration. These data and their correlation with SME rates highlight the impairment of neurobehavioral performance due to extended-duration shifts and have important implications for patient safety.

Sleep and diabetes-specific psycho-behavioral outcomes of a new automated insulin delivery system in young children with type 1 diabetes and their parents.

BACKGROUND: Data on the use of Control-IQ, the latest FDA-approved automated insulin delivery (AID) system for people with T1D 6 years of age or older is still scarce, particularly regarding nonglycemic outcomes. Children with T1D and their parents are at higher risk for sleep disturbances. This study assesses sleep, psycho-behavioral and glycemic outcomes of AID compared to sensor-augmented pump therapy (SAP) therapy in young children with T1D and their parents. METHODS: Thirteen parents and their young children (ages 7-10) on insulin pump therapy were enrolled. Children completed an initial 4-week study with SAP using their own pump and a study CGM followed by a 4-week phase of AID. Sleep outcomes for parents and children were evaluated through actigraphy watches. Several questionnaires were administered at baseline and at the end of each study phase. CGM data were used to assess glycemic outcomes. RESULTS: Actigraphy data did not show any significant change from SAP to AID, except a reduction of number of parental awakenings during the night (p = 0.036). Parents reported statistically significant improvements in Pittsburgh Sleep Quality Index total score (p = 0.009), Hypoglycemia Fear Survey total score (p = 0.011), diabetes-related distress (p = 0.032), and depression (p = 0.023). While on AID, time in range (70-180 mg/dL) significantly increased compared to SAP (p < 0.001), accompanied by a reduction in hyperglycemia (p = 0.001). CONCLUSIONS: These results suggest that use of AID has a positive impact on glycemic outcomes in young children as well as sleep and diabetes-specific quality of life outcomes in their parents.

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.

Parental income as a marker for socioeconomic position during childhood and later risk of developing a secondary care-diagnosed mental disorder examined across the full diagnostic spectrum: a national cohort study.

BACKGROUND: Links between parental socioeconomic position during childhood and subsequent risks of developing mental disorders have rarely been examined across the diagnostic spectrum. We conducted a comprehensive analysis of parental income level, including income mobility, during childhood and risks for developing mental disorders diagnosed in secondary care in young adulthood. METHODS: National cohort study of persons born in Denmark 1980-2000 (N = 1,051,265). Parental income was measured during birth year and at ages 5, 10 and 15. Follow-up began from 15th birthday until mental disorder diagnosis or 31 December 2016, whichever occurred first. Hazard ratios and cumulative incidence were estimated. RESULTS: A quarter (25.2%; 95% CI 24.8-25.6%) of children born in the lowest income quintile families will have a secondary care-diagnosed mental disorder by age 37, versus 13.5% (13.2-13.9%) of those born in the highest income quintile. Longer time spent living in low-income families was associated with higher risks of developing mental disorders. Associations were strongest for substance misuse and personality disorders and weaker for mood disorders and anxiety/somatoform disorders. An exception was eating disorders, with low parental income being associated with attenuated risk. For all diagnostic categories examined except for eating disorders, downward socioeconomic mobility was linked with higher subsequent risk and upward socioeconomic mobility with lower subsequent risk of developing mental disorders. CONCLUSIONS: Except for eating disorders, low parental income during childhood is associated with subsequent increased risk of mental disorders diagnosed in secondary care across the diagnostic spectrum. Early interventions to mitigate the disadvantages linked with low income, and better opportunities for upward socioeconomic mobility could reduce social and mental health inequalities.

Effect on Patient Safety of a Resident Physician Schedule without 24-Hour Shifts.

BACKGROUND: The effects on patient safety of eliminating extended-duration work shifts for resident physicians remain controversial. METHODS: We conducted a multicenter, cluster-randomized, crossover trial comparing two schedules for pediatric resident physicians during their intensive care unit (ICU) rotations: extended-duration work schedules that included shifts of 24 hours or more (control schedules) and schedules that eliminated extended shifts and cycled resident physicians through day and night shifts of 16 hours or less (intervention schedules). The primary outcome was serious medical errors made by resident physicians, assessed by intensive surveillance, including direct observation and chart review. RESULTS: The characteristics of ICU patients during the two work schedules were similar, but resident physician workload, described as the mean (±SD) number of ICU patients per resident physician, was higher during the intervention schedules than during the control schedules (8.8±2.8 vs. 6.7±2.2). Resident physicians made more serious errors during the intervention schedules than during the control schedules (97.1 vs. 79.0 per 1000 patient-days; relative risk, 1.53; 95% confidence interval [CI], 1.37 to 1.72; P<0.001). The number of serious errors unitwide were likewise higher during the intervention schedules (181.3 vs. 131.5 per 1000 patient-days; relative risk, 1.56; 95% CI, 1.43 to 1.71). There was wide variability among sites, however; errors were lower during intervention schedules than during control schedules at one site, rates were similar during the two schedules at two sites, and rates were higher during intervention schedules than during control schedules at three sites. In a secondary analysis that was adjusted for the number of patients per resident physician as a potential confounder, intervention schedules were no longer associated with an increase in errors. CONCLUSIONS: Contrary to our hypothesis, resident physicians who were randomly assigned to schedules that eliminated extended shifts made more serious errors than resident physicians assigned to schedules with extended shifts, although the effect varied by site. The number of ICU patients cared for by each resident physician was higher during schedules that eliminated extended shifts. (Funded by the National Heart, Lung, and Blood Institute; ROSTERS ClinicalTrials.gov number, NCT02134847.).

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.

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.

Association Between Parental Income During Childhood and Risk of Schizophrenia Later in Life.

Importance: Evidence linking parental socioeconomic position and offspring's schizophrenia risk has been inconsistent, and how risk is associated with parental socioeconomic mobility has not been investigated. Objective: To elucidate the association between parental income level and income mobility during childhood and subsequent schizophrenia risk. Design, Setting, and Participants: National cohort study of all persons born in Denmark from January 1, 1980, to December 31, 2000, who were followed up from their 15th birthday until schizophrenia diagnosis, emigration, death, or December 31, 2016, whichever came first. Data analyses were from March 2018 to June 2019. Exposure: Parental income, measured at birth year and at child ages 5, 10, and 15 years. Main Outcomes and Measures: Hazard ratios (HRs) for schizophrenia were estimated using Cox proportional hazard regression. Cumulative incidence values (absolute risks) were also calculated. Results: The cohort included 1 051 033 participants, of whom 51.3% were male. Of the cohort members, 7544 (4124 [54.7%] male) were diagnosed with schizophrenia during 11.6 million person-years of follow-up. There was an inverse association between parental income level and subsequent schizophrenia risk, with children from lower income families having especially elevated risk. Estimates were attenuated, but risk gradients remained after adjustment for urbanization, parental mental disorders, parental educational levels, and number of changes in child-parent separation status. A dose-response association was observed with increasing amount of time spent in low-income conditions being linked with higher schizophrenia risk. Regardless of parental income level at birth, upward income mobility was associated with lower schizophrenia risk compared with downward mobility. For example, children who were born and remained in the lowest income quintile at age 15 years had a 4.12 (95% CI, 3.71-4.58) elevated risk compared with the reference group, those who were born in and remained in the most affluent quintile, but even a rise from the lowest income quintile at birth to second lowest at age 15 years appeared to lessen the risk elevation (HR, 2.80; 95% CI, 2.46-3.17). On the contrary, for those born in the most affluent quintile, downward income mobility between birth and age 15 years was associated with increased risks of developing schizophrenia. Conclusions and Relevance: This study's findings suggest that parental income level and income mobility during childhood may be linked with schizophrenia risk. Although both causation and selection mechanisms could be involved, enabling upward income mobility could influence schizophrenia incidence at the population level.

Association of Childhood Exposure to Nitrogen Dioxide and Polygenic Risk Score for Schizophrenia With the Risk of Developing Schizophrenia.

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 < .001). A 10-µg/m3 increase in childhood daily NO2 exposure (AHR, 1.23; 95% CI, 1.15-1.32) and a 1-SD increase in polygenic risk score (AHR, 1.29; 95% CI, 1.23-1.35) were independently associated with increased schizophrenia risk. Conclusions and Relevance: These findings suggest that the apparent association between NO2 exposure and schizophrenia is only slightly confounded by a higher polygenic risk score for schizophrenia among individuals living in areas with greater NO2. The findings demonstrate the utility of including polygenic risk scores in epidemiologic studies.

Multiple adverse outcomes following first discharge from inpatient psychiatric care: a national cohort study.

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.

Effects on resident work hours, sleep duration, and work experience in a randomized order safety trial evaluating resident-physician schedules (ROSTERS).

STUDY OBJECTIVES: We compared resident physician work hours and sleep in a multicenter clustered-randomized crossover clinical trial that randomized resident physicians to an Extended Duration Work Roster (EDWR) with extended-duration (≥24 hr) shifts or a Rapidly Cycling Work Roster (RCWR), in which scheduled shift lengths were limited to 16 or fewer consecutive hours. METHODS: Three hundred two resident physicians were enrolled and completed 370 1 month pediatric intensive care unit rotations in six US academic medical centers. Sleep was objectively estimated with wrist-worn actigraphs. Work hours and subjective sleep data were collected via daily electronic diary. RESULTS: Resident physicians worked fewer total hours per week during the RCWR compared with the EDWR (61.9 ± 4.8 versus 68.4 ± 7.4, respectively; p < 0.0001). During the RCWR, 73% of work hours occurred within shifts of ≤16 consecutive hours. In contrast, during the EDWR, 38% of work hours occurred on shifts of ≤16 consecutive hours. Resident physicians obtained significantly more sleep per week on the RCWR (52.9 ± 6.0 hr) compared with the EDWR (49.1 ± 5.8 hr, p < 0.0001). The percentage of 24 hr intervals with less than 4 hr of actigraphically measured sleep was 9% on the RCWR and 25% on the EDWR (p < 0.0001). CONCLUSIONS: RCWRs were effective in reducing weekly work hours and the occurrence of >16 consecutive hour shifts, and improving sleep duration of resident physicians. Although inclusion of the six operational healthcare sites increases the generalizability of these findings, there was heterogeneity in schedule implementation. Additional research is needed to optimize scheduling practices allowing for sufficient sleep prior to all work shifts.Clinical Trial: Multicenter Clinical Trial of Limiting Resident Work Hours on ICU Patient Safety (ROSTERS), https://clinicaltrials.gov/ct2/show/NCT02134847.

Risk of dying unnaturally among people aged 15-35 years who have harmed themselves and inflicted violence on others: a national nested case-control study.

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.

Design and recruitment of the randomized order safety trial evaluating resident-physician schedules (ROSTERS) study.

INTRODUCTION: While the Accreditation Council for Graduate Medical Education limited first year resident-physicians to 16 consecutive work hours from 2011 to 2017, resident-physicians in their second year or higher were permitted to work up to 28 h consecutively. This paper describes the Randomized Order Safety Trial Evaluating Resident-physician Schedules (ROSTERS) study, a clustered-randomized crossover clinical trial designed to evaluate the effectiveness of eliminating traditional shifts of 24 h or longer for second year or higher resident-physicians in pediatric intensive care units (PICUs). METHODS: ROSTERS was a multi-center non-blinded trial in 6 PICUs at US academic medical centers. The primary aim was to compare patient safety between the extended duration work roster (EDWR), which included shifts ≥24 h, and a rapidly cycling work roster (RCWR), where shifts were limited to a maximum of 16 h. Information on potential medical errors was gathered and used for classification by centrally trained physician reviewers who were blinded to the study arm. Secondary aims were to assess the relationship of the study arm to resident-physician sleep duration, work hours and neurobehavioral performance. RESULTS: The study involved 6577 patients with a total of 38,821 patient days (n = 18,749 EDWR, n = 20,072 RCWR). There were 413 resident-physician rotations included in the study (n = 203 EDWR, n = 210 RCWR). Resident-physician questionnaire data were over 95% complete. CONCLUSIONS: Results from data collected in the ROSTERS study will be evaluated for the impact of resident-physician schedule roster on patient safety outcomes in PICUs, and will allow for examination of a number of secondary outcome measures. ClinicalTrials.gov Identifier: NCT02134847.

Family income inequalities and trajectories through childhood and self-harm and violence in young adults: a population-based, nested case-control study.

BACKGROUND: Childhood poverty is associated with elevated later risks for self-directed and externalised violence, but how risks are modified by parental socioeconomic mobility remains unclear. We investigated parental income trajectories during childhood and subsequent risks of self-harm and violent criminality in young adulthood. METHODS: Using Danish national registers, we delineated a nested case-control study of Danish citizens born from Jan 1, 1982, to Dec 31, 2000, with first hospital-treated self-harm episodes and first violent crime convictions at ages 15-33 years. Each case was matched on age and gender to 25 randomly selected controls. Parental income was assessed in birth-year and at ages 5 years, 10 years, and 15 years. We considered parental age, the child's number of siblings, parental mental health, and parental education to be covariates. We estimated incidence rate ratios (IRRs) by conditional logistic regression inherently adjusted for age, gender, and calendar year; we then made additional adjustments for the covariates considered. FINDINGS: We identified 21 267 first episodes of hospital-treated self-harm, to which we matched 531 675 controls, and 23 724 first violent crime convictions, to which we matched 593 100 controls. We observed inverse relationships between parental income and risks for the two outcomes for each of the ages parental income was measured. The longer a child lived in poorer circumstances, the higher their subsequent risks for self-harm and violent criminality, and vice versa for time spent living in affluent conditions. Associations were stronger for violent criminality than for self-harm. Compared with individuals who were born and remained in the most affluent families, all other income trajectories were associated with elevated risks for both outcomes. Those who remained in the least affluent quintile showed the highest risks for self-harm (IRR 7·2, 95% CI 6·6-7·9; 1174 [6%] cases) and for violent criminality (IRR 13·0; 95% CI 11·9-14·1; 1640 [7%] cases). The risk patterns were attenuated, but essentially persisted, after covariate adjustment. For any parental income level at birth, being upwardly mobile was associated with lower risk compared with downward mobility. INTERPRETATION: Parental income represents a multitude of unmeasured familial sociodemographic indices. Tackling the causes of inequality and associated psychosocial and sociocultural challenges to enable upwards socioeconomic mobility could potentially reduce risks for self-directed and externalised violence. FUNDING: European Research Council.

Suicide Methods and Specific Types of Accidental Death and Fatal Poisoning Among Discharged Psychiatric Patients: A National Cohort Study.

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.