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The prevalence of heart failure (HF) and co-morbidities are increasing. The prognostic impact of interaction between co-morbidity and HF remains unknown. The purpose of the present study was to examine if HF interacts with co-morbidity burden to increase mortality. We conducted a cohort study of all adult Danish patients (aged ≥18 years) with a hospital inpatient or outpatient clinic diagnosis of HF (n = 252,726) between 1995 and 2016. We matched each patient with up to 3 members of the general population without a history of HF (n = 744,372). Noncardiac co-morbidities were assessed using the Charlson co-morbidity index and were defined by 4 categories of co-morbidity: 0 (none), 1 (low), 2 to 3 (moderate), and ≥4 (severe). Cardiac co-morbidities were assessed individually. Among patients with HF with severe co-morbidity, 42% of the mortality rate during 30 days of follow-up was explained by the interaction with co-morbidity. The interaction effect was also substantial in patients with moderate (31%) and low co-morbidity burden (16%). During 31 to 365 days of follow-up, interaction effects were 1% for low co-morbidity, 8% for moderate co-morbidity, and 22% for severe co-morbidity. Beyond 1 year of follow-up, no interaction effect was observed. With the exception of cardiomyopathy, cardiac co-morbidities did not interact substantially with HF during the first year of follow-up. During longer follow-up, pulmonary hypertension, cardiomyopathy, and endocarditis showed interaction. In conclusion, noncardiac co-morbidities had biological interaction with HF that increased short-term mortality substantially beyond the individual effects of HF and co-morbidity.

Background: Accurate estimates of risks of poststroke outcomes from large population–based studies can provide a basis for public health policy decisions. We examined the absolute and relative risks of a spectrum of incident mental disorders following ischemic stroke and intracerebral hemorrhage. Methods: During 2004 to 2018, we used Danish registries to identify patients (≥18 years and with no hospital history of mental disorders), with a first-time ischemic stroke (n=76 767) or intracerebral hemorrhage (n=9344), as well as age-,sex-, and calendar year–matched general population (n=464 840) and myocardial infarction (n=92 968) comparators. We computed risk differences, considering death a competing event, and hazard ratios adjusted for income, occupation, education, and history of cardiovascular and noncardiovascular comorbidity. Results: Compared with the general population, following ischemic stroke, the 1-year risk difference was 7.3% (95% CI, 7.0–7.5) for mood disorders (driven by depression), 1.4% (95% CI, 1.3–1.5) for organic brain disorders (driven by dementia and delirium), 0.8% (95% CI, 0.7–0.8) for substance abuse disorders (driven by alcohol and tobacco abuse), and 0.5% (95% CI, 0.4–0.5) for neurotic disorders (driven by anxiety and stress disorders). For suicide, risk differences were near null. Hazard ratios were particularly elevated in the first year of follow-up, ranging from a 2- to a 4-fold increased hazard, decreasing thereafter. Compared with myocardial infarction patients, the 1-year risk difference was 4.9% (95% CI, 4.6 to 5.3) for mood disorders, 1.0% (95% CI, 0.8 to 1.1) for organic brain disorders, 0.1% (95% CI, 0.0 to 0.2) for substance abuse disorders, but −0.2% (95% CI, −0.2 to −0.1) for neurotic disorders. Hazard ratios during the first year of follow-up were elevated 1.1- to 1.8-fold for mood, organic brain, and neurotic disorders, while decreased 0.8-fold for neurotic disorders. Conclusions: The considerably greater risks of mental disorders following a stroke, particularly mood disorders, underline the importance of mental health evaluation after stroke.

BACKGROUND: Survival after heart transplantation has increased due to continuously refined and effective care management. Knowledge is sparse on the influence of multimorbidity and social vulnerability on management. We assessed the long-term influence of multimorbidity and socioeconomic factors on cross-sectional health care service utilization in heart transplant recipients.METHODS: First-time heart transplant recipients, from the Transplant Center at Aarhus University Hospital, were followed from transplant until December 31, 2018. We linked individual-level data from the Scandiatransplant Database to Danish national registers. We followed recipients for 15 years using descriptive statistic.RESULTS: We identified 325 recipients; 79% were male and 60% were between 41 and 60 years of age. The median (IQR) number of chronic conditions at baseline was 1.0 (1.0-2.0). The prevalence of recipients with ≥3 chronic conditions in the follow-up period 0 to 1 year was 10% and 65% within 10 to 15 years. The median use of cross-sectional health care services was higher in recipients with ≥3 chronic conditions compared to CONCLUSIONS: The use of cross-sectional health care services was higher in heart transplant recipients with increased incidence of comorbidities during follow-up intervals. A socioeconomic influence was observed in the utilization of services.

Background - The psychologic consequences of acute venous thromboembolism (VTE) have not been investigated in depth. Objectives We aimed to examine the association between VTE and the risk of subsequent depression. Methods - Using Danish nationwide registries, we established a population-based cohort of 64 596 individuals with incident VTE during 1996 to 2016 and a comparison cohort (n = 322 999) selected randomly from the general population and individually matched by birth year, sex, and calendar year of VTE. The participants were followed up for 3 years, and depression was defined as any hospital diagnosis of depression or ≥1 prescription for antidepressants. Incidence rates were computed as the number of events per 1000 person-years, and hazard ratios with 95% CIs were computed as estimates of the risk conferred by VTE using the comparison cohort as reference. We estimated absolute risks using cumulative incidence functions, treating death as a competing event. Results - Depression was observed in 6225 individuals after VTE and 16 363 members of the comparison cohort (incidence rates of 44.4 and 19.4 per 1000 person-years, respectively). The absolute risk of depression was 10.3% (95% CI, 10.1%-10.6%) in the VTE cohort and 5.6% (95% CI, 5.5%-5.6%) in the comparison cohort, corresponding to 4.7 excess cases of depression per 100 individuals with VTE. VTE was associated with a 2.35-fold (95% CI, 2.28-2.43) increased risk of depression compared with that in the comparison cohort. The association was attenuated after adjustments for socioeconomic status and comorbidities (hazard ratio, 1.91; 95% CI, 1.85-1.97). Conclusion - VTE was associated with an increased risk of depression after adjustment for comorbidities.

Background: Outcome after colorectal liver metastases (CRLM) resection has improved over time, despite increased resection rates. Hence, it's crucial to identify all patients possible to treat with curative intent. The objectives of this study were to map recurrence pattern, treatment strategy and survival depending on treatment and follow-up strategy.Methods: In the COLOFOL-trial, patients with radically resected stage II-III colorectal cancer were randomized to high-frequency (6, 12, 18, 24 and 36 months; HF) or low-frequency (12 and 36 months; LF) follow-up. In this study, all CRLM within 5 years were identified and medical files scrutinized. Overall survival (OS) was analysed in uni- and multivariable analyses. Primary endpoint was 5-year OS.Results: Of 2442 patients, 235 (9.6%) developed metachronous CRLM of which 123 (52.3%) underwent treatment with curative intent, resulting in 5-year OS of 58%. Five-year OS for patients with CRLM was 43% after HF versus 24% after LF. The survival benefit was confirmed for HF 8 years from resection of the primary tumour, HR 0.63 (CI 0.46-0.85).Conclusion: A high proportion of metachronous CRLM was possible to treat with curative intent, yielding high survival rates. More intense follow-up after colorectal cancer resection might be of value in high-risk patients. Background: Outcome after colorectal liver metastases (CRLM) resection has improved over time, despite increased resection rates. Hence, it's crucial to identify all patients possible to treat with curative intent. The objectives of this study were to map recurrence pattern, treatment strategy and survival depending on treatment and follow-up strategy.Methods: In the COLOFOL-trial, patients with radically resected stage II-III colorectal cancer were randomized to high-frequency (6, 12, 18, 24 and 36 months; HF) or low-frequency (12 and 36 months; LF) follow-up. In this study, all CRLM within 5 years were identified and medical files scrutinized. Overall survival (OS) was analysed in uni- and multivariable analyses. Primary endpoint was 5-year OS.Results: Of 2442 patients, 235 (9.6%) developed metachronous CRLM of which 123 (52.3%) underwent treatment with curative intent, resulting in 5-year OS of 58%. Five-year OS for patients with CRLM was 43% after HF versus 24% after LF. The survival benefit was confirmed for HF 8 years from resection of the primary tumour, HR 0.63 (CI 0.46-0.85).Conclusion: A high proportion of metachronous CRLM was possible to treat with curative intent, yielding high survival rates. More intense follow-up after colorectal cancer resection might be of value in high-risk patients.

Background: Previous studies of the effect of interaction between psychiatric disorders on suicide have reported mixed results. We investigated the joint effect of depression and various comorbid psychiatric disorders on suicide. Methods: We conducted a population-based case–cohort study with all suicide deaths occurring between 1 January 1995 and 31 December 2015 in Denmark (n = 14,103) and a comparison subcohort comprised of a 5% random sample of the source population at baseline (n = 265,183). We quantified the joint effect of pairwise combinations of depression and major psychiatric disorders (e.g., organic disorders, substance use disorders, schizophrenia, bipolar disorder, neurotic disorders, eating disorders, personality disorders, intellectual disabilities, developmental disorders, and behavioral disorders) on suicide using marginal structural models and calculated the relative excess risk due to interaction. We assessed for the presence of competing antagonism for negative relative excess risk due to interactions. Results: All combinations of depression and comorbid psychiatric disorders were associated with increased suicide risk. For example, the rate of suicide among men with depression and neurotic disorders was 20 times (95% CI = 15, 26) the rate in men with neither disorder. Most disorder combinations were associated with subadditive suicide risk, and there was evidence of competing antagonism in most of these cases. Conclusions: Subadditivity may be explained by competing antagonism. When both depression and a comorbid psychiatric disorder are present, they may compete to cause the outcome such that having 2 disorders may be no worse than having a single disorder with respect to suicide risk.

Tuberculosis (TB) is a risk factor for chronic obstructive pulmonary disease (COPD), but COPD is also a predictor of TB. The excess life-years lost to COPD caused by TB can potentially be saved by screening for and treating TB infection. We examined the number of life-years that could be saved by preventing TB and TB-attributable COPD. We compared the observed (no intervention) and counterfactual microsimulation models constructed from observed rates in the Danish National Patient Registry (covering all Danish hospitals between 1995 and 2014). In the Danish population of TB and COPD-naive individuals (n = 5,206,922), 27,783 persons (0.5%) developed TB. Among those who developed TB, 14,438 (52.0%) developed TB with COPD. Preventing TB saved 186,469 life-years overall. The excess number of life-years lost to TB alone was 7.07 years per person, and the additional number of life-years lost among persons who developed COPD after TB was 4.86 years per person. The life-years lost to TB-associated COPD are substantial, even in regions where TB can be expected to be identified and treated promptly. Prevention of TB could prevent a substantial amount of COPD-related morbidity; the benefit of screening and treatment for TB infection is underestimated by considering morbidity from TB alone.

Objective: Mechanistic target of rapamycin (mTOR) inhibitors are effective in animal models of granulomatous disease, but their benefit in sarcoidosis patients is unknown. We evaluated the incidence of sarcoidosis in patients treated with mTOR inhibitors versus calcineurin inhibitors. Methods: This was a cohort study using the Optum Clinformatics® Data Mart (CDM) Database (2003–2019), IBM® MarketScan® Research Database (2006–2016), and Danish health and administrative registries (1996–2018). Patients aged ≥18 years with ≥1 year continuous enrollment before and after kidney, liver, heart, or lung transplant treated with an mTOR inhibitor or calcineurin inhibitor were included. Patients diagnosed with sarcoidosis before, or up to 90 days after, transplant were excluded. The incidence of sarcoidosis by treatment group was calculated. Results: In the Optum CDM/IBM MarketScan cohort, 1,898 patients were treated with an mTOR inhibitor (mean age 49 years; 34% female) and 9,894 patients were treated with a calcineurin inhibitor (mean age 50 years; 37% female). The mean follow-up in the mTOR inhibitor group was 1.1 years, with no incident sarcoidosis diagnosed. In the calcineurin inhibitor group, the mean follow-up was 2.2 years, with 12 incident sarcoidosis cases diagnosed. In the Danish cohort, 230 patients were treated with an mTOR inhibitor (mean age 49; 45% female), with no incident sarcoidosis diagnosed. There were 3,411 patients treated with a calcineurin inhibitor (mean age 45; 40% female), with 10 incident cases of sarcoidosis diagnosed. Conclusions: This study indicates a potential protective effect of mTOR inhibitor treatment compared with calcineurin inhibitor treatment against the development of sarcoidosis.

BackgroundWomen with only pregnancy terminations or only miscarriages have an increased mortality risk. We investigated the association between vaginal bleeding (VB) in pregnancy ending in childbirth and women’s mortality.MethodsWe conducted a cohort study in Denmark, which included 1,354,181 women and their 3,162,317 pregnancies (1979-2017) followed through 2018. We ascertained 70,835 VB-affected pregnancies and comparators: 2,236,359 VB-unaffected pregnancies ending in childbirth; 589,697 terminations; and 265,940 miscarriages. We computed all-cause and cause-specific mortality rates per 10,000 person-years (PY) and hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox proportional hazards regression adjusted for age, calendar year, preexisting conditions, and socioeconomic factors.ResultsThere were 2,320 deaths from any cause among women following VB-affected pregnancy (mortality rate: 15.2, 95% CI: 14.6-15.9 per 10,000 PY); 55,030 deaths following VB-unaffected pregnancy (12.7, 12.6-1.28); 27,500 deaths following a termination (21.9, 21.6-22.1), and 10,865 deaths following a miscarriage (19.2, 18.8-19.6).For comparison of VB-affected vs VB-unaffected pregnancies, associations with all-cause (HR: 1.14, 95% CI: 1.09-1.19), natural-causes (HR: 1.15, 95% CI: 1.09-1.22) and non-natural causes (HR: 1.27, 95% CI: 1.08-1.48) mortality attenuated in a sensitivity analysis of pregnancies recorded in 1994-2017 (HR: 1.00, 95% CI: 0.90-1.12, HR: 0.98, 95% CI: 0.85-1.14, and HR: 1.04, 95% CI: 0.71-1.51, respectively). Contrasts with remaining comparators did not suggest increased risks of all-cause, natural, or non-natural mortality causes.ConclusionsWe found no evidence of an increased risk of mortality in women following VB-affected vs VB-unaffected pregnancy, termination, or miscarriage.Key MessagesPrevious studies mostly focused on short-term outcomes of the newborns and mothers following the vaginal bleeding-affected pregnancy. This study investigated the association between vaginal bleeding in pregnancy ending in childbirth and women’s mortality.This registry-based cohort study found no evidence of an increased risk of all-cause or cause-specific mortality from natural or non-natural causes in women following vaginal bleeding-affected pregnancy compared with vaginal bleeding-unaffected pregnancy, termination, or miscarriage

Background: Few studies have reported the long-term consequences of bacterial meningitis during infancy, and studies that have been done usually do not include a comparison cohort. We aimed to assess short-term and long-term risk of mortality, neurodevelopmental impairment (NDI), and health-care use and household income in cohorts of children with and without a history of bacterial meningitis during infancy in Denmark and the Netherlands. Methods: In this nationwide cohort study, infants with a history of bacterial meningitis before age 1 year were identified through the Danish Medical Birth Registry and Danish National Patient Registry using International Classification of Diseases (ICD)-10 codes and through the Netherlands Reference Laboratory for Bacterial Meningitis. Infants were matched (1:10) by sex and birth month and year to a comparison cohort of the general population without a history of bacterial meningitis. We analysed mortality using Cox proportional hazards regression. In Denmark, diagnoses of NDIs were based on ICD-10 codes; in the Netherlands, special educational needs were used as a functional NDI outcome. Risk ratios (RRs) of NDIs were estimated using modified Poisson regression. We also analysed long-term health-care use in Denmark and household income in both countries. All regression analyses were adjusted for sex and year of birth, and stratified by pathogen whenever sample size allowed. Findings: We included 2216 children with a history of bacterial meningitis (570 [25·7%] in Denmark between Jan 1, 1997, and Dec 31, 2018, and 1646 [74·3%] in the Netherlands between Jan 1, 1995, and Dec 31, 2018), matched to 22 127 comparison cohort members. Median age at diagnosis was 2·8 months (IQR 0·4–7·1) in Denmark and 4·3 months (0·7–7·4) in the Netherlands. Mortality risks within 3 months after disease onset were 3·9% (95% CI 2·6–5·8%) in Denmark and 5·9% (4·7–7·0) in the Netherlands, compared with 0·0% (p

OBJECTIVE: Irritable bowel syndrome (IBS) is a chronic disorder associated with an abnormal gastrointestinal microbiome. Microbiome-host interactions are known to influence organ function including in the central nervous system; thus, we sought to identify whether IBS may be a risk factor for the development of glaucoma.DESIGN: Two prospective cohort studies.SUBJECTS: The 1958 United Kingdom Birth Cohort (UKBC; 9091 individuals) and the Danish National Registry of Patients (DNRP; 62,541 individuals with IBS and 625,410 matched general population cohort members).METHODS: In the UKBC, participants were surveyed throughout life (including at ages 42 and 50). The DNRP contains records of hospital-based contacts and prescription data from the national prescription database.MAIN OUTCOME MEASURE: The main outcome measure was incidence of glaucoma. In the UKBC, incident glaucoma at age 50 (n = 48) was determined through comparison of survey responses at ages 42 and 50 years. In the DNRP, glaucoma was assessed by hospital diagnosis (n = 1510), glaucoma surgery (n = 582) and initiation of glaucoma medications (n = 1674).RESULTS: In the UKBC, the odds ratio (OR) of developing glaucoma between ages 42 and 50 in persons with a chronic IBS diagnosis was increased [OR: 5.84, 95% confidence interval (CI): 2.26-15.13]. People with an IBS diagnosis in the DNRP had a hazard ratio (HR) of 1.35 for developing physician-diagnosed glaucoma (95% CI: 1.16-1.56), an HR of 1.35 for undergoing glaucoma surgery (95% CI: 1.06-1.70) and an HR of 1.19 for initiating glaucoma medication (95% CI: 1.03-1.38).CONCLUSIONS: In two large European cohort studies, IBS is a risk factor for glaucoma.

Objectives: Sarcoidosis may have an infectious trigger, including Mycobacterium spp. The Bacille Calmette-Guérin (BCG) vaccine provides partial protection against tuberculosis and induces trained immunity. We examined the incidence rate (IR) of sarcoidosis in Danish individuals born during high BCG vaccine uptake (born before 1976) compared with individuals born during low BCG vaccine uptake (born in or after 1976). Methods: We performed a quasi-randomized registry-based incidence study using data from the Danish Civil Registration System and the Danish National Patient Registry between 1995 and 2016. We included individuals aged 25–35 years old and born between 1970 and 1981. Using Poisson regression models, we calculated the incidence rate ratio (IRR) of sarcoidosis in individuals born during low BCG vaccine uptake versus high BCG vaccine uptake, adjusting for age and calendar year (separately for men and women). Results: The IR of sarcoidosis was increased for individuals born during low BCG vaccine uptake compared with individuals born during high BCG vaccine uptake, which was largely attributed to men. The IRR of sarcoidosis for men born during low BCG vaccine uptake versus high BCG vaccine uptake was 1.22 (95% confidence interval [CI] 1.02–1.45). In women, the IRR was 1.08 (95% CI 0.88–1.31). Conclusion: In this quasi-experimental study that minimizes confounding, the time period with high BCG vaccine uptake was associated with a lower incidence rate of sarcoidosis in men, with a similar effect seen in women that did not reach significance. Our findings support a potential protective effect of BCG vaccination against the development of sarcoidosis. Future interventional studies for high-risk individuals could be considered.

Suicide attempts are a leading cause of injury globally. Accurate prediction of suicide attempts might offer opportunities for prevention. This case-cohort study used machine learning to examine sex-specific risk profiles for suicide attempts in Danish nationwide registry data. Cases were all persons who made a nonfatal suicide attempt between 1995 and 2015 (n = 22,974); the subcohort was a 5% random sample of the population at risk on January 1, 1995 (n = 265,183). We developed sex-stratified classification trees and random forests using 1,458 predictors, including demographic factors, family histories, psychiatric and physical health diagnoses, surgery, and prescribed medications. We found that substance use disorders/treatment, prescribed psychiatric medications, previous poisoning diagnoses, and stress disorders were important factors for predicting suicide attempts among men and women. Individuals in the top 5% of predicted risk accounted for 44.7% of all suicide attempts among men and 43.2% of all attempts among women. Our findings illuminate novel risk factors and interactions that are most predictive of nonfatal suicide attempts, while consistency between our findings and previous work in this area adds to the call to move machine learning suicide research toward the examination of high-risk subpopulations.

The incidence of venous thromboembolism (VTE) in cancer patients may have changed in the past decade, possibly due to novel cancer therapies, improved survival, and high-resolution imaging. Danish medical registries were used to identify 499 092 patients with a first-time cancer diagnosis between 1997 and 2017, who were matched to 1 497 276 comparison individuals without cancer from the general population. We computed cumulative incidences of VTE 6 and 12 months after the diagnosis/index date. Hazard ratios (HRs) were calculated using Cox regression. Risk factors were examined by computing subdistribution hazard ratios (SHRs) in a competing-risk analysis. Cumulative incidence of VTE 12 months after the cancer diagnosis/index date was 2.3% (95% confidence interval [CI], 2.2% to 2.3%) in the cancer cohort and 0.35% (95% CI, 0.34% to 0.36%) in the comparison cohort (HR, 8.5; 95% CI, 8.2-8.8). Important risk factors for cancer patients were prior VTE (SHR, 7.6; 95% CI, 7.2-8.0), distant metastasis (SHR, 3.2; 95% CI, 2.9-3.4), and use of chemotherapy (SHR, 3.4; 95% CI, 3.1-3.7), protein kinase inhibitors (SHR, 4.1; 95% CI, 3.4-4.9), antiangiogenic therapy (SHR, 4.4; 95% CI, 3.8-5.2), and immunotherapy (SHR, 3.6; 2.8-4.6). Twelve-month incidence in the cancer cohort increased from 1.0% (95% CI, 0.9% to 1.2%) in 1997 to 3.4% (95% CI, 2.9% to 4.0%) in 2017, which was paralleled by improved 12-month survival and increased use of computed tomography scans, chemotherapy, and targeted therapies. In conclusion, the risk of VTE in cancer patients is increasing steadily and is ninefold higher than in the general population.

Background and aims Persons with substance use disorders (SUDs) are at elevated risk of suicide death. We identified novel risk factors and interactions that predict suicide among men and women with SUD using machine learning. Design Case-cohort study. Setting Denmark. Participants The sample was restricted to persons with their first SUD diagnosis during 1995-2015 (n = 13,179). Cases were persons who died by suicide in Denmark during 1995-2015 (n = 2,774) and the comparison subcohort was a 5% random sample of individuals in Denmark drawn on January 1, 1995. Measurements Suicide death was recorded in the Danish Cause of Death Registry. Predictors included social and demographic information, mental and physical health diagnoses, surgeries, medications, and poisonings. Findings Persons among the highest risk for suicide, as identified by the classification trees, were men prescribed antidepressants in the 4 years before suicide and had a poisoning diagnosis in the 4 years before suicide; and women who were 30+ years old and had a poisoning diagnosis 4 years before and 12 months before suicide. Among men with SUD, the random forest identified five variables that were most important in predicting suicide: reaction to severe stress and adjustment disorders, drugs used to treat addictive disorders, age 30+ years, antidepressant use, and poisoning in the 4 prior years. Among women with SUD, the random forest found that the most important predictors of suicide were prior poisonings and reaction to severe stress and adjustment disorders. Individuals in the top 5% of predicted risk accounted for 15% of all suicide deaths among men and 24% of all suicides among women. Conclusions In Denmark, prior poisoning and comorbid psychiatric disorders may be among the most important indicators of suicide risk among persons with substance use disorders, particularly among women.

BackgroundSuicide risk is high in the 30 days after discharge from psychiatric hospital, but knowledge of the profiles of high-risk patients remains limited.AimsTo examine sex-specific risk profiles for suicide in the 30 days after discharge from psychiatric hospital, using machine learning and Danish registry data.MethodWe conducted a case–cohort study capturing all suicide cases occurring in the 30 days after psychiatric hospital discharge in Denmark from 1 January 1995 to 31 December 2015 (n = 1205). The comparison subcohort was a 5% random sample of all persons born or residing in Denmark on 1 January 1995, and who had a first psychiatric hospital admission between 1995 and 2015 (n = 24 559). Predictors included diagnoses, surgeries, prescribed medications and demographic information. The outcome was suicide death recorded in the Danish Cause of Death Registry.ResultsFor men, prescriptions for anxiolytics and drugs used in addictive disorders interacted with other characteristics in the risk profiles (e.g. alcohol-related disorders, hypnotics and sedatives) that led to higher risk of postdischarge suicide. In women, there was interaction between recurrent major depression and other characteristics (e.g. poisoning, low income) that led to increased risk of suicide. Random forests identified important suicide predictors: alcohol-related disorders and nicotine dependence in men and poisoning in women.ConclusionsOur findings suggest that accurate prediction of suicide during the high-risk period immediately after psychiatric hospital discharge may require a complex evaluation of multiple factors for men and women.

Background Data are limited regarding long-term consequences of invasive GBS (iGBS) disease in early infancy, especially from low- and middle-income countries (LMIC) where most cases occur. We aimed to estimate risk of neurodevelopmental impairment (NDI) in children with a history of iGBS disease. Methods A multi-country matched cohort study was undertaken in South Africa, India, Mozambique, Kenya, and Argentina from October 2019 to April 2021. The exposure of interest was defined as a history of iGBS disease (sepsis or meningitis) before 90 days of age, amongst children now aged 1·5–18 years. Age and sex-matched, children without history of GBS were also recruited. Age-appropriate, culturally-adapted assessments were used to define NDI across multiple domains (cognitive, motor, hearing, vision, emotional-behaviour, growth). Pooled NDI risk was meta-analysed across sites. Association of iGBS exposure and NDI outcome was estimated using modified Poisson regression with robust variance estimator. Findings Amongst 138 iGBS survivors and 390 non-iGBS children, 38·1% (95% confidence interval [CI]: 30·0% – 46·6%) of iGBS children had any NDI, compared to 21·7% (95% CI: 17·7% - 26·0%) of non- iGBS children, with notable between-site heterogeneity. Risk of moderate/severe NDI was 15·0% (95% CI: 3·4% - 30·8%) among GBS-meningitis, 5·6% (95% CI: 1·5% - 13·7%) for GBS-sepsis survivors. The adjusted risk ratio (aRR) for moderate/severe NDI among iGBS survivors was 1.27 (95% CI: 0.65, 2.45), when compared to non-GBS children. Mild impairment was more frequent in iGBS (27.6% (95% CI: 20.3 – 35.5%)) compared to non-GBS children (12.9% (95% CI: 9.7% - 16.4%)). The risk of emotional-behavioural problems was similar irrespective of iGBS exposure (aRR=0.98 (95% CI: 0.55, 1.77)). Interpretation Our findings suggest that iGBS disease is on average associated with a higher risk of moderate/severe NDI, however substantial variation in risk was observed between sites and data are consistent with a wide range of values. Our study underlines the importance of long-term follow-up for at-risk neonates and more feasible, standardised assessments to facilitate diagnosis in research and clinical practice. Funding This work was supported by a grant (INV-009018) from the Bill & Melinda Gates Foundation to the London School of Hygiene & Tropical Medicine.

Background: Group B streptococcus (GBS) colonisation during pregnancy can lead to invasive GBS disease (iGBS) in infants, including meningitis or sepsis, with a high mortality risk. Other outcomes include stillbirths, maternal infections, and prematurity. There are data gaps, notably regarding neurodevelopmental impairment (NDI), especially after iGBS sepsis, which have limited previous global estimates. In this study, we aimed to address this gap using newly available multicountry datasets. Methods: We collated and meta-analysed summary data, primarily identified in a series of systematic reviews published in 2017 but also from recent studies on NDI and stillbirths, using Bayesian hierarchical models, and estimated the burden for 183 countries in 2020 regarding: maternal GBS colonisation, iGBS cases and deaths in infants younger than 3 months, children surviving iGBS affected by NDI, and maternal iGBS cases. We analysed the proportion of stillbirths with GBS and applied this to the UN-estimated stillbirth risk per country. Excess preterm births associated with maternal GBS colonisation were calculated using meta-analysis and national preterm birth rates. Findings: Data from the seven systematic reviews, published in 2017, that informed the previous burden estimation (a total of 515 data points) were combined with new data (17 data points) from large multicountry studies on neurodevelopmental impairment (two studies) and stillbirths (one study). A posterior median of 19·7 million (95% posterior interval 17·9–21·9) pregnant women were estimated to have rectovaginal colonisation with GBS in 2020. 231 800 (114 100–455 000) early-onset and 162 200 (70 200–394 400) late-onset infant iGBS cases were estimated to have occurred. In an analysis assuming a higher case fatality rate in the absence of a skilled birth attendant, 91 900 (44 800–187 800) iGBS infant deaths were estimated; in an analysis without this assumption, 58 300 (26 500–125 800) infant deaths from iGBS were estimated. 37 100 children who recovered from iGBS (14 600–96 200) were predicted to develop moderate or severe NDI. 40 500 (21 500–66 200) maternal iGBS cases and 46 200 (20 300–111 300) GBS stillbirths were predicted in 2020. GBS colonisation was also estimated to be potentially associated with considerable numbers of preterm births. Interpretation: Our analysis provides a comprehensive assessment of the pregnancy-related GBS burden. The Bayesian approach enabled coherent propagation of uncertainty, which is considerable, notably regarding GBS-associated preterm births. Our findings on both the acute and long-term consequences of iGBS have public health implications for understanding the value of investment in maternal GBS immunisation and other preventive strategies. Funding: Bill & Melinda Gates Foundation.

Background: It is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia. Objective: To assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer’s disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes). Methods: We conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000–2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (

Background: The birth of a child with a major congenital anomaly may create chronic caregiving stress for mothers, yet little is known about their psychiatric outcomes. Aims: To evaluate the association of the birth of a child with a major congenital anomaly with subsequent maternal psychiatric risk. Methods: This Danish nationwide cohort study included mothers who gave birth to an infant with a major congenital anomaly (n = 19 220) between 1997 and 2015. Comparators were randomly selected mothers, matched on maternal age, year of delivery and parity (n = 195 399). The primary outcome was any new-onset psychiatric diagnosis. Secondary outcomes included specific psychiatric diagnoses, psychiatric in-patient admissions and redeemed psychoactive medicines. Cox models were used to estimate hazard ratios (HRs), adjusted for socioeconomic and medical variables. Results: Mothers of affected infants had an elevated risk for a new-onset psychiatric disorder vs. the comparison group (adjusted HR, 1.16, 95% CI 1.11–1.22). The adjusted HR was particularly elevated during the first postpartum year (1.65, 95% CI 1.42–1.90), but remained high for years, especially among mothers of children with multiorgan anomalies (1.37, 95% CI 1.18–1.57). The risk was also elevated for most specific psychiatric diagnoses, admissions and medicines. Conclusions: Mothers who give birth to a child with a major congenital anomaly are at increased risk of new-onset psychiatric disorders, especially shortly after birth and for mothers of children with more severe anomalies. Our study highlights the need to screen for mental illness in this high-risk population, as well as to integrate adult mental health services and paediatric care.

Introduction: This study aimed to estimate risks of cardiovascular and cerebrovascular events in patients treated with lisdexamfetamine dimesylate (LDX) compared with patients previously treated with other attention-deficit/hyperactivity disorder (ADHD) medications (amphetamine, dexamphetamine, methylphenidate or atomoxetine). Methods: This population-based cohort study used data from Danish and Swedish medical and administrative national registers. The LDX cohort included adult patients initiating LDX with at least 12 months’ data preceding first LDX dispensing (index date). A random sample of patients treated with at least one non-LDX ADHD medication in the 6–24 months (but not less than 6 months) before index date (previous-users cohort) were matched to LDX users on age, sex, region and calendar year. The primary outcome, a composite of major adverse cardiovascular and cerebrovascular events (MACE), included first hospitalisation for acute myocardial infarction or stroke and out-of-hospital coronary heart disease or cerebrovascular disease death. Incidence rates (IRs) and IR ratios (IRRs) with 95% confidence intervals (CIs) of MACE were estimated using Poisson regression. Results: From Denmark/Sweden, 5516/40,163 LDX users and 27,494/200,389 previous users were included. In Denmark, IRs of MACE/1000 person-years (95% CI) were similar for LDX (1.63 [0.85–3.14]) and previous users (1.61 [1.28–2.01]). In Sweden, IRs (95% CI) were 1.40 (1.09–1.79) in LDX users and 1.17 (1.00–1.38) in previous users. Adjusted MACE IRRs (95% CI) for LDX versus previous use were 1.01 (0.48–2.13) in Denmark, 1.13 (0.75–1.71) in Sweden, and 1.10 (0.77–1.58) in the pooled analysis. Conclusion: Our findings suggest little to no increased risk of cardiovascular and cerebrovascular events in patients treated with LDX compared with patients previously treated with other ADHD medications.

Immigrants may have increased risk of mental disorders compared with native-born persons. We aimed to expand the limited research on immigrants' posttraumatic psychopathology related to traumatic experiences in their country of resettlement.We obtained data from a cohort of Danish residents with ≥ 1 traumatic event recorded in health and administrative national registries during 1994-2016. We calculated risks of posttraumatic stress disorder (PTSD), depression, and substance use disorders (SUD) within 5 years post-trauma among native-born Danes and immigrants who had been in Denmark for ≥ 10 years at the time of their index trauma (including immigrants overall and immigrants from specific regions). Risks were compared via age- and sex-standardized risk ratios (SRR) with 95% confidence intervals (CI). We restricted to persons with no record of the disorder under investigation in the 10 years pre-trauma, and stratified by non-interpersonal (e.g., transport accidents) versus interpersonal trauma (e.g., assaults).Following non-interpersonal trauma, immigrants were more likely than native-born Danes to be diagnosed with PTSD (SRR = 5.2, 95% CI 4.6, 5.9), about as likely to be diagnosed with depression (SRR = 0.98, 95% CI 0.92, 1.1), and less likely to be diagnosed with SUD (SRR = 0.89, 95% CI 0.82, 0.95). Results were similar following interpersonal trauma, except the SRR for PTSD was reduced in magnitude (SRR = 3.0, 95% CI 1.7, 5.4). There were differences by region of birth.Immigrants to Denmark have higher risk of PTSD following traumatic experiences than do native-born Danes, possibly due to the combined influence of adverse pre-, peri-, and/or post-migration experiences.

Research on posttraumatic psychopathology has focused primarily on posttraumatic stress disorder (PTSD); other posttraumatic psychiatric diagnoses are less well documented. The present study aimed to (a) develop a methodology to derive a cohort of individuals who experienced potentially traumatic events (PTEs) from registry-based data and (b) examine the risk of psychopathology within 5 years of experiencing a PTE. Using data from Danish national registries, we created a cohort of individuals with no age restrictions (range: 0–108 years) who experienced at least one of eight possible PTEs between 1994 and 2016 (N = 1,406,637). We calculated the 5-year incidence of nine categories of ICD-10 psychiatric disorders among this cohort and examined standardized morbidity ratios (SMRs) comparing the incidence of psychopathology in this group to the incidence in a nontraumatic stressor cohort (i.e., nonsuicide death of a relative; n = 423,270). Stress disorders (2.5%), substance use disorders (4.1%), and depressive disorders (3.0%) were the most common diagnoses following PTEs. Overall, the SMRs for the associations between any PTE and psychopathology varied from 1.9, 95% CI [1.9, 2.0], for stress disorders to 5.2, 95% CI [5.1. 5.3], for personality disorders. All PTEs except pregnancy-related trauma were associated with all forms of psychopathology. Associations were consistent regardless of whether a stress disorder was present. Traumatic experiences have a broad impact on psychiatric health. The present findings demonstrate one approach to capturing trauma exposure in medical record registry data. Increased traumatic experience characterization across studies will help improve the field's understanding of posttraumatic psychopathology.