Mental Health Conditions Among Children and Adolescents With Congenital Heart Disease: A Danish Population-Based Cohort Study.

BACKGROUND: Despite the known mental health burden among children with congenital heart disease (CHD), the literature is constrained by a lack of comparison cohorts and population-based follow-up data. We examined the incidence of mental health conditions among children with CHD, relative to 3 comparison cohorts. METHODS: This population-based cohort study identified all children with CHD (<18 years of age; n=16 473) in Denmark from 1996 to 2017, through linkage of individual-level data across national registries. This allowed for complete follow-up of the population. Comparison cohorts included children from the general population (n=162 204), siblings of children with CHD (n=20 079), and children with non-CHD major congenital anomalies (n=47 799). Mental health conditions were identified using inpatient and outpatient hospital discharge codes, prescription data, and data on use of community-based psychology, psychiatry, and psychotherapy services. We computed cumulative incidence by 18 years of age, incidence rates, and adjusted hazard ratios (aHRs) using Cox regression. aHRs accounted for sex, year of CHD diagnosis, parental mental health, and socioeconomic status. All estimates were stratified by age, sex, and CHD complexity. RESULTS: The cumulative incidence of mental health conditions by 18 years of age in the CHD cohort was 35.1% (95% CI, 34.0%-36.1%), corresponding to aHRs of 1.64 (95% CI, 1.58-1.71), 1.41 (95% CI, 1.30-1.52), and 1.02 (95% CI, 0.98-1.07) compared with the general population, sibling, and major congenital anomaly cohorts, respectively. Mental health incidence rates showed prominent peaks in early childhood and adolescence. Males and children with severe or single-ventricle CHD demonstrated higher incidence rates of mental health conditions relative to females and children with mild or moderate CHD, respectively. Compared with the general population and sibling cohorts, incidence rates and aHRs in the CHD cohort were highest for severe stress reactions, attention deficit/hyperactivity disorder, intellectual disability, and autism spectrum disorder. Compared with children in the major congenital anomaly cohort, the aHRs were close to 1. CONCLUSIONS: More than one-third of children with CHD were diagnosed or treated for a mental health condition by 18 years of age. Mental health conditions began early in life and were most prominent among males and children with severe or single-ventricle heart disease.

Association between maternal employment status and presence of children with major congenital anomalies in Denmark.

IMPORTANCE: The burden of caring for children with complex medical problems such as major congenital anomalies falls principally on mothers, who in turn suffer a variety of potentially severe economic consequences. As well, health consequences of caregiving often further impact the social and economic prospects of mothers of children with major congenital anomalies (MCMCAs). Evaluating the long-term economic consequences of extensive in-home caregiving among MCMCAs can inform strategies to mitigate these effects. OBJECTIVE: To assess whether MCMCAs face reduced employment and increased need for disability benefits over a 20-year period. DESIGN: A population-based matched cohort study. SETTING: Denmark. PARTICIPANTS: All women who gave birth to a singleton child with a major congenital anomaly in Denmark between January 1, 1997 and December 31, 2017 (n = 23,637) and a comparison cohort of mothers matched by maternal age, parity, and infant's year of birth (n = 234,586). EXPOSURES: Liveborn infant with a major congenital anomaly. MAIN OUTCOMES AND MEASURES: The primary outcome was mothers' employment status, stratified by their child's age. Employment status was categorized as employed, outside the workforce (on temporary leave, holding a flexible job, or pursuing education), or unemployed; the number of weeks in each category was measured over time. The secondary outcome was time to receipt of a disability pension, which in Denmark implies permanent exit from the labor market. We used a negative binomial regression model to estimate the number of weeks in each employment category, stratified by the child's age (i.e., 0-1 year, > 1-6 years, 7-13 years, 14-18 years). A Cox proportional hazards regression model was used to compute hazard ratios as a measure of the relative risk of receiving a disability pension. Rate ratios and hazard ratios were adjusted for maternal demographics, pregnancy history, health, and infant's year of birth. RESULTS: During 1-6 years after delivery, MCMCAs were outside the workforce for a median of 50 weeks (IQR, 6-107 weeks), while members of the comparison cohort were outside the workforce for a median of 48 weeks (IQR, 4-98 weeks), corresponding to an adjusted rate ratio [ARR] of 1.05 (95% confidence interval [CI], 1.04-1.07). During the first year after delivery, MCMCAs were more likely to be employed than mothers in the comparison cohort (ARR, 1.08; 95% CI, 1.06-1.10). At all timepoints thereafter, MCMCAs had a lower rate of workforce participation. The rate of being outside the workforce was 5% higher than mothers in the comparison cohort during 1-6 years after delivery (ARR, 1.05; 95% CI, 1.04-1.07), 9% higher during 7-13 years after delivery (ARR, 1.09; 95% CI, 1.06-1.12), and 12% higher during 14-18 years after delivery (ARR, 1.12; 95% CI, 1.07-1.18). Overall, MCMCAs had a 20% increased risk of receiving a disability pension during follow-up than mothers in the matched comparison cohort [incidence rates 3.10 per 1000 person-years (95% CI, 2.89-3.32) vs. 2.34 per 1000 person-years (95% CI, 2.29-2.40), adjusted hazard ratio, 1.20; 95% CI, 1.11-1.29]. CONCLUSION AND RELEVANCE: MCMCAs were less likely to participate in the Danish workforce, less likely to be employed, and more likely to receive disability pensions than mothers of unaffected children. The rate of leaving the workforce intensified as their affected children grew older. The high demands of caregiving among MCMCAs may have long-term employment consequences even in nations with comprehensive and heavily tax-supported childcare systems, such as Denmark.

Risk and Prognosis of Cancer in Patients With Cerebral Venous Thrombosis Compared With the Danish General Population.

BACKGROUND: Whether cerebral venous thrombosis (CVT) is a marker of cancer in clinical practice remains unknown. Little is known about the prognosis of cancer detected subsequent to CVT. METHODS: We used Danish nationwide registries (1996-2019) to identify patients with a first-time primary inpatient diagnosis of CVT without a history of cancer (N=811, 65% women, median age 42 years). We assessed the risk of an incident cancer diagnosis using standardized incidence ratios (SIRs). This measure contrasts the number of observed cancers among patients with CVT to the number of expected cancers where patients with CVT have the same cancer risk as the general population. We used Kaplan-Meier survival analysis and Cox regression to compare the survival of patients with both cancer and CVT with the survival of patients with cancer but without CVT, matched on cancer site, sex, age, and year of cancer diagnosis. RESULTS: Observing 43 incident cancer cases during follow-up, the overall SIR was unity (SIR, 1.04 [95% CI, 0.75-1.40]). However, the risk was ≈7-fold the expected level in the first 3 months following CVT diagnosis (SIR, 7.00 [95% CI, 3.02-13.80]) and ≈2-fold the expected level from 3 to 12 months following CVT diagnosis (SIR, 2.21 [95% CI, 0.89-4.56]). By 12 months following CVT diagnosis, the risk resembled the expected level (SIR, 0.76 [95% CI, 0.50-1.09]). Survival among cancer patients with prior CVT versus cancer patients without prior CVT was 91% versus 87% after 6 months and 65% versus 70% after 5 years. The adjusted hazard ratio of death was 0.78 (95% CI, 0.44-1.38). CONCLUSIONS: Patients with CVT were not at overall increased risk of a cancer diagnosis, except in the first 3 months after diagnosis during which period the risk was elevated ≈7-fold. The estimate from this early period, however, was based on only a few cancer diagnoses. Unlike other forms of venous thrombosis, a prior diagnosis of CVT did not negatively impact cancer survival.

Fever of Unknown Origin and Incidence of Cancer.

BACKGROUND: Diagnostic tools for determining causes of fever of unknown origin (FUO) have improved over time. We examined if cancer incidence among these patients changed over a 20-year period. METHODS: Population-based cohort study using nationwide Danish registries. We identified individuals diagnosed with FUO (1998-2017) to quantify their excess risk of cancer compared with the general population. Follow-up for cancer started 1 month after FUO. We computed absolute risks and standardized incidence ratios (SIRs) of cancer, and mortality rate ratios adjusted for age, sex, and cancer stage. RESULTS: Among 6620 patients with FUO (46.9% male; median age: 39 years), 343 were diagnosed with cancer (median follow-up: 6.5 years). The 1- to <12-month risk was 1.2%, and the SIR was 2.3 (95% CI, 1.8-2.9). The increased 1- to <12-month SIR was mainly due to an excess of Hodgkin lymphoma (SIR = 41.7) non-Hodgkin lymphoma (SIR = 16.1), myelodysplastic syndrome/chronic myeloproliferative diseases (SIR = 6.0), lower gastrointestinal cancer (SIR = 3.3), and urinary tract cancer (SIR = 2.9). Beyond 1-year follow-up, malignant melanoma, hepatobiliary tract/pancreatic cancer, and brain/CNS/eye cancer were diagnosed more often than expected. The 1- to <12-month cancer SIR attenuated over time, and for the 2013-2017 period we found no excess risk. Patients diagnosed with cancer ≤1 year after FUO had similar mortality to cancer patients without this diagnosis. CONCLUSIONS: Patients with FUO have a higher 1- <12-month cancer SIR; thereafter, the incidence for most cancers equals that of the general population. Decreasing SIRs over time suggests improvements in the initial diagnostic workup for FUO.

Cancer risk in patients with migraine: A population-based cohort study in Denmark.

OBJECTIVE: The purpose of this study was to examine overall and site-specific cancer risk among individuals diagnosed with migraine compared with the general population. BACKGROUND: Current evidence regarding migraine and risk of cancer is sparse and inconclusive. METHODS: We conducted a nationwide population-based cohort study with data collected routinely and prospectively from Danish population-based registries from 1995 to 2017. We computed the age- and sex-standardized incidence ratio (SIR) as the ratio of observed to expected cancers among patients diagnosed with migraine in the study population overall, and by encounter type of first diagnosis (inpatient, outpatient specialty clinic, and emergency department). Site-specific cancers were grouped according to etiology. RESULTS: We identified 72,826 patients with a first-time hospital migraine diagnosis. There were 3090 observed overall cancer cases among individuals diagnosed with migraine as compared with 3108 expected cases (SIR 0.99, 95% confidence interval [CI]: 0.96-1.03). The cumulative incidence of all cancers combined from 1995 to 2017 among those with a first-time migraine diagnosis was 9.47% (95% CI: 9.08-9.87). The SIRs for most cancers were consistent with absence of an association: 1.00 (95% CI: 0.94-1.06) for hormone-related cancers, 0.96 (95% CI: 0.88-1.03) for smoking-related cancers, 1.10 (95% CI: 0.98-1.24) for hematologic cancers, and 0.95 (95% CI: 0.85-1.06) for immune-related cancers. Exceptions were SIRs for gastrointestinal cancers (0.78, 95% CI: 0.70-0.87) and for cancers of neurological origin (1.57, 95% CI: 1.40-1.76). CONCLUSIONS: For most cancer groups, our results did not support an association with migraine. The exceptions were an increased risk for cancers of neurological origin and a decreased risk for gastrointestinal cancers. These findings may reflect a true difference in risk among individuals with migraine, or more plausibly they reflect other forces, such as differences in medication use, detection bias and reverse causation, or shared risk factors.

Cardiovascular events and all-cause mortality in patients with chronic obstructive pulmonary disease using olodaterol and other long-acting beta2-agonists.

PURPOSE: We examined the effect of olodaterol on the risk of myocardial ischaemia, cardiac arrhythmia, and all-cause mortality compared with use of other long-acting beta2-agonists (LABAs). Channelling bias was also explored. METHODS: This Danish population-based cohort study used data linked from registries of hospital diagnoses, outpatient dispensings, and deaths. It included patients (aged ≥40 years) with a diagnosis of chronic obstructive pulmonary disease (COPD) who initiated olodaterol or another LABA. Using matching and propensity score (PS) stratification, we calculated adjusted incidence rate ratios (IRRs) using Poisson regression, followed by several additional analyses to evaluate and control channelling bias. RESULTS: The IRRs of cardiac arrhythmias or myocardial ischaemia among users of olodaterol (n = 14 239) compared to users of other LABAs (n = 51 167) ranged from 0.96 to 1.65 in various analyses, although some estimates had low precision. Initial analysis suggested an increased risk for death with olodaterol compared with other LABAs (IRR, 1.63; 95% CI, 1.44-1.84). Because olodaterol prescribing was associated with COPD severity, the mortality association was attenuated by using different methods of tighter confounding control: the IRRs were 1.26 (95% CI, 0.97-1.64) among LABA-naïve LABA/LAMA users without recent COPD hospitalisation; 1.27 (95% CI, 1.03-1.57) in a population with additional trimming from the tails of the PS distribution; and 1.32 (95% CI, 1.19-1.48) after applying overlap-weights analysis. CONCLUSIONS: Olodaterol users had a similar risk for cardiac arrhythmias or myocardial ischaemia as other LABA users. The observed excess all-cause mortality associated with olodaterol use could be due to uncontrolled channelling bias.

Syncope as a sign of occult cancers: a population-based cohort study.

BACKGROUND: We examined if syncope was a marker of an occult cancer by comparing the risk in patients with a syncope episode with that of the general population. METHODS: Using Danish population-based medical registries, we identified all patients diagnosed with syncope during 1994-2013 and followed them until a cancer diagnosis, emigration, death or end of follow-up, whichever came first. We computed cumulative risks and standardised incidence ratios (SIR) with 95% confidence intervals (CI). RESULTS: Among 208,361 patients with syncope, 20,278 subsequent cancers were observed. The 6-month cumulative risk of any cancer was 1.2%, increasing to 17.9 % for 1-20 years of follow-up. The highest cumulative risks after 6 months of follow-up were lung cancer (0.2%), colorectal cancer (0.2%), prostate cancer (0.1%) and brain cancer (0.1%). The 6-month SIR were 2.7 (95% CI: 2.4-3.0) for lung cancer, 2.0 (95% CI: 1.8-2.2) for colorectal cancer, 1.7 (95% CI: 1.5-1.9) for prostate cancer and 10.0 (95% CI: 8.6-11.4) for brain cancer. CONCLUSIONS: Syncope was a weak marker of an occult cancer. In short-term the highest cumulative risks were observed for lung, colorectal, prostate and brain cancers. An aggressive search for occult cancer in a patient with syncope is probably not warranted.

Risk of primary urological and genital cancers following incident breast cancer: a Danish population-based cohort study.

PURPOSE: The prevalence of breast cancer survivors has increased due to dissemination of population-based mammographic screening and improved treatments. Recent changes in anti-hormonal therapies for breast cancer may have modified the risks of subsequent urological and genital cancers. We examine the risk of subsequent primary urological and genital cancers in patients with incident breast cancer compared with risks in the general population. METHODS: Using population-based Danish medical registries, we identified a cohort of women with primary breast cancer (1990-2017). We followed them from one year after their breast cancer diagnosis until any subsequent urological or genital cancer diagnosis. We computed incidence rates and standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) as the observed number of cancers relative to the expected number based on national incidence rates (by sex, age, and calendar year). RESULTS: Among 84,972 patients with breast cancer (median age 61 years), we observed 623 urological cancers and 1397 genital cancers during a median follow-up of 7.4 years. The incidence rate per 100,000 person-years was stable during follow-up (83 for urological cancers and 176 for genital cancers). The SIR was increased for ovarian cancer (1.37, 95% CI 1.23-1.52) and uterine cancer (1.37, 95% CI 1.25-1.50), but only during the pre-aromatase inhibitor era (before 2007). Moreover, the SIR of kidney cancer was increased (1.52, 95% CI 1.15-1.97), but only during 2007-2017. The SIR for urinary bladder cancer was marginally increased (1.15, 95% CI 1.04-1.28) with no temporal effects. No associations were observed for cervical cancer. CONCLUSION: Breast cancer survivors had higher risks of uterine and ovarian cancer than expected, but only before 2007, and of kidney cancer, but only after 2007. The risk of urinary bladder cancer was moderately increased without temporal effects, and we observed no association with cervical cancer.

Incident psychiatric comorbidity following stress disorder diagnoses in Danish school-aged children: prospective population-based study.

BACKGROUND: Prospective population-based studies of psychiatric comorbidity following trauma and severe stress exposure in children are limited. AIMS: To examine incident psychiatric comorbidity following stress disorder diagnoses in Danish school-aged children using Danish national healthcare system registries. METHOD: Children (6-15 years of age) with a severe stress or adjustment disorder (ICD-10) between 1995 and 2011 (n = 11 292) were followed prospectively for an average of 5.8 years. Incident depressive, anxiety and behavioural disorder diagnoses were examined relative to an age- and gender-matched comparison cohort (n = 56 460) using Cox proportional hazards regression models. Effect modification by gender was examined through stratified analyses. RESULTS: All severe stress and adjustment disorder diagnoses were associated with increased rates for all incident outcome disorders relative to the comparison cohort. For instance, adjustment disorders were associated with higher rates of incident depressive (rate ratio RR = 6.8; 95% CI 6.0-7.7), anxiety (RR = 5.3; 95% CI 4.5-6.4), and behavioural disorders (RR = 7.9; 95% CI 6.6-9.3). Similarly, PTSD was also associated with higher rates of depressive (RR = 7.4; 95% CI 4.2-13), anxiety (RR = 7.1; 95% CI 3.5-14) and behavioural disorder (RR = 4.9; 95% CI 2.3-11) diagnoses. There was no evidence of gender-related differences. CONCLUSIONS: Stress disorders varying in symptom constellation and severity are associated with a range of incident psychiatric disorders in children. Transdiagnostic assessments within a longitudinal framework are needed to characterise the course of post-trauma or severe stressor psychopathology.

Posttraumatic Stress Disorder and Incident Infections: A Nationwide Cohort Study.

BACKGROUND: It is unknown whether posttraumatic stress disorder (PTSD) is associated with incident infections. This study's objectives were to examine (1) the association between PTSD diagnosis and 28 types of infections and (2) the interaction between PTSD diagnosis and sex on the rate of infections. METHODS: The study population consisted of a longitudinal nationwide cohort of all residents of Denmark who received a PTSD diagnosis between 1995 and 2011, and an age- and sex-matched general population comparison cohort. We fit Cox proportional hazards regression models to examine associations between PTSD diagnosis and infections. To account for multiple estimation, we adjusted the hazard ratios (HRs) using semi-Bayes shrinkage. We calculated interaction contrasts to assess the presence of interaction between PTSD diagnosis and sex. RESULTS: After semi-Bayes shrinkage, the HR for any type of infection was 1.8 (95% confidence interval: 1.6, 2.0), adjusting for marital status, non-psychiatric comorbidity, and diagnoses of substance abuse, substance dependence, and depression. The association between PTSD diagnosis and some infections (e.g., urinary tract infections) were stronger among women, whereas other associations were stronger among men (e.g., skin infections). CONCLUSIONS: This study's findings suggest that PTSD diagnosis is a risk factor for numerous infection types and that the associations between PTSD diagnosis and infections are modified by sex.

Pericarditis as a Marker of Occult Cancer and a Prognostic Factor for Cancer Mortality.

BACKGROUND: Pericarditis may be a serious complication of malignancy. Its significance as a first symptom of occult cancer and as a prognostic factor for cancer survival is unknown. METHODS: Using Danish medical databases, we conducted a nationwide cohort study of all patients with a first-time diagnosis of pericarditis during 1994 to 2013. We excluded patients with previous cancer and followed up the remaining patients for subsequent cancer diagnosis until November 30, 2013. We calculated risks and standardized incidence ratios of cancer for patients with pericarditis compared with the general population. We assessed whether pericarditis predicts cancer survival by the Kaplan-Meier method and Cox regression using a matched comparison cohort of cancer patients without pericarditis. RESULTS: Among 13 759 patients with acute pericarditis, 1550 subsequently were diagnosed with cancer during follow-up. The overall cancer standardized incidence ratio was 1.5 (95% confidence interval [CI], 1.4-1.5), driven predominantly by increased rates of lung, kidney, and bladder cancer, lymphoma, leukemia, and unspecified metastatic cancer. The <3-month cancer risk among patients with pericarditis was 2.7%, and the standardized incidence ratio was 12.4 (95% CI, 11.2-13.7). The 3- to <12-month standardized incidence ratio of cancer was 1.5 (95% CI, 1.2-1.7), subsequently decreasing to 1.1 (95% CI, 1.0-1.2). Three-month survival after the cancer diagnosis was 80% and 86% among those with and without pericarditis, respectively, and the hazard ratio was 1.5 (95% CI, 1.3-1.8). One-year survival was 65% and 70%, respectively, corresponding to a 3- to <12-month hazard ratio of 1.3 (95% CI, 1.1-1.5). CONCLUSIONS: Pericarditis may be a marker of occult cancer and augurs increased mortality after a cancer diagnosis.

Metastasis directed therapy for liver and lung metastases from colorectal cancer-A population-based study.

About 10-20% of patients with metastatic colorectal cancer (mCRC) are candidates for metastasis directed therapies such as surgical resection, ablation and stereotactic radiotherapy. We examined the temporal changes in use of metastasis directed therapies and established prognostic factors for survival in a nationwide cohort study. The Danish nationwide medical registries were used to retrieve data on treatment for liver and/or lung metastasis in patients with metastatic colorectal cancer in the period 2000-2013. Overall survival through 2014 was calculated from the time of treatment of metastases by Kaplan-Meier method and mortality between groups was assessed using Cox regression. We report 2,912 patients undergoing a total of 3,602 procedures with an increased use of all modalities during 14 calendar years. Median survival was 3.7 years (interquartile range (IQR) 2.0-9.7 years). In the multivariate analysis, the nodal stage of the primary tumor had the most pronounced association with survival with a hazard ratio for mortality of 1.56 (95% CI: 1.33-1.83) for N2 stage with reference to N0. Furthermore, female gender, age, comorbidity, surgical treatment, administration of chemotherapy, and left-sided primary tumors were associated with improved prognosis in the multivariate analysis.

Diagnosis of hyponatremia and increased risk of a subsequent cancer diagnosis: results from a nationwide population-based cohort study.

BACKGROUND: Hyponatremia has recently been associated with subsequent cancer risk. This population-based nationwide study assessed whether the diagnosis of hyponatremia can predict a cancer diagnosis within most common cancers. MATERIAL AND METHODS: Using Danish medical registries, we identified 16,220 patients with a first-time diagnosis of hyponatremia, without a cancer diagnosis, from January 2006 through November 2013. We quantified the relative risk of a subsequent cancer diagnosis by standardized incidence ratios (SIRs), comparing observed cancer incidence among patients diagnosed with hyponatremia to that expected, based on national cancer incidence during that period. RESULTS: During 40,207 person-years of follow-up, we observed 1546 cancer diagnoses compared to 956 expected (SIR: 1.62; 95% confidence interval (CI), 1.54-1.70). The increase in risk of a cancer diagnosis following a hyponatremia diagnosis was most pronounced within 0-6 months of follow-up (SIR 4.16; 95% CI, 3.85-4.48) and in the younger age group; 0-29 years (SIR 8.71; 95% CI, 2.82-20.28), 30-49 years (SIR 3.16; 95% CI, 2.26-4.31), 50-69 years (SIR 2.29; 95% CI, 2.10-2.48) and 70 + years (SIR 1.35; 95% CI, 1.27-1.44). Within six months after a hyponatremia diagnosis, the SIRs increased 10-fold for cancers of the lung (SIR 17.14; 95% CI, 15.15-19.32), brain (SIR 13.52; 95% CI, 8.90-19.66) and liver (SIR 13.26; 95% CI, 7.57-21.53) and increased 5 to 10-fold for cancers of the pancreas (SIR 8.25; 95% CI, 5.72-11.53), esophagus (SIR 6.59; 95% CI, 3.15-12.12), kidney (SIR 6.36; 95% CI, 3.39-10.88), pharynx (SIR 6.15; 95% CI, 1.27-17.97) and non-Hodgkin lymphoma (SIR 6.10; 95% CI, 4.17-8.61). The rate increased across virtually all types of cancers, except melanoma and basal cell carcinomas. CONCLUSIONS: A diagnosis of hyponatremia may be a marker of occult neoplasms, especially cancers of the lung, brain, liver, pancreas, esophagus, kidney, pharynx and non-Hodgkin lymphoma. Hyponatremia may aid in early detection of cancer.

Adjustment disorder and type-specific cancer incidence: a Danish cohort study.

BACKGROUND: Although adjustment disorder is common, there is a dearth of research on its physical health consequences. Earlier studies, biological mechanisms and stress-related behaviors suggest that cancer may be a potential sequelae of adjustment disorder. This study examined the association between adjustment disorder and type-specific cancer incidence in a nationwide cohort. METHODS: Data were obtained from the comprehensive nationwide medical and administrative registries of Denmark. We calculated the incidence of type-specific cancers from 1995 to 2013 in patients with a prior adjustment disorder diagnosis (n = 58,712), and compared it with the incidence in the general population by calculating standardized incidence ratios (SIRs) with accompanying 95% confidence intervals (CIs). SIRs were adjusted using semi-Bayes shrinkage. RESULTS: The SIR for any type of cancer was 1.0 (95% CI: 0.99, 1.1). Adjustment disorder was associated with a 10% lower rate of immune-related cancers (SIR = 0.9, 95% CI: 0.84, 0.97) and with a 20% higher rate of smoking- and alcohol-related cancers (SIR = 1.2, 95% CI: 1.1, 1.3). We found null associations for hematological (SIR = 1.1, 95% CI: 0.89, 1.3) and hormone-related (SIR = 0.98, 95% CI: 0.91, 1.1) malignancies. After semi-Bayes adjustment, type-specific cancer SIRs indicated no association between adjustment disorder and cancer incidence. CONCLUSIONS: This study provides persuasive evidence for a null association between adjustment disorder and type-specific cancer incidence in a nationwide study cohort.

Asthma and risk of myelodysplastic syndromes: a population-based cohort study.

BACKGROUND: Risk factors for the development of myelodysplastic syndromes (MDS) include age, exposure to ionising radiation, and cytotoxic drug treatment. Recently, asthma also has been suggested as a risk factor for MDS. METHODS: We undertook this nationwide population-based cohort study on patients with a first-time hospital-based asthma diagnosis during 2002-2013 and followed them for the development of MDS/chronic myelomonocytic leukaemia (CMML). RESULTS: We identified 75 995 patients with incident asthma and no previous MDS/CMML diagnosis. Seventy-eight patients subsequently developed MDS and nine patients developed CMML during 402 892 person-years. The cumulative risks of developing MDS/CMML among asthma patients were 0.02% (95% CI: 0.01-0.04%) and 0.07% (95% CI: 0.05-0.09%) during the first year and the first five years of follow-up, respectively. The standardised incidence ratio of MDS/CMML among asthma patients overall was 1.6 (95% CI: 1.3-2.0) with little variation across subgroups. CONCLUSIONS: Asthma may be a risk factor for the development of MDS/CMML.

Changes in Prescription Drug Use After Gastric Bypass Surgery: A Nationwide Cohort Study.

OBJECTIVES: To evaluate changes over time in drug use among patients undergoing Roux-en-Y gastric bypass (RYGB) surgery and a matched population-based comparison cohort. BACKGROUND: A little is known about the prescription drug use before and after RYGB surgery. METHODS: Nationwide population-based cohort study included 9908 patients undergoing RYGB in Denmark during 2006 to 2010 and 99,080 matched general population members. We calculated prevalence ratios (PRs) comparing prescription drug use 36 months after RYGB/index date with use 6 months before this date (baseline). RESULTS: At baseline, more RYGB patients (median 40 years, 22% males) used a prescription drug (81.5% vs 49.1%). After 3 years, the use had decreased slightly among RYGB patients [PR = 0.93; 95% confidence interval (CI) = (0.91, 0.94)], but increased in the comparison cohort (PR = 1.05; 95% CI = 1.04-1.06). In the RYGB cohort, large, sustained decreases occurred for treatment of metabolic syndrome-related conditions, such as any glucose-lowering drug (PR = 0.28; 95% CI = 0.25-0.31) and lipid-modifying drugs PR = 0.50; 95% CI = 0.46-0.55). Use of inhalants for obstructive airway diseases (PR = 0.79; 95% CI = 0.74-0.85) also decreased. Use of neuropsychiatric drugs was two-fold higher at baseline in the RYGB cohort (22.8% vs 10.9%) and increased further after RYGB-that is, antidepressants (PR = 1.13; 95% CI = 1.07-1.19), antipsychotics (PR = 1.39; 95% CI = 1.21-1.60), and potential treatment of neuropathy (PR = 1.39; 95% CI = 1.28-1.51). CONCLUSIONS: Three years after RYGB surgery, we found large reductions in the use of treatment of metabolic syndrome-related conditions, inhalants for obstructive airway diseases and glucocorticoid use. In contrast, frequent use of neuropsychiatric drugs further increased after RYGB.

Posttraumatic Stress Disorder and Gastrointestinal Disorders in the Danish Population.

BACKGROUND: Evidence for the association between posttraumatic stress disorder (PTSD) and gastrointestinal (GI) disorders is mixed, owing in part to methodologic differences across studies. Furthermore, studies which have combined GI disorders or symptoms for examination as one overall category may potentially obscure associations between PTSD and individual GI diagnoses. METHODS: This nationwide cohort study examined the incidence of all major nonmalignant GI disorders in patients with a prior PTSD diagnosis (n = 4,076), compared with the general population incidence from 1995 to 2013, using Danish medical registry data. We examined differences by sex, age, marital status, psychiatric and somatic comorbidity, and follow-up time. Risks, standardized incidence rates (SIRs), and confidence intervals (95% CIs) were calculated. RESULTS: Risk of any GI disorder among PTSD patients was 25% (95% CI: 21%, 29%); the SIR for any GI disorder was 1.8 (95% CI: 1.7, 2.0). Risk and SIRs varied by disorder (e.g., no association with diverticula of the intestines [SIR: 1.1, 95% CI: 0.83, 1.5]; stronger association with peptic ulcer, site unspecified [SIR: 3.3, 95% CI: 1.8, 5.5]). Stratified analyses revealed that some associations were stronger for persons ages 16-39 or unmarried at PTSD diagnosis, persons with comorbid psychiatric diagnoses, and in the year following PTSD diagnosis. CONCLUSIONS: This study documents associations between clinician-diagnosed PTSD and all major nonmalignant GI disorders in an unselected nationwide cohort with long follow-up. Differences in associations across GI disorders and important modifiers may account for previous conflicting research findings.

Risk of cardiovascular events and pulmonary hypertension following splenectomy - a Danish population-based cohort study from 1996-2012.

Splenectomized patients are at increased risk of cardiovascular events, but it remains unclear whether this is due to lack of the spleen or due to the underlying disease leading to splenectomy. We aimed to assess the risk of myocardial infarction, pulmonary hypertension, and stroke following splenectomy. We identified patients splenectomized in Denmark between 1996 and 2012. We constructed two comparison cohorts: an age- and sex-matched general population cohort and a disease-matched cohort based on the splenectomy-related underlying disease. We computed 5-year cumulative incidences and adjusted hazard ratios of myocardial infarction, pulmonary hypertension, and stroke for the three cohorts. The study included 5,306 splenectomized patients, 53,060 members of the general population, and 11,651 disease-matched patients. During the 5-year follow-up, 1.3% of splenectomized patients had a myocardial infarction versus 1.8% of the population cohort. The adjusted hazard ratio for myocardial infarction in splenectomized patients versus the population cohort was 1.24 (95% confidence interval: 1.01-1.52). The 5-year cumulative incidence of pulmonary hypertension was 0.4% among splenectomized subjects and 0.2% in the population cohort [adjusted hazard ratio 3.25 (95% confidence interval: 1.93-5.45)], while that of stroke was 3.3% among splenectomized patients versus 2.6% in the population cohort [adjusted hazard ratio 2.04 (95% confidence interval: 1.78-2.35)]. When comparing splenectomized subjects with the disease-matched cohort, only stroke risk was elevated, with 5-year risks of 3.0% and 2.3%, respectively [adjusted hazard ratio 1.56 (95% confidence interval: 1.26-1.92)]. In conclusion, splenectomized patients were at increased risk of stroke. Additionally, we found that underlying splenectomy-related diseases explained the increased risk of myocardial infarction and pulmonary hypertension following splenectomy.

Human papillomavirus infection and lymphoma incidence using cervical conization as a surrogate marker: a Danish nationwide cohort study.

Persistent human papillomavirus (HPV) infection may promote carcinogenesis by hyperactivation of the immune system. We, therefore, explored the associations between HPV infection and risk of Hodgkin and non-Hodgkin lymphoma in a nationwide cohort study using conization as a surrogate marker. We identified all Danish women who underwent conization between 1978 and 2011. We computed standardized incidence ratios and 95% confidence intervals for Hodgkin and non-Hodgkin lymphoma based on national cancer incidence rates. Among 87 435 women who underwent conization, we noted an increased incidence of Hodgkin (standardized incidence ratio 1.48, 95% confidence interval 1.05-2.02) but only a slight increase for non-Hodgkin lymphoma (standardized incidence ratio 1.10, 95% confidence interval 0.97-1.25). As measured by conization, HPV infection is associated with an increased risk of lymphoma. This association may be attributable to a chronic immune activation induced by persistent HPV infection and/or failure of the immune system both to clear HPV infection and to control lymphoma development. Copyright © 2015 John Wiley & Sons, Ltd.

Venous thromboembolism in patients with implantable cardioverter-defibrillators.

AIMS: To examine the incidence of venous thromboembolism (VTE) and its risk factors among patients with implantable cardioverter-defibrillators (ICDs). METHODS AND RESULTS: All first-time ICD recipients in Denmark during 2000-12 were identified from medical databases. Incident VTEs were ascertained, overall and according to gender, age, Charlson Comorbidity Index score (no, moderate, or severe comorbidity), prior pacemaker or cardiac resynchronization therapy (CRT-D) implantation, and ICD type (single-chamber, dual-chamber, or CRT-D). We computed the risk of VTE within 3 months and 5 years of implantation, taking death into account as a competing risk. We used Cox proportional hazards regression to compute hazard ratios as estimates of incidence rate ratios (IRRs). Among 8132 ICD recipients, 136 VTEs were diagnosed during up to 13 years of follow-up (median = 3.0 years). The VTE incidence rate was thus 4.5 per 1000 person-years [95% confidence interval (CI): 3.7-5.2]. Venous thromboembolism risk was 0.3% (95% CIs ranging from 0.1 to 0.7%) within 3 months following ICD implantation regardless of comorbidity level. Within 5 years following implantation it was 1.4% (95% CI: 0.8-2.3%), 1.3% (1.0-1.8%), and 3.2% (95% CI: 2.4-4.1%) for patients with no, moderate, and severe comorbidity, respectively. Overall, severe comorbidity conferred a 2.7-fold higher incidence rate ratio than no comorbidity (95% CI: 1.6-4.6). Incidence rate ratios did not differ by gender, age, or ICD type. CONCLUSION: Three-month risk of VTE following ICD implantation was 0.3% regardless of comorbidity level. Five-year risk of VTE following ICD implantation was 1.9% and more than twice as high for patients with severe comorbidity as for patients without comorbidity.