Mental Health Conditions in Partners and Adult Children of Stroke Survivors.

Importance: Family caregiving after critical illness has been associated with several adverse health outcomes, including various aspects of mental health, but research focusing specifically on family members of stroke survivors is limited. Objectives: To examine the associations of stroke in a partner or parent with the risk of depression, substance use disorders, anxiety disorders, and self-harm or suicide. Design, Setting, and Participants: This nationwide, population-based cohort study used data from Danish nationwide administrative and clinical registries (2004-2021). Participants included partners and adult children of survivors of stroke. Data analysis was performed from March to December 2023. Exposure: Having a partner or parent who survived stroke. Main Outcomes and Measures: The Aalen-Johansen estimator was used to compute propensity score-weighted 3-year absolute risks, risk differences, and risk ratios for depression, substance use disorders, anxiety disorders, and self-harm or suicide among partners or children of survivors of stroke compared with partners or children of survivors of myocardial infarction (MI) and matched individuals from the general population. Results: The study included a total of 1 923 732 individuals: 70 917 partners of stroke survivors (median [IQR] age, 68 [59-76] years; 46 369 women [65%]), 70 664 partners of MI survivors (median [IQR] age, 65 [55-73] years; 51 849 women [73%]), 354 570 partners of individuals from the general population (median [IQR] age, 68 [59-76] years; 231 833 women [65%]), 207 386 adult children of stroke survivors (median [IQR] age, 45 [36-52] years; 99 382 women [48%]), 183 309 adult children of MI survivors (median [IQR] age, 42 [33-49] years; 88 078 women [48%]), and 1 036 886 adult children of individuals from the general population (median [IQR] age, 45 [36-52] years; 496 875 women [48%]). Baseline characteristics were well balanced across cohorts after propensity score weighting. Among partners of stroke survivors, the 3-year absolute risk was 1.0% for depression, 0.7% for substance use disorders, 0.3% for anxiety disorders, and 0.04% for self-harm or suicide. Risk ratio point estimates for the assessed outcomes ranged from 1.14 to 1.42 compared with the general population and from 1.04 to 1.09 compared with partners of MI survivors. The elevated risk of depression in partners of stroke survivors was more pronounced after severe or moderate stroke than after mild stroke. Among adult children of stroke survivors, the 3-year absolute risk was 0.6% for depression, 0.6% for substance use disorders, 0.2% for anxiety disorders, and 0.05% for self-harm or suicide. Both absolute risks and risk ratios for adult children of stroke survivors were smaller than those reported in the partner analyses. Conclusions and Relevance: In this cohort study of partners and adult children of stroke survivors, risks of several mental health conditions and self-harm or suicide were moderately higher compared with the general population and, to a lesser extent, partners and adult children of MI survivors. These findings highlight the potential consequences of stroke among family members, particularly partners, and its findings may possibly serve as a quantitative foundation for the development of future stroke rehabilitation services.

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.

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.

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.

Increased Cancer Risk in Patients with Kidney Disease and Venous Thromboembolism: A Population-Based Cohort Study.

BACKGROUND: Venous thromboembolism (VTE) may be a harbinger of cancer in the general population. Patients with kidney disease have an a priori increased VTE risk. However, it remains unknown how a VTE affects subsequent cancer risk in these patients. OBJECTIVES: To examine the cancer risk in patients with kidney disease following a VTE. METHODS: We conducted a nationwide population-based cohort study in Denmark (1996-2017), including all VTE patients with a diagnosis of kidney disease. We calculated absolute risks of cancer (accounting for competing risk of death) and age-, sex-, and calendar-period standardized incidence ratios (SIRs) comparing the observed cancer incidence with national cancer incidence rates and cancer incidence rates of VTE patients without kidney disease. RESULTS: We followed 3,362 VTE patients with kidney disease (45.9% females) for a median follow-up time of 2.4 years (interquartile range: 0.6-5.4). During follow-up, 464 patients were diagnosed with cancer, of whom 169 (36.4%) were diagnosed within the first year. The 1-year absolute risk of any cancer was 5.0% (95% confidence interval [CI]: 4.3-5.8), with a SIR of 2.9 (95% CI: 2.5-3.4) when compared with the general population, and 2.0 (95% CI: 1.8-2.4) when compared with VTE patients without kidney disease. During subsequent years of follow-up, the SIRs declined to 1.5 (95% CI: 1.3-1.6) when compared with the general population, and 1.1 (95% CI: 0.9-1.2) compared with VTE patients without kidney disease. CONCLUSION: Patients with hospital-diagnosed kidney disease have increased cancer risk after VTE, especially within the first year following the VTE diagnosis.

Cancer Diagnosis and Prognosis After Guillain-Barré Syndrome: A Population-Based Cohort Study.

Introduction: It is unclear whether Guillain-Barré syndrome (GBS) can be a marker of a paraneoplastic syndrome. We examined whether GBS is associated with cancer and whether the prognosis of GBS patients with cancer differs from that of other cancer patients. Materials and Methods: We conducted a population-based cohort study of patients diagnosed with GBS between 1978 and 2017 using Danish registry-data. Main outcome measures were cancer incidence and mortality after cancer diagnosis. We calculated absolute risks of a cancer diagnosis, treating death as competing risk, and standardized incidence ratios (SIRs) as measures of relative risk. We matched each GBS cancer patient with up to 10 cancer patients without a GBS diagnosis and examined the six-month survival after cancer diagnosis using Cox regression analysis. Results: We identified 7897 patients (58% male, median age 57 years) with GBS. During a median follow-up of 9.5 years, the one-year risk of cancer was 2.7% (95% confidence interval (CI), 2.4-3.1). The SIR was increased throughout follow-up, but most noticeably during the first year after diagnosis (SIR: 3.35, 2.92-3.83). SIRs were particularly elevated for hematologic cancers (SIR: 8.67, 6.49-11.34), smoking-related cancers (SIR: 3.57, 2.81-4.47), and cancers of neurological origin (SIR: 8.60, 5.01-13.77). Lung cancer was the main contributor to the overall excess risk, which persisted after 36 months of follow-up (SIR: 1.17, 1.09-1.25). The mortality rate ratio comparing patients diagnosed with any cancer within one year of their GBS diagnosis and matched GBS-free cancer cohort members was 1.56 (95% CI, 1.27-1.90). Conclusion: GBS patients had a three-fold increased risk of cancer diagnosis in the first year of follow-up. The absolute cancer risk was almost 3.0%. A GBS diagnosis was an adverse prognostic marker for survival following cancer diagnosis. Clinicians should consider occult cancer in patients hospitalized with GBS.

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.

Mortality Among Danish Patients with a Hospital Diagnosis of Overweight or Obesity Over a 40-Year Period.

Purpose: Data on long-term mortality among patients with hospital-diagnosed overweight/obesity are limited. Thus, we aim to examine 40-year mortality among patients with hospital-diagnosed overweight/obesity, including cause-specific deaths, secular time trends, and potential effect modification by age, comorbidity, and socioeconomic factors. Patients and Methods: From national registries, we identified all Danes with a first hospital-based overweight/obesity diagnosis (N=331,185), 1979-2018, and constructed an age- and gender-matched general population comparison cohort (N=1,655,925). We computed mortality rates (MRs) per 1000 person-years and adjusted mortality rate ratios (aMRRs) with 95% confidence intervals (CIs), using Cox regression with adjustment for comorbidities and educational level. We performed stratified analyses on age, comorbidities, and socioeconomic factors. Results: The overall aMRR was 1.70 (95% CI: 1.68-1.72) for patients with overweight/obesity, mainly due to diabetes and other endocrine diseases (aMRR=2.68 [95% CI: 2.57-2.81]), cardiovascular (aMRR=1.95 [95% CI: 1.91-1.98]), and respiratory diseases (aMRR=1.83 [95% CI: 1.77-1.89]). The 1-10-year aMRR decreased from 2.06 (95% CI: 2.01-2.11) in 1979-1989 to 1.29 (95% CI: 1.26-1.32) in 2000-2009. We found effect modification by age: age 18 to <30 years: aMRR=2.44 (95% CI: 2.24-2.66) vs age ≥70 years: 1.35 (95% CI: 1.33-1.37); comorbidities: baseline comorbidities: aMRR=1.13 (95% CI: 1.10-1.15) vs no comorbidities: aMRR=1.83 (95% CI: 1.80-1.85); and educational level: high educational level: aMRR=1.81 (95% CI: 1.74-1.88) vs low educational level: aMRR=1.70 (95% CI: 1.67-1.72). Conclusion: Patients with overweight/obesity had a substantially increased long-term mortality, mainly due to diabetes, cardiovascular, and respiratory diseases. The excess mortality decreased during recent decades. Age, comorbidities, and socioeconomic factors modified the association.

Cancer Risk in Pulmonary Hypertension Patients.

BACKGROUND: Strong evidence indicates that venous thromboembolism is a presenting symptom of cancer. Cancer is a known cause of pulmonary hypertension; however, it remains unknown whether pulmonary hypertension is a marker of occult cancer. We examined the association between a pulmonary hypertension diagnosis and cancer risk in a cohort study using population-based data from the Danish health system. PATIENTS AND METHODS: Using Danish nationwide registries, we identified 6335 patients with a pulmonary hypertension diagnosis and without a previous cancer diagnosis between 1995 and 2017. We computed the age-, sex-, and calendar year-standardized incidence ratio (SIR) as the ratio of observed to expected number of cancers using national incidence rates as the reference. We performed a subgroup analysis among patients with chronic thromboembolic pulmonary hypertension in the period in which a specific ICD-10 code was available (2006-2017). RESULTS: We identified 212 cancers within the first year of follow-up and 796 cancers thereafter. The one-year risk of cancer was 3.3% and the one-year SIR was 1.96 (95% confidence interval [CI]: 1.70-2.23). In the second and subsequent years, the SIR remained elevated (SIR: 1.15 [95% CI: 1.08-1.24]). In patients with chronic thromboembolic pulmonary hypertension, the one-year SIR was 1.41 (95% CI: 0.82-2.25). CONCLUSION: Cancer risk was clearly higher in patients with pulmonary hypertension compared with the general population. The association was particularly strong in the first year of follow-up, but remained elevated thereafter. However, absolute risks were low, limiting the clinical relevance of pursuing early cancer detection in these patients.

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.

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.

Acute urinary retention and risk of cancer: population based Danish cohort study.

OBJECTIVE: To examine the risk of urogenital, colorectal, and neurological cancers after a first diagnosis of acute urinary retention. DESIGN: Nationwide population based cohort study. SETTING: All hospitals in Denmark. PARTICIPANTS: 75 983 patients aged 50 years or older with a first hospital admission for acute urinary retention during 1995-2017. MAIN OUTCOME MEASURES: Absolute risk of urogenital, colorectal, and neurological cancer and excess risk of these cancers among patients with acute urinary retention compared with the general population. RESULTS: The absolute risk of prostate cancer after a first diagnosis of acute urinary retention was 5.1% (n=3198) at three months, 6.7% (n=4233) at one year, and 8.5% (n=5217) at five years. Within three months of follow-up, 218 excess cases of prostate cancer per 1000 person years were detected. An additional 21 excess cases per 1000 person years were detected during three to less than 12 months of follow-up, but beyond 12 months the excess risk was negligible. Within three months of follow-up the excess risk for urinary tract cancer was 56 per 1000 person years, for genital cancer in women was 24 per 1000 person years, for colorectal cancer was 12 per 1000 person years, and for neurological cancer was 2 per 1000 person years. For most of the studied cancers, the excess risk was confined to within three months of follow-up, but the risk of prostate and urinary tract cancer remained increased during three to less than 12 months of follow-up. In women, an excess risk of invasive bladder cancer persisted for several years. CONCLUSIONS: Acute urinary retention might be a clinical marker for occult urogenital, colorectal, and neurological cancers. Occult cancer should possibly be considered in patients aged 50 years or older presenting with acute urinary retention and no obvious underlying cause.

Venous thromboembolism and risk of cancer in users of statins: A Danish population-based cohort study.

BACKGROUND: Venous thromboembolism (VTE) may be the first symptom of cancer. Statins are suggested to prevent VTE, but the risk of cancer in VTE patients using statins remains poorly understood. OBJECTIVES: To examine if VTE is a marker of cancer in users of statins. METHODS: We identified all Danish patients during 1996-2017 with a first-time diagnosis of VTE and a filled prescription for a statin within 90 days prior to the VTE diagnosis. We classified patients as prevalent users if the first filling of a statin occurred more than one year preceding the VTE diagnosis, and as new users if the first filling occurred within the preceding year. We computed cumulative incidences of cancer, with death as a competing risk, and age-, sex-, and calendar-period standardized incidence ratios (SIRs), comparing the observed cancer incidence with the expected based on national cancer statistics. RESULTS: Among 9280 (85%) prevalent users of statin and 1580 (15%) new users, the one-year cumulative incidence of any cancer was 6.6 (95% CI: 6.1-7.2) for prevalent users and 6.4 (95% CI: 5.2-7.6) for new users; the corresponding SIRs were 3.1 (95% CI: 2.9-3.3) and 3.5 (95% CI: 2.9-4.3). In the second and subsequent years, the SIRs diminished and approached unity for both prevalent (1.1 [95% CI: 1.1-1.2]) and new users (1.1 [95% CI: 0.9-1.3]). CONCLUSIONS: VTE patients using statins had a 3-fold increased rate of cancer in the first year after diagnosis. A first VTE serves as an important marker of cancer, regardless of statin use.

Unspecified stress disorders and risk of arterial and venous thromboembolic disease in the Danish population.

BACKGROUND: Posttraumatic stress disorder is a well-documented risk factor for cardiovascular disease. Whether non-specific stress-related psychopathology also increases risk is less well known. METHODS: In a cohort of adult Danish-born residents of Denmark with an incident diagnosis of unspecified reaction to severe stress ("unspecified stress reaction") between 1995 and 2011 (N = 24,534), we assessed incidence of seven arterial and venous cardiovascular events/conditions between 1996 and 2013. We calculated standardized incidence ratios (SIRs) comparing incidence of each outcome among the cohort to expected incidence based on sex-, age-, and calendar-time-specific national rates. We conducted stratified analyses by demographic characteristics, comorbidities, and length of follow-up time. RESULTS: Incidence over the study period ranged from 1.1% for provoked VTE to 5.7% for stroke, adjusting for competing risk of death. Unspecified stress reaction was associated with all outcomes (SIRs ranging from 1.3, 95% confidence interval (CI): 1.1-1.4 for atrial fibrillation/flutter to 1.9, 95% CI: 1.7-2.2 for unprovoked VTE and 1.9, 95% CI: 1.6-2.3 for provoked VTE). Associations persisted, but were attenuated, when restricting to persons without alcohol use disorder and to persons without physical health comorbidities. LIMITATIONS: Unspecified stress reaction has less precise criteria than other stress-related diagnoses, and we could not adjust for some potential confounders. CONCLUSIONS: Our results augment literature on stress disorders and cardiovascular disease by highlighting the additional importance of unspecified stress disorders. Further research on this diagnostic category, which may represent subsyndromal psychopathology, is warranted. These findings support considering persons with non-specific stress-related psychopathology in treatment and tertiary prevention activities.

Motor Neuron Disease and Risk of Cancer: A Population-Based Cohort Study in Denmark.

BACKGROUND: Some neurogenerative diseases have been linked to a reduced risk of cancer, but the association between motor neuron disease and cancer risk is not well understood. We hypothesized that cancer risk would be lower among those with motor neuron disease and its most common subtype, amyotrophic lateral sclerosis. METHODS: We conducted a population-based cohort study of motor neuron disease and cancer risk using routinely collected data from population-based registries in Denmark. We examined cancer incidence among patients diagnosed with motor neuron disease between January 1980 and December 2013 followed through 2013. Using Danish national cancer rates for the study period, we computed standardized incidence ratios as a measure of relative risks. RESULTS: In the cohort of 5053 patients with a motor neuron disease, the overall standardized incidence ratio of any cancer was 1.17 (95% confidence interval [CI], 1.03-1.31); the corresponding standardized incidence ratio for amyotrophic lateral sclerosis was 1.24 (95% CI, 0.96-1.57). The standardized incidence ratios of any cancer in the cohort with motor neuron disease was 1.52 (95% CI, 1.22-1.87) for <1 year of follow-up; 0.87 (95% CI, 0.68-1.09) for years 1-5 of follow-up; and 1.22 (95% CI, 1.01-1.46) for >5 years of follow-up. Beyond one year of follow-up, patients in the motor neuron disease had elevated standardized incidence ratios for lymphoid leukemia, non-Hodgkin lymphoma, and basal cell skin cancer. CONCLUSION: Findings fail to support the hypothesis that motor neuron disease or amyotrophic lateral sclerosis is associated with reduced cancer incidence. An elevated risk of cancer during the first year of follow-up may be attributable to heightened surveillance.

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.

Risk of lower gastrointestinal bleeding and colorectal neoplasms following initiation of low-dose aspirin: a Danish population-based cohort study.

OBJECTIVE: Aspirin may increase the risk of lower gastrointestinal bleeding (LGIB) from precursors of colorectal cancer (CRC). We investigated whether use of low-dose aspirin, through initiation of LGIB, may lead patients to undergo colonoscopy and polypectomy before manifest CRC. DESIGN: We conducted a historical cohort study (2005-2013) of all Danish residents who initiated low-dose aspirin treatment (n=412 202) in a setting without screening for CRC. Each new aspirin user was matched with three non-users (n=1 236 560) by age, sex and region of residence on the date of their matched new user's first-time aspirin prescription (index date). We computed absolute risks (ARs), risk differences and relative risks (RRs) of LGIB, lower gastrointestinal endoscopy, colorectal polyps and CRC, comparing aspirin users with non-users. RESULTS: The ARs were higher for new users than non-users for LGIB, lower gastrointestinal endoscopy, colorectal polyps and CRC within 3 months after index. Comparing new users with non-users, the RRs were 2.79 (95% CI 2.40 to 3.24) for LGIB, 1.73 (95% CI 1.63 to 1.84) for lower gastrointestinal endoscopy, 1.56 (95% CI 1.42 to 1.72) for colorectal polyps and 1.73 (95% CI 1.51 to 1.98) for CRC. The RRs remained elevated for more than 12 months after the index date, with the exception of CRC where the RRs were slightly decreased during the 3-5 years (RR 0.90, 95% CI 0.83 to 0.98) and more than 5 years (RR 0.91, 95% CI 0.82 to 1.00) following the index date. CONCLUSION: These findings indicate that aspirin may contribute to reduce CRC risk by causing premalignant polyps to bleed, thereby expediting colonoscopy and polypectomy before CRC development.

Risk of primary gastrointestinal cancers following incident non-metastatic breast cancer: a Danish population-based cohort study.

OBJECTIVE: We examined the risk of primary gastrointestinal cancers in women with breast cancer and compared this risk with that of the general population. DESIGN: Using population-based Danish registries, we conducted a cohort study of women with incident non-metastatic breast cancer (1990-2017). We computed cumulative cancer incidences and standardised incidence ratios (SIRs). RESULTS: Among 84 972 patients with breast cancer, we observed 2340 gastrointestinal cancers. After 20 years of follow-up, the cumulative incidence of gastrointestinal cancers was 4%, driven mainly by colon cancers. Only risk of stomach cancer was continually increased beyond 1 year following breast cancer. The SIR for colon cancer was neutral during 2-5 years of follow-up and approximately 1.2-fold increased thereafter. For cancer of the oesophagus, the SIR was increased only during 6-10 years. There was a weak association with pancreas cancer beyond 10 years. Between 1990-2006 and 2007-2017, the 1-10 years SIR estimate decreased and reached unity for upper gastrointestinal cancers (oesophagus, stomach, and small intestine). For lower gastrointestinal cancers (colon, rectum, and anal canal), the SIR estimate was increased only after 2007. No temporal effects were observed for the remaining gastrointestinal cancers. Treatment effects were negligible. CONCLUSION: Breast cancer survivors were at increased risk of oesophagus and stomach cancer, but only before 2007. The risk of colon cancer was increased, but only after 2007.

Associations between adjustment disorder and hospital-based infections in the Danish population.

OBJECTIVE: There is some evidence that posttraumatic stress disorder (PTSD) is associated with increased risk of infections, and it is unknown whether adjustment disorder is as well. We assessed the association between adjustment disorder and subsequent infections, and assessed additive interaction with sex. METHODS: The study population included a nationwide cohort of all Danish-born residents of Denmark diagnosed with adjustment disorder between 1995 and 2011, and an age- and sex-matched general population comparison cohort. We compared rates of infections requiring inpatient or outpatient hospitalization in the two cohorts. We fit Cox proportional hazards models to compute adjusted hazard ratios (aHR) for the associations between adjustment disorder and 32 types of infections, and calculated interaction contrasts to assess interaction between adjustment disorder and sex. RESULTS: Adjustment disorder was associated with increased rates of infections overall (n = 19,838 infections, aHR = 1.8, 95% confidence interval = 1.8. 1.9), and increased rates of each individual infection type (aHRs for 30 infections ranged from 1.5 to 2.3), adjusting for baseline psychiatric and somatic comorbidities and marital status. For many infection types (e.g., skin infections, pneumonia), interaction contrasts indicated rate differences were greater among men than women, while for two (urinary tract infections and sexually transmitted infections), rate differences were greater for women. CONCLUSIONS: These findings are consistent with studies examining the relationship between psychological stress and infections, and between PTSD and infections. They may be explained by a combination of the triggering of unhealthy behaviors as well as immune responses to stress.