Danish National Registry Research Articles

Transthyretin Tetramer Destabilization and Increased Mortality in the General Population

Transthyretin tetramer destabilization is the rate-limiting step in the development of transthyretin cardiac amyloidosis, an underrecognized contributor to mortality in older adults. To test the hypothesis that transthyretin tetramer destabilization is associated with all-cause and cardiovascular mortality in the general population. In this cohort study including individuals aged 20 to 80 years, genetic data were analyzed from 2 similar prospective studies of the Danish general population, the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS). Observational data from a subsample of the same studies where transthyretin was measured consecutively were also analyzed. In both studies, individuals were followed up from the examination date (1991-1994 in CCHS and 2003-2015 in CGPS) until death or the end of follow-up in December 2018. Data were analyzed from November 1, 2023, to August 15, 2024. Missense variants in TTR associated with increasing transthyretin tetramer destabilization in primary genetic analyses, and plasma transthyretin level in secondary observational analyses. All-cause and cardiovascular mortality identified from the national Danish Civil Registration System and the national Danish Register of Causes of Death. A total of 102 204 individuals (median [IQR] age, 57 [47-66] years; 56 445 [55%] female) were included. Median follow-up was 10 years (range, <1-27 years). In genetic analyses, p.T139M, a transthyretin tetramer stabilizing variant that is more stable than noncarriers' tetramer stability, was used as the reference. For noncarriers who have intermediate tetramer stability and for heterozygotes for amyloidogenic variants (p.V142I, p.H110N, and p.D119N) who have the lowest tetramer stability, respective hazard ratios (HRs) were 1.37 (95% CI, 1.06-1.77) and 1.65 (95% CI, 0.95-2.88) for all-cause mortality (P for trend = .01), and 1.63 (95% CI, 0.92-2.89) and 2.23 (95% CI, 0.78-6.34) for cardiovascular mortality (P for trend = .06). Furthermore, compared with p.T139M, plasma transthyretin decreased stepwise by TTR genotype: -18% for noncarriers and -29% for heterozygotes for amyloidogenic variants (p.V142I, p.H110N, p.D119N; P for trend < .001). Therefore, genetically determined, increasingly lower plasma transthyretin could be considered a surrogate marker for transthyretin tetramer destabilization. Observationally, among 19 619 individuals, noncarriers with plasma transthyretin concentrations less than 20 mg/dL vs 20 to 40 mg/dL had HRs of 1.12 (95% CI, 1.02-1.23) for all-cause mortality and 1.16 (95% CI, 0.97-1.39) for cardiovascular mortality. Transthyretin tetramer destabilization was associated with all-cause and cardiovascular mortality in the Danish general population. These findings may suggest a need for large-scale assays to measure transthyretin destabilization for detection of transthyretin amyloidosis before clinical manifestations emerge, since early treatment improves the prognosis.

Biological Heterogeneity in Susceptibility to Glucocorticoid-Induced Bone Loss: Short- and Long-Term Hip BMD Trajectories.

Glucocorticoids (GCs) are widely used for their anti-inflammatory and immunosuppressive properties. Their effect on bone health is predominantly negative by decreasing bone formation and increasing risk of fractures. This work aimed to quantify the short- and long-term changes in total hip bone mineral density (THBMD) after initiating systemic GC treatment in previously GC treatment-naive adults without bone protective agents. An observational study was conducted using THBMD data from dual-energy x-ray absorptiometry (DXA). Individuals were stratified by sex and tertiles of GC exposure. Individuals not GC-exposed served as a reference group. Routine-care DXA scans were obtained from the main public hospitals servicing the Island of Funen in Denmark. A total of 15 099 adults underwent routine DXA at Odense University Hospital between 2006 and 2021. Data were enriched with Danish national registers. Intervention included systemic GCs (observational data). The short-term outcome included annualized THBMD changes between first 2 DXA scans. The long-term outcome included greater than 5% annualized THBMD loss over a 10-year follow-up. Strong associations between GC exposure and THBMD loss was found for both outcomes, with larger losses in the middle and upper tertiles of GC exposure. The risk of experiencing greater than 5% annualized THBMD loss was elevated, especially in the first 2 years of initiating GC treatment. There is significant heterogeneity in THBMD responses, with approximately 1 in 5 patients experiencing no nominal bone loss despite receiving upper tertile levels of GC exposure. The findings confirm the association between initial GC exposure and significant bone loss. The heterogeneity in individual responses emphasizes the need for early monitoring and personalized approaches in managing bone health for patients undergoing GC treatment.

Post-Marketing Safety of Ustekinumab Based on 14-Year Follow-Up in Danish National Patient Data.

Psoriasis (PsO), a chronic inflammatory skin disorder affecting a substantial proportion of populations globally, often necessitates systemic treatment including biologics. This 14-year cohort study, based on Danish national register data, aimed to investigate the enduring safety profile of ustekinumab compared to other systemic psoriasis treatments. Using comprehensive Danish national register data, this study scrutinized patients diagnosed with psoriasis or psoriatic arthritis (PsA) who received ustekinumab. The treatment group comparators were non-biological systemic treatment (non-biologic), tumor necrosis factor α inhibitor medicine groups (TNF-α), interleukin (IL)-17 inhibitors (IL-17), and IL-23 inhibitors (IL-23). The study periods for comparisons were 2009-2022 for non-biologic and TNF-α, 2015-2022 for IL-17, and 2018-2022 for IL-23. Outcomes were malignancies, cardiovascular events, serious infections, and serious hypersensitivity reactions. Cox proportional hazards regression models were employed to analyze two estimands: a standard intention-to-treat (ITT) estimand and a continuous-index-treatment (CIT) estimand, which considered switch and re-initiation of treatments within individuals. Users of ustekinumab were found to be younger on average, with an average age of 45.1 years compared to 51.6, 47.2, 49.0, and 48.4 years in the non-biologic, TNF-α, IL-17, and IL-23 groups, respectively. Also, 57.3% of the ustekinumab users were male, compared to 46.7%, 48.9%, 50.9%, and 58.3% for the non-biologic, TNF-α, IL-17, and IL-23 groups, respectively. Although the hazard ratio estimates varied across comparators, ustekinumab was found to be safe: regardless of PsA status, no discernible safety signals in terms of malignancy, MACE, severe infections, or severe hypersensitivity reactions were observed for ustekinumab when compared to the treatment comparators. The present study corroborated the enduring safety of ustekinumab in the context of PsO treatment.

Selected chronic diseases in children and adolescents conceived with intracytoplasmic sperm injection

PurposeToday about 12.5% of all children are conceived using assisted reproductive technology. Intracytoplasmic sperm injection (ICSI) was introduced without knowledge of the possible long-term adverse consequences on the offspring health. We aimed to examine risk of neurodevelopmental disorders, asthma, epilepsy, inflammatory bowel disease, rheumatoid arthritis, thyroid disease, and diabetes in the offspring conceived with ICSI, compared with offspring conceived with in vitro fertilization (IVF) and natural conception. Patients and methodsAll offspring conceived using ICSI, IVF, and natural conception in Denmark from July 9th, 1994 until December 31st, 2019 were included in this nationwide cohort study using Danish national health registries. ResultsMedian follow-up time was 10 years (6–16 years, interquartile range (IQR)) for offspring conceived with ICSI (n = 22,906), 13 years (7–20 years, IQR) for offspring conceived with IVF (n = 32,458), and 13 years (8–20, IQR) for offspring born after natural conception (n = 1,397,791). Several of the outcomes occurred rarely. The most frequent outcome in offspring conceived with ICSI was neurodevelopmental disorder which did not show an increased risk when comparing offspring conceived with ICSI with offspring conceived with IVF (hazard ratio 1.02 (95 % CI: 0.92;1.12)) and natural conception (hazard ratio 0.96 (95 % CI: 0.88;1.40)). ConclusionReassuringly, there were no statistically significantly increased risks of the examined outcomes in offspring conceived with ICSI. Before any firm conclusions are made, this study should be replicated in large populations with longer follow-up time.

Opioids and Dementia in the Danish Population.

Opioids have been studied as a potential risk factor for dementia, but evidence concerning long-term noncancer opioid use and exclusive use of weak opioids and associated dementia risk is sparse. To assess the association between cumulative noncancer use of opioids and risk of age-related all-cause dementia. This nested case-control study within a population-based cohort included 1 872 854 individuals without previous dementia, cancer, opioid addiction, or opioid use in terminal illness. Data were obtained from national Danish registers. Each individual who developed dementia during follow-up was incidence-density matched to 5 dementia-free controls. Statistical analysis was performed from August 2023 to March 2024. Cumulative opioid exposure was based on filled prescriptions available from 1995 through 2020. Conditional logistic regression provided adjusted incidence rate ratios (IRRs) for associations between opioids and dementia. Among 1 872 854 individuals without previous dementia, cancer, opioid addiction, or opioid use in terminal illness included in the study, 93 638 (5.0%) developed all-cause dementia during follow-up (51 469 [55.0%] female; median [IQR] age, 78.1 [73.0-82.8] years) and were matched to 468 190 control individuals (257 345 [55.0%] female; median [IQR] age, 78.0 [73.0-82.8] years). Opioid use up to 90 total standardized doses (TSDs) was not consistently associated with dementia risk. Opioid exposure above 90 TSDs yielded increased IRRs of dementia occurring before age 90 years ranging from 1.29 (95% CI, 1.17-1.42) for 91 to 200 TSDs to 1.59 (95% CI, 1.44-1.76) for greater than 500 TSDs for age-band 60 to 69 years at dementia diagnosis. Corresponding IRRs were 1.16 (95% CI, 1.11-1.22) to 1.49 (95% CI, 1.42-1.57) for age-band 70 to 79 years and 1.08 (95% CI, 1.03-1.14) to 1.21 (95% CI, 1.16-1.27) for 80 to 89 years. Sensitivity analyses corroborated associations in individuals with chronic noncancer pain and with use of weak opioids. This study found that opioid use of less than 90 TSDs was not significantly associated with increased dementia risk. Above 90 TSDs of opioid use was associated with an elevated dementia risk before age 90 years, which persisted in individuals with chronic noncancer pain and in individuals solely exposed to weak opioids. Further research should ascertain whether the findings denote causality between opioids and dementia risk.

Abstract 4137424: Circulating Levels of the Pro-Fibrotic Collagen Hormone Endotrophin are Associated with the Risk of Experiencing Major Adverse Cardiovascular Events in Individuals with Type 2 Diabetes – The Thousand&amp;2 Study

Introduction: Cardiovascular disease (CVD) complications are the leading cause of mortality in individuals with type 2 diabetes (T2D). Abnormal extracellular matrix (ECM) remodelling leads to the release of ECM protein fragments into circulation, reflecting these complications. Endotrophin, a pro-fibrotic and -inflammatory hormone, released during collagen type 6 formation, has been linked to adverse outcomes in T2D, but not previously in a long-term perspective. Aim: To assess the 12-year prognostic value of circulating endotrophin levels, measured by PRO-C6, to predict the risk of major adverse cardiovascular events (MACE) in a large cohort of individuals with T2D. Methods: Endotrophin levels were measured with the NordicPRO-C6™ ELISA in 909 serum samples from the Thousand&amp;2 study, which was initiated in 2011 and examined individuals with T2D, with and without known CVD. Clinical data were collected at baseline. Follow-up was 100% complete and performed on the 1 st of May 2024 with the registration of data on MACE from the Danish national registers. The primary outcome was MACE, defined as incident events of hospital admission for ischemic heart disease, heart failure, stroke, or all-cause mortality. PRO-C6 was split into tertiles and examined for survival probability by Kaplan-Meier analysis. Univariate Cox proportional hazard regression analysis was conducted to examine the association between PRO-C6 and the risk of MACE. A multivariable Cox model was additionally conducted, adjusted for age at baseline, sex, systolic blood pressure, duration of diabetes, HbA1c, estimated glomerular filtration rate, use of statins, albuminuria status, and current or prior smoking. Results: The baseline mean (±SD) age of the cohort was 64 (±10) years, 66% were males, mean (±SD) PRO-C6 was 11.9 (±7.01) ng/ml, the median follow-up time was 10.6 years, and number of MACE recorded was 472. The risk of experiencing MACE was significantly higher in the third tertile compared to the first and second tertile (Log-Rank p &lt; 0.001). In the univariate Cox model, the estimated hazard ratio (HR), corresponding to a 2-fold increase of PRO-C6, was HR [95% Confidence Interval(CI)] = 2.1 [1.8-2.4], P &lt;0.001. In the fully adjusted Cox model, PRO-C6 remained significantly associated with the risk of MACE (HR [95% CI] = 1.5 [1.2-1.8], P &lt;0.001). Conclusion: Elevated circulating endotrophin is associated with MACE in T2D, independent of common risk factors.

Investigating the association of mechanical restraint with somatic harmful outcomes: national register-based study.

Coercive measures to manage disruptive or violent behaviour are accepted as standard practice in mental healthcare, but systematic knowledge of potentially harmful outcomes is insufficient. To examine the association of mechanical restraint with several predefined somatic harmful outcomes. We conducted a population-based, observational cohort study linking data from the Danish national registers from 2007 to 2019. The primary analyses investigated the association of mechanical restraint with somatic adverse events, using panel regression analyses (within-individual analysis) to account for repeated exposures and outcomes. Secondary between-group analyses were performed with a control group exposed to types of coercion other than mechanical restraint. The study population comprised 13 022 individuals. We report a statistically significant association of mechanical restraint with thromboembolic events (relative risk 4.377, number needed to harm (NNH) 8231), pneumonia (relative risk 5.470, NNH 3945), injuries (relative risk 2.286, NNH 3240) and all-cause death (relative risk 5.540, NNH 4043) within 30 days after mechanical restraint. Estimates from the between-group analyses (comparing the exposed group with a control group of 22 643 individuals) were non-significant or indicated increased baseline risk in the control group. A positive dose-response analysis for cardiac arrest, injury and death supported a causative role of mechanical restraint in the reported associations. Although the observed absolute risk increases were small, the derived relative risks were non-negligible considering that less restrictive interventions are available. Clinicians and decision makers should be aware of the excess risk in future decisions on the use of mechanical restraint versus alternative interventions.

Traumatic spinal cord injury and its correlation to risk of autoimmune/-inflammatory disease.

Nationwide epidemiological open cohort study. To evaluate whether individuals with traumatic spinal cord injury (TSCI) are more prone to develop autoimmune diseases compared to a general non-TSCI population. Danish public national registries. An open nationwide cohort, including individuals born in Denmark from or alive during 1945-2018 was collected and the study period was 1980-2018. Poissons Log-linear regression estimated the incidence rate ratio (IRR) for developing eight groups of autoimmune diseases. A dose-response relationship based on the cervical/thoracic level of injury was assessed by stratification. The cohort included 3,272 individuals with TSCI and 4.8 million background individuals, accounting for 50,865 and 140 million person-years respectively. The TSCI population had an overall IRR of 1.81 (95% CI, 1.59 to 2.05) of getting any autoimmune disease. Subgroup analysis found positive associations for; a) Other neurologic IRR 5.19 (95% CI, 2.79 to 9.65), b) multiple sclerosis IRR 3.70 (95% CI, 2.54 to 5.40), c) Dermatologic IRR 2.57 (95% CI, 1.86 to 3.55), d) Type 1 diabetes mellitus IRR 2.01 (95% CI, 1.54 to 2.61), e) Systemic 1.92 (95% CI, 1.44 to 2.55), and f) Gastroenterologic IRR 1.42 (95% CI, 1.05 to 1.92). Cervical levels of TSCI showed an IRR of 1.70 (95% CI, 1.43 to 2.02), while thoracic levels had an IRR 1.98 (95% CI, 1.63 to 2.39). TSCI may be an individual risk factor of developing an autoimmune disease. There does not appear to exist a dose-response relationship from the level of injury. None.

Effect of exercise referral schemes and self-management strategies on healthcare service utilisation among community-dwelling older adults: secondary analyses of two randomised controlled trials.

The objective of this study is to explore whether offering an integrated self-management strategy and exercise referral scheme intervention (ERS+SMS) or a stand-alone ERS intervention is more effective in reducing healthcare service utilisation among community-dwelling older adults over time compared with a stand-alone SMS/control intervention. Secondary analyses of two randomised controlled trials (RCTs) with linkage to Danish national health registries. Three Danish municipalities: Esbjerg, Slagelse and Odense. Danish community-dwelling older adults, aged 65 years or older, were included in the study. Participants originated from two completed RCTs: the Welfare Innovation in Primary Prevention (WIPP, n=115) and the SITLESS project (SITLESS, n=333). Participants in the two trials were randomly assigned to one of three intervention groups: ERS in combination with SMS (ERS+SMS), ERS alone or an SMS/control intervention. Annual number of days with contact to general practice (GP) and days hospitalised for all causes. No statistically significant between-group difference was observed in the annual number of days with contact with GP between participants randomised to ERS+SMS (p=0.759) or ERS only (p=0.156) compared with those randomised to the SMS/control group. In addition, no statistically significant between-group differences in days hospitalised were observed when comparing the ERS+SMS (p=0.222) or ERS only (p=0.060) group to the SMS/control group. Neither the integrated intervention (ERS+SMS) nor the ERS alone intervention was more effective in reducing healthcare service utilisation during a 2-year follow-up period compared with a stand-alone SMS/control intervention. A potential stabilising effect of ERS and/or SMS interventions on the general age-related increase in healthcare service utilisation cannot be ruled out but needs further exploration in future studies along with the exploration of the effects of long-term interventions. NCT04531852 : and : NCT02629666 : .

Healthcare utilization in general practice and hospitals preceding a diagnosis of systemic sclerosis: a nationwide registry study.

Irreversible tissue damage is frequently present at the time of diagnosis in systemic sclerosis (SSc), which calls for earlier diagnosis. This study estimated healthcare utilization three years before the diagnosis of SSc. We conducted a population-based cohort study using data from Danish national registries. Incident patients diagnosed with SSc between January 1, 2005, and December 31, 2018, were matched by age and gender with 10 references without SSc. The date of diagnosis was the index date. We estimated quarterly rates and adjusted incidence rate ratios (IRRs) with 95% confidence intervals (CI) of healthcare utilization in the three years preceding the diagnosis for patients with SSc and their references. A total of 1,650 SSc patients (1,255 women and 395 men) and 16 500 non-SSc references were included. The mean age was 58 years (interquartile range 48-68). Three years before diagnosis, patients with SSc had more contacts with general practice (IRRwomen= 1.43 [95% CI: 1.33; 1.53], IRRmen= 1.47 [95% CI: 1.26; 1.71]) and hospitals (IRRwomen= 1.86 [95% CI: 1.62; 2.14], IRRmen= 2.70 [95% CI: 2.04; 3.58]) compared with their references. In the last three months before diagnosis, patients with SSc had significantly more contacts with general practice (IRRwomen= 2.30 [95% CI: 2.16; 2.44], IRRmen= 2.98 [95% CI: 2.64; 3.35]) and hospitals (IRRwomen= 5.62 [95% CI: 5.08; 6.20], IRRmen= 9.53 [95% CI: 7.81; 11.63]). The higher use of healthcare services in general practice and hospitals in the three years before diagnosis suggests an opportunity to facilitate earlier diagnosis and treatment of SSc.

Difference in long-term mortality after takotsubo syndrome. The role of gender, socioeconomic profile, and psychological distress

Abstract Background While Takotsubo Syndrome is less common in men, their mortality rates surpass those of women. The influence of socioeconomic factors and psychological distress, remains unexplored in this context. The aim of the study was: 1) to investigate gender differences in socioeconomic profile, and psychological distress in patients with incident Takotsubo Syndrome. And 2) to investigate gender differences in survival in patients discharged alive after incident takotsubo syndrome when taking into account differences in socioeconomic profile and psychological distress. Method A nationwide cohort study using the Danish national registers was performed. All patients discharged alive from Danish hospitals with an incident Takotsubo Syndrome diagnosis between 2008 and 2018 were eligible. Socioeconomic factors covering marital status, cohabitation status, labour market attachment, highest formal education and family income, and psychological distress was explored, and compared. Multivariable Cox-regression models were performed to assess the mortality risk. Results A total of 662 patients with Takotsubo Syndrome were discharged alive from Danish hospitals. Of those, 79 (11.9%) were men with a median age of 67 years (IQR 62-77). Men with Takotsubo Syndrome were socioeconomically disadvantaged compared to their women counterparts, and this disparity was also reflected in mortality rates. Secondly, mortality within three years after an incident Takotsubo Syndrome diagnose was higher among men than women, HR 2.19, 95%CI 1.04-4.61, most pronounced among men with a low family income, HR 2.08, 95% CI 1.03-4.18, and increase in comorbidity score, HR 1.23, 95% CI 1.06-1.43. Conclusion Results unveiled notable gender differences in the socioeconomic profile of individuals diagnosed with TS. Furthermore, the identified gender disparities in mortality can be attributed to socioeconomic and sociodemographic factors, the use of psychiatric medication as an indicator of psychological distress, and a greater comorbidity burden.Survival according to socioeconomy

Healthcare resource utilisation and cost of care of systemic inflammation in individuals with atherosclerotic cardiovascular disease and chronic kidney disease

Abstract Background Atherosclerotic cardiovascular disease (ASCVD) is a chronic disease, progressed by localised or systemic inflammation (SI). Chronic kidney disease (CKD) facilitates the presence of SI and is associated with an increased risk of ASCVD. Previous studies have estimated that 1–2% of the population in Western countries suffer from both conditions. Purpose To investigates the healthcare costs and resource utilisation for individuals diagnosed with ASCVD and CKD, with or without SI. Method The study applied data from the Danish national health and administrative registries from 1994-2022. Patients with ASCVD were identified by ICD-10 codes. CKD was identified by eGFR [15-59mL/min/1.73m2], in the Register of Laboratory Results for Research (RLRR). The latter date of diagnosis of the two diseases were used as index date. CRP-test results were extracted from RLRR. Individuals with conditions associated with CRP-levels and tests observed in association with CVD events or antibiotic/antiviral drug use were excluded. Individuals with at least two valid CRP tests were included. If two CRP-test results ≥2mg/L to &amp;lt;20mg/L were observed less than six month apart, and within two years of index, the individuals were classified to have SI. Individuals diagnosed in the first year of available eGFR were excluded to ensure only incident individuals in the study. Outcomes included costs and use of inpatient (duration ≥12h) and outpatient (&amp;lt;12h) hospital care, cost of primary care and prescription drugs (adjusted to 2022 currency). Results were derived using linear regression models. Results A total of 19,162 individuals’ incident between 2012-2022 were identified – 68% had SI. SI individuals had higher healthcare costs from five years before to three years after index. Individuals generated a total healthcare cost of EUR 69,554 (SI) and EUR 39,540 (no SI) in the study period (difference EUR 30,014, p&amp;lt;0.001). In adjusted analysis, the attributable cost in the three years following index was 1.4 times higher for individuals with SI, compared to individuals with no SI (difference EUR 12,922, p&amp;lt;0.001). Inpatient care accounted for 85% of the cost. SI individuals had significantly more inpatient hospital contacts from four years before to five years after index (7 attributable contacts total, 4.7 attributable contacts after index, 1.2 times more, p&amp;lt;0.001), and more outpatient contacts from five years before to three years after index (6.2 attributable contacts total, 2.3 attributable contacts after index, 1.3 times more, p&amp;lt;0.001). The largest difference was found in the year following index, where the difference was EUR 7,666 (1.5 times higher, p&amp;lt;0.001) cost, 1.5 (1.3 times higher, p&amp;lt;0.001) inpatient hospital contacts, and 1.1 (1.3 times higher, p&amp;lt;0.001) outpatient hospital contacts (adjusted estimates). Conclusion Individuals with SI represent a significant burden to the healthcare system, both in terms of healthcare cost and healthcare resource utilisation.Total healthcare costsAttributable hospital contacts

Incidence and risk of autoimmune disease in patients with a previous diagnosis of myocarditis - a nationwide Danish register-based cohort study

Abstract Introduction Myocarditis is a severe condition with an acute onset characterized by myocardial inflammation. The aetiology is heterogenous ranging from viral infections to autoimmune diseases (AD). However, it is currently unknown if patients with a first-time diagnosis of myocarditis are at higher risk of developing an autoimmune disease (AD) at a later stage. Purpose To estimate the risk of developing AD in patients with a first-time diagnosis of myocarditis during 20 years of follow-up. Methods Data source and study design: Nationwide register-based cohort study using data from Danish national administrative registers containing data on ICD-10 codes of diagnoses, prescription of pharmaceuticals, as well as date of birth and death on all Danish citizens. Study population: All Danish patients with a diagnosis of myocarditis from 2002-2020. Patients with previous diagnosis of AD were excluded. A control population without a diagnosis of myocarditis nor AD was sex and aged matched 1:5. Endpoints: Receiving a diagnosis of AD out of 35 recognized AD, and all-cause mortality. Statistics: Cumulative incidence of AD diagnosis was calculated by use of Aalen-Johansen estimation and all-cause mortality rate by Kaplan-Meier estimation. Hazard ratio (HR) by multivariate Cox regression modelling, standardized to sex, age, and comorbidities. Standardized relative (RR) and absolute (AR) risk derived from Cox regression by estimated Average Treatment Effect. Continuous variables are presented as median [1st quartile, 3rd quartile]. Results Study population: Myocarditis cohort: n=2,684. Control cohort: n=13,420. Median follow-up time: 9.5 years [5.4, 14.6]. Median age: 46 years [28, 67]. 69.5 % were of male sex. Comorbidities including hypertension, heart failure, and ischemic heart disease were significantly more common in patients with myocarditis. Autoimmune disease: At 20 years of follow-up, the cumulative incidence of AD diagnosis was 14.1% in the myocarditis cohort, and 5.8% in the control cohort. Adjusted HR for AD diagnosis in myocarditis vs. control cohorts was 2.65 (95% CI 2.19-3.17). Adjusted RR at 1 and 20 years of follow-up was 2.26 (95% CI 2.13-3.11) and 2.47 (95% CI 2.03-2.90), respectively. Figure 1 (left) shows AR of developing an AD at 20 years of follow-up, stratified by sex and age group. Mortality: Kaplan-Meier all-cause mortality was 40.5% in the myocarditis cohort, and 28.5% in the control cohort. Adjusted HR: 1.84 (95% CI 1.67-2.03). Adjusted RR at 1 and 20 years of follow-up: 1.77 (95% CI 1.60-1.93) and 1.31 (95% CI 1.25-1.36), respectively. Figure 1 (right) shows stratified AR of all-cause mortality at 20 years of follow-up. Conclusions Patients with a diagnosis of myocarditis had a significantly higher risk of developing AD in addition to significantly higher all-cause mortality compared to patients without previous myocarditis diagnosis. These findings suggest underlying and subsequent AD should be considered in patients with myocarditis.20-year AR of AD and all-cause mortalityICD-10 codes of AD investigated

The majority of 30-days survivors return to work one-year after in-hospital cardiac arrest

Abstract Background Surviving in-hospital cardiac arrest poses a significant risk of anoxic brain damage, which can impede survivors’ ability to return to work. Purpose This study aimed to examine return to work among in-hospital cardiac arrest survivors. Methods In this cohort study we included all 30-day survivors of working age (18-64 years), who experienced an in-hospital cardiac arrest between January 1st, 2013, and December 31st, 2018. Data was obtained from the national Danish in-hospital cardiac arrest registry (DANARREST) and employment status was retrieved from a registry from the Danish National Labor Market Authorities. We used a previously validated definition of "working" as any individual who was not on any social benefits, except state education fund grants, maternity leave pays, or leave-of-absence. Only patients working four weeks prior to the event were included in the study. Kaplan-Meier survival analysis was applied to estimate the probability of returning to work. Results Among 7,254 in-hospital cardiac arrest patients in Denmark from 2013-2018, 1,781 were of working-age, with 734 surviving at least 30 days. A total of 348 patients, who were working four weeks before their event, formed the final study population (Figure 1). Median age was 54 (Interquartile range (IQR) 46-59) and 70.4% were male. The cumulative incidence for return to work was 67.0% (95% CI: 62.0%-71.9%) with 4.6% (95% CI: 2.4%-6.8%) dying by one-year post-arrest as a competing risk (Figure 2). Age and sex distribution were comparable between survivors returning to work, those who did return to work, and those who died. A higher proportion of survivors returning to work had a Carlson’s Comorbidity Index score of 1 (70.8%) compared to survivors without work (58.1%) and those who died (33.3%). Additionally, an initial shockable rhythm was more frequent among survivors returning to work (49.8%) compared to survivors who did not return to work (45.2%), and those who died (9.1%). Conclusion We found that 67% of 30-day survivors of in-hospital cardiac arrest returned to work one year after their event. While survivors retuning to work shared comparable age and sex distributions with survivors who did not return to work and non-survivors, factors such as a lower Carlson’s Comorbidity Index score and a higher proportion with an initial shockable rhythm were distinguishing characteristics for those who returned to work.FlowchartCumulative incidence curves

High-Sensitivity Troponin-T and heart failure risk in individuals with suspected acute coronary syndrome

Abstract Background In individuals with suspected acute coronary syndrome (ACS), serial assessments of high-sensitivity cardiac troponin-T (hsTnT) levels demonstrate associations with both short- and long-term mortality and recurrent ischemic events. Nonetheless, the relationship with subsequent heart failure remains inadequately characterized. Purpose We investigated the association between single and serial hsTnT levels and subsequent hospitalization or outpatient medical encounters related to heart failure in individuals presenting with suspected ACS. Methods Utilizing Danish national registries from 2012 to 2019, we identified individuals without known heart failure who underwent dual hsTnT assessments ( 99th percentile upper reference limit: 13.5 ng/l), spaced 1-7 hours apart during hospitalization for myocardial infarction (MI), unstable angina, observation for suspected MI, or chest pain. Participants were categorized based on their hsTnT concentration patterns from the first to the second measurement (primary groups: normal, rising, persistently elevated, or falling) and the extent of hsTnT concentration alterations (secondary groups: &amp;lt;20%, &amp;gt;20 to 50%, or &amp;gt;50% in either direction). Additionally, they were grouped into quartiles based on the initial hsTnT measurement (&amp;lt;=9 ng/l, 10-15 ng/l, 16-66 ng/l, &amp;gt;=67 ng/l) to assess whether heightened hsTnT concentrations correlated with an increased risk of heart failure. Standardized risks of hospitalization or outpatient contacts for heart failure were computed using multivariable logistic regression with average treatment effect modeling. Results The study encompassed 26,835 individuals, of whom 38.9% received discharge diagnoses of MI, 5.1% were diagnosed with unstable angina, and 56.1% with observation for suspected MI or chest pain. Median age was 64.2 years, with 59.5% males. Prevalence of known cardiovascular disease included coronary disease in 18.1% of cases, prior revascularization in 7.2%, atrial fibrillation or flutter in 7.9%, and a history of stroke in 6.3%. Within the initial 30 days, 628 persons received a heart failure diagnosis, with an additional 960 diagnosed between days 31-365. Subjects displaying two normal hsTnT values exhibited the lowest standardized absolute risk (0.39% in days 0-30; 0.58% in days 31-365), while those with persistently elevated concentrations demonstrated the highest risk (6.45% in days 0-30; 7.05% in days 31-365) (Figure). Notably, the magnitude of hsTnT within each primary group did not affect heart failure risk. Conversely, heart failure risk exhibited a positive association with hsTnT concentrations measured in the initial sample. Conclusions In individuals presenting with suspected ACS, subjects with a sustained elevation in hsTnT levels showed the highest risk of subsequent heart failure events. Moreover, a dose-response association was observed between hsTnT concentrations and heart failure risk.Figure

Socioeconomic status and emergency department visits in adults with a history of severe childhood asthma: a register-based study

ABSTRACT Background and Objective Our knowledge of socioeconomic status (SES) and emergency department (ED) visits in adults with a history of severe childhood asthma is limited. Our aim was, therefore, to investigate these variables in individuals with a history of severe childhood asthma compared to a control population. Methods The Kongsberg cohort comprises Danish individuals with a history of severe childhood asthma and a previous 4-month stay at an asthma care facility in Kongsberg, Norway, between 1950 and 1979. The cohort was compared 1:1 to sex and age matched controls with no previous diagnosis of or treatment for obstructive airway disease (OAD). Data from the national Danish health registries were used for comparing cases and controls. Results A total of 1394 adults from the Kongsberg cohort were alive and residing in Denmark (mean age 63 years, 43% females) at the index date (June 2022). A Charlson comorbidity index score of ≥1 was higher in the study cohort compared to controls (7% versus 3%) (p < 0.01). Cases had a 1.5-fold increased likelihood of having a high educational level (p < 0.001) compared to controls. Compared to the controls, cases had a higher risk of all-cause ED visits, with individuals having lower educational levels showing the highest proportion of ED visits. Furthermore, 31.2% and 22.9%, respectively, of cases and controls with high educational levels had had ED visits. Compared to controls, logistic regression analysis revealed a 1.7-fold higher risk of all-cause ED visits in cases (p < 0.001). Conclusions In adults with a history of severe childhood asthma, educational level, comorbidity burden, and risk of ED visit were higher compared to matched controls with no history of obstructive airway disease.

6597 An Unusual Case of Klinefelter Syndrome with Both Primary and Superimposed Secondary Hypogonadism

Abstract Disclosure: A. Krueger: None. E. Pelley: None. Introduction: Klinefelter syndrome (KS) (47, XXY) is a sex-chromosome disorder that is a common cause of infertility and hypogonadism in men. Clinical phenotype includes tall stature, delayed or incomplete puberty, small testes (&amp;lt;4ml), gynecomastia, and oligo or azoospermia. The extra X chromosome leads to fibrosis and hyalinization of seminiferous tubules resulting in impaired sperm production. Leydig cells also function abnormally and fail to stimulate with LH. Common biochemical evaluation results in low serum testosterone, elevated FSH and LH concentrations, and azoospermia. Case Report: 37-year-old male presented with long standing history of low libido and a perception that he had never fully progressed through puberty. Physical exam was notable for a height of 6’ 4”, obesity, fine pubic and axillary hair, and testes &amp;lt;4mL bilaterally. Initial biochemical work up revealed low serum total testosterone 43 (ref 300-1080 ng/dL), low free testosterone 8.1 (ref 47-244 pg/mL), inappropriately normal LH 10.8 (ref 0.6-12.1 mlU/mL), and elevated FSH 28.3 (ref 1.0-12.0 mlU/mL). Patient was referred to Endocrinology. Labs were repeated with consistent results in addition to chromosome analysis which confirmed diagnosis of Klinefelter syndrome with (47, XXY) karyotype. Due to inappropriately normal LH and mixed picture of primary and superimposed secondary hypogonadism, an MRI of the pituitary was obtained and revealed an 8mm x7mm x 14mm pituitary macroadenoma. Evaluation for pituitary hypersecretion and other deficiencies was unremarkable. Conclusion: Data from the Danish National registry shows that only 25% of Klinefelter patients are correctly diagnosed. Klinefelter syndrome should be considered in the differential for the evaluation of hypogonadism and infertility. Diagnosis can be made by karyotyping. The degree of impaired spermatogenesis and testosterone production in Klinefelter syndrome can be variable. Biochemical evaluation should be interpreted in conjunction with clinical context. Patients with known causes of primary hypogonadism who demonstrate an inappropriate gonadotropin response require evaluation for causes of secondary hypogonadism. In this case, the inappropriately normal LH was the sole clue leading to the identification of his pituitary macroadenoma. Presentation: 6/1/2024

Barriers to clinical follow-up visits in multiple sclerosis: A nationwide register-based study

Background In Denmark, specialized multiple sclerosis (MS) clinics offer free-of-charge treatment to people with MS. However, not all people with MS attend regular clinical follow-up. Objective To identify people with MS who do not attend Danish MS clinics and identify barriers to treatment. Methods The Danish Multiple Sclerosis Registry was linked to other national Danish registries with follow-up from 2000–2020. We used a time-dependent Cox regression to rank factors associated with low attendance to clinical follow-up visits based on the magnitude of hazard ratios (HRs). Results We included 10,175 adults with MS, of which 3862 (38%) had less than one visit annually. The five top-ranked factors that reduced the risk of visits occurring included never having received diseases modifying treatment (HR: 0.48; 95%CI: 0.46–0.49), been diagnosed with MS before 2009 (0.79; 0.78–0.81), association with MS center in an outer region of Denmark (0.82; 0.80–0.84), having progressive MS type (0.88; 0.86–0.91) and not having received symptomatic treatment at diagnosis (0.91; 0.89–0.93). Conclusion Our results highlight disease-specific and geographic inequalities in the management of people with MS in Denmark. Strategies to prevent this inequality, especially for people with progressive phenotypes and those who need supportive and non-medical treatment and care, should be implemented.

Estimation of the maximum potential cost saving from reducing serious adverse events in hospitalized patients.

The increasing use of advanced medical technologies to detect adverse events, for instance, artificial intelligence-assisted technologies, has shown promise in improving various aspects within health care but may also come with substantial expenses. Therefore, understanding the potential economic benefits can guide decision-making processes regarding implementation. We aimed to estimate the potential cost savings associated with reducing length of stay and avoiding readmissions within the framework of an artificial intelligence-assisted vital signs monitoring system. We used data from Danish national registries and coarsened exact matching to estimate the difference in length of stay and probability of readmission among adult in-hospital patients exposed to and not exposed to serious adverse events. We used these estimates to calculate the maximum potential savings that could be achieved by early detection of adverse events to reduce length of stay and avoid readmissions. Patients exposed to serious adverse events during admission had 2.4 (95% CI: 2.4-2.5) additional hospital bed days and had 14% (95% CI 11%-17%) higher odds of readmissions compared with patients not exposed to such events. A base case scenario yielded maximum potential savings if one patient avoided a serious adverse event of EUR 2040 due to reduced length of stay and EUR 43 due to avoidance of readmissions caused by serious adverse events. Reductions in serious adverse events are associated with decreased healthcare costs due to reduced length of stay and avoided readmissions. Artificial intelligence-assisted vital signs monitoring systems are one potential approach to reduce serious adverse events, however, the ability of this technology to reduce adverse events remains unclear. Comprehensive prospective analyses of such systems including the intervention and implementation costs are necessary to understand their full economic impact.

Bladder cancer incidence and mortality among men with and without castration therapy for prostate cancer - a nation-wide cohort study.

Bladder cancer (BC) is a common malignancy in the Western World with men being diagnosed almost four times as often as women. The etiology of bladder cancer may involve sex hormones. Prostate cancer (PCa) patients treated with chemical castration, such as androgen deprivation therapy, or surgical castration, may therefore have a lower risk of developing bladder cancer. In a nation-wide population-based cohort study using national Danish registry data, we included a cohort of men with a first-time PCa diagnosis between 2002 and 2018 divided according to antihormonal treatment in the first year after PCa diagnosis and a comparison cohort consisting of 10 age-matched persons for each PCa patient. Each individual was followed from 1 year after PCa diagnosis until death or end of follow-up. We computed cumulative incidences (risk) and hazard ratios (HRs) for BC. In a second cohort analysis, we determined overall survival and BC-specific mortality, determined from date of BC diagnosis until death. We included 48,776 PCa patients of whom 13,592 were treated with chemical castration, 2,261 with surgical castration, and 32,923 received no antihormonal treatment. The 5-year risk of BC for each PCa group was 1.1%, 0.7%, and 1.3%, respectively, corresponding to an adjusted HR of 1.13 (95% CI 0.98; 1.31), 0.95 (95% CI 0.62; 1.47), and 1.18 (95% CI 1.09; 1.28) compared to individuals without PCa. Patients receiving antihormonal treatment had a slightly lower incidence of BC compared to individuals without PCa, however, this was not supported by the HRs. The treatment, however, was not associated with overall survival.