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1.  Exposure to Mebendazole and Pyrvinium during Pregnancy: A Danish Nationwide Cohort Study 
Purpose. Families with children are frequently exposed to pinworm infection and treatment involves the whole family. Information on consequences of exposure during, pregnancy is limited. The aim of this study was to investigate the exposure to pyrvinium and mebendazole before, during, and after pregnancy in a Danish nationwide cohort. Methods. From nationwide administrative registers, we identified 718, 900 births in Denmark between January 1997 and December 2007 as well as maternal prescription data of anthelmintics and maternal characteristics. Redemption of a prescription for pyrvinium or mebendazole was used to identify exposure. Results. 4715 women redeemed a prescription for pyrvinium or mebendazole during pregnancy; 1606 for pyrvinium, 2575 for mebendazole, and 534 for both drugs. Having >2 children compared to having no previous children was associated with exposure to pyrvinium (OR: 7.1, 95% CI: 5.8–8.7) and mebendazole (OR: 20.8, 95% CI: 17.3–24.9). Conclusion. 4715 pregnant women redeemed a prescription for either mebendazole or pyrvinium. We believe the exposure to be even higher since pyrvinium is also sold over-the-counter. Limited information on birth outcomes is available at present time, and considering the number of exposed pregnancies, we recommend that studies are to be undertaken to assess the safety of pyrvinium and mebendazole during pregnancy.
doi:10.1155/2012/769851
PMCID: PMC3458300  PMID: 23028209
2.  Perceived stress as a risk factor for peptic ulcers: a register-based cohort study 
BMC Gastroenterology  2016;16:140.
Background
The association between stress and peptic ulcers has been questioned since the discovery of helicobacter pylori. This study examined whether high perceived everyday life stress was associated with an increased risk of either receiving a triple treatment or being diagnosed with a peptic ulcer.
Methods
Cohen’s perceived stress scale measured the level of stress in a general health survey in 2010 of 17,525 residents of northern Jutland, Denmark, and was linked with National Danish registers on prescription drugs and hospital diagnoses. Cox proportional hazard regression was used to estimate the risk of either receiving a triple treatment or being diagnosed in a hospital with a peptic ulcer, in relation to quintiles of stress levels.
Results
A total of 121 peptic ulcer incidents were recorded within 33 months of follow-up. The lowest stress group had a cumulative incidence proportion of either receiving triple treatment or being diagnosed with peptic ulcer of approximately 0.4%, whereas the highest stress group had a cumulative incidence proportion of approximately 1.2%. Compared with that of the lowest stress group, those in the highest stress group had a 2.2-fold increase in risk of either receiving triple treatment or being diagnosed with peptic ulcer (HR 2.24; CI 95% 1.16:4.35) after adjustment for age, gender, socioeconomic status, non-steroid anti-inflammatory drug use, former ulcer and health behaviours. There was no difference in risk between the four least stressed quintiles. Subgroup analysis of diagnosed peptic ulcer patients revealed the same pattern as the main analysis, although the results were not significant.
Conclusion
The highest level of perceived everyday life stress raised the risk of either receiving triple treatment or being diagnosed with peptic ulcer during the following 33 months more than twice compared with that of the lowest level of perceived stress.
doi:10.1186/s12876-016-0554-9
PMCID: PMC5126869  PMID: 27894275
Peptic ulcer; Psychological stress; NSAID; Cohen’s perceived stress scale; PSS-10; Eradication therapy; Smoking
3.  Alcohol consumption and mortality in patients undergoing coronary artery bypass graft (CABG)-a register-based cohort study 
Background
Previous studies have shown that compared with abstinence and heavy drinking, moderate alcohol consumption is associated with a reduced risk of mortality among the general population and patients with heart failure and myocardial infarction. We examined the association between alcohol consumption and mortality in coronary artery bypass graft (CABG) patients.
Method
We studied 1,919 first-time CABG patients using data on alcohol consumption and mortality obtained from Danish national registers from March 2006 to October 2011. Alcohol consumption was divided into the following groups: abstainers (0 units/week), moderate consumers (1–14 units/week), moderate-heavy drinkers (15–21 units/week) and heavy drinkers (>21 units/week). Hazard ratios (HR) of all-cause mortality were calculated using Cox proportional hazard regression analysis.
Results
The median follow-up was 2.2 years [IQR 2.0]. There were 112 deaths, of which 96 (86 %) were classified as cardiovascular. Adjustments for age and sex showed no increased risk of all-cause mortality for the abstainers (HR 1.61, 95 % CI, 1.00–2.58) and moderate-heavy drinkers (HR 1.40, 95 % CI, 0.73–2.67) compared with moderate consumers. However, heavy drinkers had a high risk of all-cause mortality compared with moderate consumers (HR 2.44, 95 % CI, 1.47–4.04). A full adjustment showed no increase in mortality for the abstainers (HR 1.59, 95 % CI, 0.98–2.57) and moderate-heavy drinkers (HR 1.68, 95 % CI, 0.86–3.29), while heavy drinkers were associated with an increased mortality rate (HR 1.88, 95 % CI, 1.10–3.21). There was no increased risk of 30-day mortality for the abstainers (HR 0.74, 95 % CI, 0.23–2.32), moderate-heavy drinkers (HR 0.36, 95 % CI, 0.07–1.93) and heavy drinkers (HR 2.20, 95 % CI, 0.65–7.36).
Conclusion
There was no increased risk of mortality for abstainers (0 units/week) or moderate-heavy drinkers (15–21 units/week) following a CABG. Only heavy drinking (>21 units/week) were significantly associated with an increased mortality rate. These results suggest that only heavy drinking present a risk factor among CABG patients.
doi:10.1186/s12872-016-0403-3
PMCID: PMC5105266  PMID: 27835965
CABG; Coronary artery bypass graft; Alcohol consumption; Mortality; Cox regression models
4.  Association between hemoglobin and prognosis in patients admitted to hospital for COPD 
Low concentrations of hemoglobin have previously been demonstrated in many patients with COPD. There is evidence of anemia as a prognostic factor in acute exacerbations, but the detailed relationship between concentrations of hemoglobin and mortality is not known. A register-based cohort of patients admitted for the first time to Danish hospitals for acute exacerbations of COPD from 2007 through 2012 was established. Age, sex, comorbidities, medication, renal function, and concentrations of hemoglobin were retrieved. Sex-specific survival analyses were fitted for different rounded concentrations of hemoglobin. The cohort encompassed 6,969 patients. Hemoglobin below 130 g/L was present in 39% of males and below 120 g/L in 24% of females. The in-hospital mortality rates for patients with hemoglobin below or above these limits were 11.6% and 5.4%, respectively. After discharge, compared to hemoglobin 130 g/L, the hazard ratio (HR) for males with hemoglobin 120 g/L was 1.45 (95% confidence interval [CI] 1.22–1.73), adjusted HR 1.37 (95% CI 1.15–1.64). Compared to hemoglobin 120 g/L, the HR for females with hemoglobin 110 g/L was 1.4 (95% CI 1.17–1.68), adjusted HR 1.28 (95% CI 1.06–1.53). In conclusion, low concentrations of hemoglobin are frequent in COPD patients with acute exacerbations, and predict long-term mortality.
doi:10.2147/COPD.S116269
PMCID: PMC5108499  PMID: 27877035
pulmonary disease; chronic obstructive; anemia; mortality; polycythemia; epidemiology
5.  Outcomes Associated With Familial Versus Nonfamilial Atrial Fibrillation: A Matched Nationwide Cohort Study 
Background
We examined all‐cause mortality and long‐term thromboembolic risk (ischemic stroke, transient ischemic attack, systemic thromboembolism) in patients with and without familial atrial fibrillation (AF).
Methods and Results
Using Danish nationwide registry data, we identified all patients diagnosed with AF (1995–2012) and divided them into those with familial AF (having a first‐degree family member with a prior AF admission) and those with nonfamilial AF. We paired those with and without familial AF according to age, year of AF diagnosis, and sex in a 1:1 match. Using cumulative incidence and multivariable Cox models, we examined the risk of long‐term outcomes. We identified 8658 AF patients (4329 matched pairs) with and without familial AF. The median age was 50 years (interquartile range 43–54 years), and 21.4% were women. Compared with nonfamilial AF patients, those with familial AF had slightly less comorbid illness but similar overall CHA 2 DS 2‐VASc score (P=0.155). Median follow‐up was 3.4 years (interquartile range 1.5–6.5 years). Patients with familial AF had risk of death and thromboembolism similar to those with nonfamilial AF (adjusted hazard ratio 0.91 [95% CI 0.79–1.04] for death and 0.90 [95% CI 0.71–1.14] for thromboembolism).
Conclusions
Although family history of AF is associated with increased likelihood for development of AF, once AF developed, long‐term risks of death and thromboembolic complications were similar in familial and nonfamilial AF patients.
doi:10.1161/JAHA.116.003836
PMCID: PMC5210350  PMID: 27866162
atrial flutter; complication; family history; genetics; Epidemiology; Atrial Fibrillation
6.  Danish Nationwide Data Reveal a Link between Diabetes Mellitus, Diabetic Retinopathy, and Glaucoma 
Journal of Diabetes Research  2016;2016:2684674.
Aims. To determine the association between treatment against diabetes mellitus (DM) and treatment with antiglaucomatous drugs in the entire Danish population and to investigate the comorbidity between DM and its complications with antiglaucomatous treatment. Methods. Retrospective nationwide cohort study with data over a 16-year follow-up period. The National Danish Registry of Medicinal Products Statistics was used to identify all claimed prescriptions for antiglaucomatous medication and DM drugs. ICD-10 classifications were furthermore used to identify comorbidities between antiglaucomatous medication and the DM complications, diabetic retinopathy (DR), and nephropathy. Results. A total of 6,343,747 individuals in the period between 1996 and 2012 were analyzed. The overall incidence rate of new-onset glaucoma patients was 0.07 per 1000 person-years for the reference population compared to 36 per 1000 person-years for all diagnosed DM cases. Patients treated with DM drugs had about two times higher relative risk of glaucoma, when adjusting for a range of factors. The presence of DR alone or in combination with nephropathy increased the risk of glaucoma. Conclusions. The present study reports a strong association between DM and onset of glaucoma treatment in the entire Danish population.
doi:10.1155/2016/2684674
PMCID: PMC5107855  PMID: 27872861
7.  Mental health and school dropout across educational levels and genders: a 4.8-year follow-up study 
BMC Public Health  2016;16:976.
Background
Education is a key determinant of future employment and income prospects of young people. Poor mental health is common among young people and is related to risk of dropping out of school (dropout). Educational level and gender might play a role in the association, which remains to be studied.
Methods
Mental health was measured in 3146 Danish inhabitants aged 16–29 years using the 12-Item Short-Form Health Survey and examined across genders and educational levels. For students, educational level at baseline was used; for young people who were not enrolled in school at baseline (non-students), the highest achieved educational level was used. The risk of dropout in students was investigated in administrative registers over a 4.8–year period (1st March 2010–31th December 2014). Odds ratios (OR) and 95 % confidence intervals (CI) were calculated for mental health and in relation to dropout in logistic regression models, adjusting for age, gender, educational level, parental education, parental income and ethnicity.
Results
Poor mental health was present in 24 % (n = 753) of the participants, 29 % (n = 468) in females and 19 % (n = 285) in males (p < 0.0001). The prevalence differed from 19 to 39 % across educational levels (p < 0.0001). Females had a statistically significantly higher adjusted risk of poor mental health than males (OR = 1.8, CI = 1.5–2.2). Among the students the lowest risk was found at the elementary level (OR = 1.3, CI = 0.8–2.3), while students in higher education had a statistically significantly higher risk (OR = 1.9, CI = 1.2–2.9). The lowest-educated non-students had the highest OR of poor mental health (OR = 3.3, CI = 2.1–5.4). Dropout occurred in 8 % (n = 124) of the students. Poor mental health was associated to dropout in vocational (OR = 1.8, CI = 1.0–3.2) and higher education (OR = 2.0, CI = 1.0–4.2). For males in higher education, poor mental health was a predictor of dropout (OR = 5.2, CI = 1.6–17.3), which was not seen females in higher education (OR = 1.2, CI = 0.5–3.1).
Conclusions
Poor mental health was significantly associated to dropout among students in vocational and higher education. Males in higher education had five times the risk of dropout when reporting poor mental health, while no such association was found for females.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-016-3622-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12889-016-3622-8
PMCID: PMC5024430  PMID: 27627885
Mental health; Gender differences; Education; Educational Dropout; Young Adults; Early School Leaving
8.  Risk of Ischemic Stroke, Hemorrhagic Stroke, Bleeding, and Death in Patients Switching from Vitamin K Antagonist to Dabigatran after an Ablation 
PLoS ONE  2016;11(8):e0161768.
Background
Safety regarding switching from vitamin K antagonist (VKA) to dabigatran therapy in post-ablation patients has never been investigated and safety data for this is urgently needed. The objective of this study was to examine if switch from VKA to dabigatran increased the risk of stroke, bleeding, and death in patients after ablation for atrial fibrillation.
Methods
Through the Danish nationwide registries, patients with non-valvular atrial fibrillation undergoing ablation were identified, in the period between August 22nd 2011 and December 31st 2015. The risk of ischemic stroke, hemorrhagic stroke, bleeding, and death, related to switching from VKA to dabigatran was examined using a multivariable Poisson regression model, where Incidence rate ratios (IRR) were estimated using VKA as reference.
Results
In total, 4,236 patients were included in the study cohort. The minority (n = 470, 11%) switched to dabigatran in the follow up period leaving the majority (n = 3,766, 89%) in VKA treatment. The patients in the dabigatran group were older, were more often males, and had higher CHA2DS2-VASc, and HAS-BLED scores. The incident rates of bleeding and death were almost twice as high in the dabigatran group compared with the VKA group. When adjusting for the individual components included in the CHA2DS2-VASc and HAS-BLED scores, the multivariable Poisson analyses yielded a non-significant IRR (95%CI) of 1.64 (0.72–3.75) for bleeding and of 1.41 (0.66–3.00) for death associated with the dabigatran group, compared to the VKA group. A significant increased risk of bleeding was found in the 110mg bid group with an IRR (95%CI) of 4.49(1.40–14.5).
Conclusion
Shifting from VKA to dabigatran after ablation was associated with twice as high incidence of bleeding compared to the incidence in patients staying in VKA treatment. The only significant increased risk found in the adjusted analyses was for bleeding with 110mg bid dabigatran and not for 150mg bid. Since there was no dose-response for bleeding, the switch from VKA to dabigatran in itself was not a risk factor for bleeding.
doi:10.1371/journal.pone.0161768
PMCID: PMC4999147  PMID: 27560967
9.  Non-vitamin K antagonist oral anticoagulation usage according to age among patients with atrial fibrillation: Temporal trends 2011–2015 in Denmark 
Scientific Reports  2016;6:31477.
Among atrial fibrillation (AF) patients, Danish nationwide registries (2011–2015) were used to examine temporal trends of initiation patterns of oral anticoagulation (OAC) treatment according to age. Overall, 43,299 AF patients initiating vitamin K antagonists (VKA) (42%), dabigatran (29%), rivaroxaban (13%), or apixaban (16%) were included with mean age (SD) 72.1 (11.3), 71.5 (11.0), 74.3 (11.1), and 75.3 (11.1) years, respectively. Patients aged ≥85 years comprised 15%. Trend tests showed increase in patients ≥85 years initiating OAC (p < 0.0001). VKA usage decreased from 92% to 24% (p < 0.0001). This decrease was independent of age. Dabigatran was the most common non-VKA OAC (NOAC) (40% users), but usage decreased from 2014 until study end (6%) (p < 0.0001). Apixaban was the most used OAC at study end (41%), in particular among those ≥85 years (44%). Compared with patients aged <65 years, the odds ratios associated with initiating VKA, dabigatran, rivaroxaban, or apixaban for patients aged ≥85 years were 0.81 (95% CI 0.75–0.86), 0.65 (95% CI 0.60–0.70), 1.52 (95% CI 1.38–1.67), and 2.09 (95% CI 1.89–2.30), respectively. In conclusion, substantial increase in NOAC usage has occurred. Increasing age was associated with upstart of rivaroxaban or apixaban with reference to age <65 within the specific agent.
doi:10.1038/srep31477
PMCID: PMC4980590  PMID: 27510920
10.  Effect of Chronic Kidney Diseases on Mortality among Digoxin Users Treated for Non-Valvular Atrial Fibrillation: A Nationwide Register-Based Retrospective Cohort Study 
PLoS ONE  2016;11(7):e0160337.
Purpose
This study investigated the impact of chronic kidney disease on all-causes and cardiovascular mortality in patients with atrial fibrillation treated with digoxin.
Methods
All patients with non-valvular atrial fibrillation and/or atrial flutter as hospitalization diagnosis from January 1, 1997 to December 31, 2012 were identified in Danish nationwide administrative registries. Cox proportional hazard model was used to compare the adjusted risk of all-causes and cardiovascular mortality among patients with and without chronic kidney disease and among patients with different chronic kidney disease stages within 180 days and 2 years from the first digoxin prescription.
Results
We identified 37,981 patients receiving digoxin; 1884 patients had the diagnosis of chronic kidney disease. Cox regression analysis showed no statistically significant differences in all-causes (Hazard Ratio, HR 0.89; 95% confident interval, CI 0.78–1.03) and cardiovascular mortality (HR 0.88; 95%CI 0.74–1.05) among patients with and without chronic kidney disease within 180 days of follow-up period. No statistically significant differences was found using a 2 years follow-up period neither for all causes mortality (HR 0.90; 95%CI 0.79–1.03), nor for cardiovascular mortality (HR 0.87; 95%CI 0.74–1.02). No statistically significant differences was found comparing patients with and without estimated Glomerular Filtration Rate <30ml/min/1.73m2 and patients with different stages of chronic kidney disease, for all-causes and cardiovascular mortality within 180 days and 2 years from the first digoxin prescription.
Conclusions
This study suggest no direct effect of chronic kidney disease and chronic kidney disease stages on all-causes and cardiovascular mortality within both 180 days and 2 years from the first digoxin prescription in patients treatment-naïve with digoxin for non-valvular atrial fibrillation.
doi:10.1371/journal.pone.0160337
PMCID: PMC4965154  PMID: 27467520
11.  Trends in One-Year Outcomes of Dialysis-Requiring Acute Kidney Injury in Denmark 2005-2012: A Population-Based Nationwide Study 
PLoS ONE  2016;11(7):e0159944.
Background
Dialysis-requiring acute kidney injury (AKI) is associated with substantial mortality and risk of end-stage renal disease (ESRD). Despite considerable growth in incidence of severe AKI, information pertaining to trends in outcomes remains limited. We evaluated time trends in one year risks of ESRD and death in patients with dialysis-requiring AKI over an eight year period in Denmark.
Methods
In a retrospective nationwide study based on national registers, all adults requiring acute renal replacement therapy between 2005 and 2012 were identified. Patients with preceding ESRD were excluded. Through individual-level cross-referencing of administrative registries, information pertaining to comorbidity, preceding surgical interventions, and concurrent other organ failure and sepsis was ascertained. Comparisons of period-specific one year odds ratios for ESRD and death were calculated in a multiple logistic regression model.
Results
A total of 13,819 patients with dialysis-requiring AKI were included in the study. Within one year, 1,017 (7.4%) patients were registered with ESRD, and 7,908 (57.2%) patients died. The one-year rate of ESRD decreased from 9.0% between 2005 and 2006 to 6.1% between 2011 and 2012. Simultaneously, the one-year mortality rate decreased from 58.2% between 2005 and 2006 to 57.5% between 2011 and 2012. Consequently, the adjusted odds ratios for the period 2011–2012 (with the period 2005–2006 as reference) were 0.75 (0.60–0.95, p = 0.015) and 0.87 (95% CI 0.78–0.97, p = 0.010) for ESRD and death, respectively.
Conclusions
In a nationwide retrospective study on time trends in one year outcomes following dialysis-requiring AKI, risk of all-cause mortality and ESRD decreased over a period of 8 years.
doi:10.1371/journal.pone.0159944
PMCID: PMC4961397  PMID: 27459297
12.  Incidence and impact on prognosis of peri-procedural myocardial infarction in 2760 elective patients with stable angina pectoris in a historical prospective follow-up study 
Background
The clinical significance of myocardial infarction related to treatment with percutaneous coronary intervention (PCI) has been subject of great discussion. This subject has been studied for many years using different definitions of peri-procedural myocardial infarction and different biomarkers, the results have varied greatly depending on methods and time of the study. This study was to determine the incidence and prognostic significance of elevated cardiac biomarkers after elective PCI in patients with stable angina pectoris using the current cut-off set by the Third Universal Definition of Myocardial Infarction and current biomarkers.
Methods
We performed a historical prospective follow-up study of all patients with stable angina pectoris who underwent elective PCI at Aalborg University Hospital, Denmark from January 1st 2000 to December 31st 2012. We stratified patients according to peak post-PCI troponin T (cTnT) and Creatine Kinase MB mass (CK-MBmass).
Results
Follow-up for time to all-cause mortality was mean 5.8 years and total 15,891 years and mean 3.7 years and total 10,160 years for the combined endpoint of all-cause mortality and new onset heart failure. During the follow up period 399 of 2760 patients died (14.5 %) and 1095 (39.7 %) suffered the combined endpoint. Post-PCI concentration of cTnT and CK-MBmass was elevated above the defined cut-off in 419 patients (15.2 %) and 113 patients (4.1 %) respectively. There was no statistically significant difference between the groups in stratified analysis of the hazard rates by time regarding all-cause mortality for cTnT nor CK-MBmass. Regarding the combined endpoint the results were ambiguous. The results were unchanged in multivariable analyses that included age and gender.
Conclusion
The incidence of elevated biomarkers after elective PCI in patients with stable angina pectoris using the defined cut-off (>5 x URL) was 15.2 % using cTnT and 4.1 % using CK-MBmass. The independent prognostic value for both cardiac biomarkers of any cut-off showed no statistical significance for all-cause mortality, whereas the combined endpoint (all-cause mortality or new-onset heart failure) were ambiguous in both short- and long-term follow-up.
doi:10.1186/s12872-016-0293-4
PMCID: PMC4910200  PMID: 27305902
Troponin; Elective; Prognosis; Myocardial infarction; Peri-procedural; Percutaneous coronary intervention
13.  The relationship between self-reported mental health and redeemed prescriptions of antidepressants: a register-based cohort study 
BMC Psychiatry  2016;16:189.
Background
Poor mental health is a major problem in most western societies, especially predominant among young adults. However, associations of self-reported poor mental health with subsequent psychiatric or medical treatment are unknown. We examined the relation between self-reported mental health and redeeming prescriptions of antidepressants among three age groups.
Methods
We analyzed data from 16,233 individuals aged 16 years and over randomly selected to participate in the 2010 North Denmark Region Health Survey completed in February 2010. Mental health was defined according to the Short-Form 12 instrument (SF-12) and dichotomized into poor and good. Outcome data were retrieved from administrative information on redeemed prescriptions of antidepressants between February 2010 and December 2012. Crude cumulative incidence curves were produced to illustrate the probability of redeeming new prescriptions of antidepressants over time. Cox regression analysis was used to estimate risk of redeeming prescriptions of antidepressants when having poor mental health, adjusted for preselected explanatory covariates.
Results
Among the young (16–29 years-old), 620 (23 %) participants suffered from poor mental health. Among the adults (30–59 years-old) and elderly (60 years-old or over), 1592 (18 %) participants and 723 (15 %) reported poor mental health, respectively. Overall, women were more likely than men to rate their mental health as poor. For all age groups, there was an increased probability for redeeming prescriptions of antidepressants when having poor mental health. The hazard ratio [HR] for redeeming prescriptions of antidepressants for those reporting poor versus good mental health, adjusted for sex, ethnicity, marital status, education level, occupational status, smoking and physical activity was 3.1 (95 % confidence interval [CI] 2.20–4.29) for young participants. For adults, the HR was 2.3 (95 % CI 1.86–2.78) and for elderly, it was 3.5 (95 % CI 2.66–4.57).
Conclusion
Self-reported poor mental health was more frequent among younger than older participants. Overall, antidepressants were the most often used treatment. An increased probability of redeeming antidepressant prescriptions when having self-reported poor mental health was observed in all age groups. These findings suggest that frequent reporting of poor mental health is a common issue for all age groups that needs more attention.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-016-0893-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12888-016-0893-7
PMCID: PMC4897872  PMID: 27267897
Mental health; Antidepressant agents; Young; Sex differences
14.  Exercise therapy after ultrasound-guided corticosteroid injections in patients with subacromial pain syndrome: a randomized controlled trial 
Background
Subacromial pain syndrome (SAPS) accounts for around 50 % of all cases of shoulder pain. The most commonly used treatments are glucocorticosteroid (steroid) injections and exercise therapy; however, despite treatment SAPS patients often experience relapse of their symptoms. Therefore the clinical effect of combining steroid and exercise therapy is highly relevant to clarify. The aim of this randomized controlled trial was to investigate if exercise therapy added to steroid injection in patients with SAPS will improve the effect of the injection therapy on shoulder pain.
Methods
In this two-arm randomized trial running over 26 weeks, patients with unilateral shoulder pain (> 4 weeks) and thickened subacromial bursa (> 2 mm on US) were included. At baseline all participants received two steroid injections into the painful shoulder with an interval of one week. Subsequently they were randomized (1:1) to either 10 weeks exercise of the involved shoulder (intervention group) or exercise of the uninvolved shoulder (control group). The patients were re-examined after the exercise program (at week 13) and again at week 26. The primary outcome assessed after 26 weeks was change in shoulder pain analyzed using the intention-to-treat principle (non-responder imputation).
Results
Ninety-nine SAPS patients (58 female) participated (49 intervention/50 control). At both follow up visits (week 13 and 26) no statistically significant between-group differences in pain changes on a visual analog scale (mm) were seen (13 weeks: pain at rest 1.7 (95 % CI –3.6 to 7.0; P = 0.53); pain in activity 2.2 (95 % CI –6.5 to 10.9; P = 0.61), 26 weeks: rest 5.6 (95 % CI –0.9 to 12.1; P = 0.09); activity 2.2 (95 % CI –6.8 to 11.2; P = 0.62). The reduction in pain was most evident in the control group at all four pain measurements. The only difference between groups was seen by US examination at week 13, where fewer participants with impingement were observed in the intervention group compared with the controls (9 vs. 19 participants; P = 0.03).
Conclusion
Exercise therapy in the painful shoulder in SAPS patients did not improve the effectiveness of steroid injections for shoulder pain in patients with unilateral SAPS and enlarged subacromial bursa on US examination.
Trial registration
ClinicalTrials.gov (NCT01506804). Registration date 5 May 2011.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-1002-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-016-1002-5
PMCID: PMC4893247  PMID: 27262892
Subacromial pain syndrome; Glucocorticosteroid injection; Exercise therapy; Ultrasound imaging; Randomized controlled trial
15.  Antidepressants and the risk of hyponatremia: a Danish register-based population study 
BMJ Open  2016;6(5):e011200.
Objective
To examine the association between classes of antidepressants and hyponatremia, and between specific antidepressants and hyponatremia.
Design
Retrospective register-based cohort study using nationwide registers from 1998 to 2012.
Setting
The North Denmark Region.
Participants
In total, 638 352 individuals were included.
Primary and secondary outcome measures
Plasma sodium was obtained from the LABKA database. The primary outcome was hyponatremia defined as plasma sodium (p-sodium) below 135 mmol/L and secondary outcome was severe hyponatremia defined as p-sodium below 130 mmol/L. The association between use of specific antidepressants and hyponatremia was analysed using multivariable Poisson regression models.
Results
An event of hyponatremia occurred in 72 509 individuals and 11.36% (n=6476) of these events happened during treatment with antidepressants. Incidence rate ratios and CIs for the association with hyponatremia in the first p-sodium measured after initiation of treatment were for citalopram 7.8 (CI 7.42 to 8.20); clomipramine 4.93 (CI 2.72 to 8.94); duloxetine 2.05 (CI 1.44 to 292); venlafaxine 2.90 (CI 2.43 to 3.46); mirtazapine 2.95 (CI 2.71 to 3.21); and mianserin 0.90 (CI 0.71 to 1.14).
Conclusions
All antidepressants except mianserin are associated with hyponatremia. The association is strongest with citalopram and lowest with duloxetine, venlafaxine and mirtazapine.
doi:10.1136/bmjopen-2016-011200
PMCID: PMC4874104  PMID: 27194321
Hyponatremia
16.  Assisted ventilation in COPD – association between previous hospitalizations and mortality 
Background
In general, previous studies have shown an association between prior exacerbations and mortality in COPD, but this association has not been demonstrated in the subpopulation of patients in need of assisted ventilation. We examined whether previous hospitalizations were independently associated with mortality among patients with COPD ventilated for the first time.
Patients and methods
In the Danish National Patient Registry, we established a cohort of patients with COPD ventilated for the first time from 2003 to 2011 and previously medicated for obstructive airway diseases. We assessed the number of hospitalizations for COPD in the preceding year, age, sex, comorbidity, mode of ventilation, survival to discharge, and days to death beyond discharge.
Results
The cohort consisted of 6,656 patients of whom 66% had not been hospitalized for COPD in the previous year, 18% once, 8% twice, and 9% thrice or more. In-hospital mortality was 45%, and of the patients alive at discharge, 11% died within a month and 39% within a year. In multivariate models, adjusted for age, sex, mode of ventilation, and comorbidity, odds ratios for in-hospital death were 1.26 (95% confidence interval [CI]: 1.11–1.44), 1.43 (95% CI: 1.19–1.72), and 1.56 (95% CI: 1.30–1.87) with one, two, and three or more hospitalizations, respectively. Hazard ratios for death after discharge from hospital were 1.32 (95% CI: 1.19–1.46), 1.76 (95% CI: 1.52–2.02), and 2.07 (95% CI: 1.80–2.38) with one, two, and three or more hospitalizations, respectively.
Conclusion
Preceding hospitalizations for COPD are associated with in-hospital mortality and after discharge in the subpopulation of patients with COPD with acute exacerbation treated with assisted ventilation for the first time.
doi:10.2147/COPD.S97830
PMCID: PMC4860999  PMID: 27217743
pulmonary disease; chronic obstructive; respiration; artificial; patient readmission; hospital mortality; critical care
17.  What are the barriers to implementation of cardiopulmonary resuscitation training in secondary schools? A qualitative study 
BMJ Open  2016;6(4):e010481.
Objective
Cardiopulmonary resuscitation (CPR) training in schools is recommended to increase bystander CPR and thereby survival of out-of-hospital cardiac arrest, but despite mandating legislation, low rates of implementation have been observed in several countries, including Denmark. The purpose of the study was to explore barriers to implementation of CPR training in Danish secondary schools.
Design
A qualitative study based on individual interviews and focus groups with school leadership and teachers. Thematic analysis was used to identify regular patterns of meaning both within and across the interviews.
Setting
8 secondary schools in Denmark. Schools were selected using strategic sampling to reach maximum variation, including schools with/without recent experience in CPR training of students, public/private schools and schools near to and far from hospitals.
Participants
The study population comprised 25 participants, 9 school leadership members and 16 teachers.
Results
School leadership and teachers considered it important for implementation and sustainability of CPR training that teachers conduct CPR training of students. However, they preferred external instructors to train students, unless teachers acquired the CPR skills which they considered were needed. They considered CPR training to differ substantially from other teaching subjects because it is a matter of life and death, and they therefore believed extraordinary skills were required for conducting the training. This was mainly rooted in their insecurity about their own CPR skills. CPR training kits seemed to lower expectations of skill requirements to conduct CPR training, but only among those who were familiar with such kits.
Conclusions
To facilitate implementation of CPR training in schools, it is necessary to have clear guidelines regarding the required proficiency level to train students in CPR, to provide teachers with these skills, and to underscore that extensive skills are not required to provide CPR. Further, it is important to familiarise teachers with CPR training kits.
doi:10.1136/bmjopen-2015-010481
PMCID: PMC4853997  PMID: 27113236
PUBLIC HEALTH; QUALITATIVE RESEARCH; EDUCATION & TRAINING (see Medical Education & Training); CARDIOPULMONARY RESUSCITATION; SCHOOLS
18.  Three-dimensional Doppler ultrasound findings in healthy wrist and finger tendon sheaths - can feeding vessels lead to misinterpretation in Doppler-detected tenosynovitis? 
Background
The aim was to investigate the presence of feeding vessels in or in close proximity to extensor and flexor tendon sheaths at the wrists level and in finger flexor tendon sheaths in healthy controls, using 3D ultrasound (US), which may cause pitfalls, in order to ensure correct interpretation of Doppler signals when diagnosing tenosynovitis.
Method
Forty healthy participants (20 women and 20 men age 23-67 years) without prior history of arthritis, tendon diseases or present pain in their hands were included. Twenty participants had 3D Doppler US of the second and third finger and twenty of the right wrist. US was carried out using a GE Logiq E9 unit with a 3D US probe. The colour Doppler settings were to published recommendation.
Results
The feeding vessels in or in close proximity to the tendon sheaths were found in the flexor and extensor tendons sheaths at least once in each participant. No significant difference in feeding vessels was seen between the radial and carpal level in the wrist (p = 0.06) or between the second and third flexor tendon sheath (p = 0.84).
Conclusion
Doppler findings in or in close proximity to the tendon sheaths were common in wrists and fingers in healthy participants. These feeding vessels can be a source of error, not only due to their presence but also because they may be interpreted as being inside the tendon sheath due to blooming and reverberations artefacts. These vessels should be taken into consideration when diagnosing Doppler tenosynovitis.
doi:10.1186/s13075-016-0968-3
PMCID: PMC4797218  PMID: 26993979
Ultrasonography; Tenosynovitis; Rheumatoid arthritis
19.  Associations between metabolic disorders and risk of cancer in Danish men and women – a nationwide cohort study 
BMC Cancer  2016;16:133.
Background
The prevalence of metabolic disorders is increasing and has been suggested to increase cancer risk, but the relation between metabolic disorders and risk of cancer is unclear, especially in young adults. We investigated the associations between diabetes, hypertension, and hypercholesterolemia on risk of all-site as well as site-specific cancers.
Methods
We consecutively included men and women from nationwide Danish registries 1996–2011, if age 20–89 and without cancer prior to date of entry. We followed them throughout 2012. Metabolic disorders were defined using discharge diagnosis codes and claimed prescriptions. We used time-dependent sex-stratified Poisson regression models adjusted for age and calendar year to assess associations between metabolic disorders, and risk of all-site and site-specific cancer (no metabolic disorders as reference).
Results
Over a mean follow-up of 12.6 (±5.7 standard deviations [SD]) years, 4,826,142 individuals (50.2 % women) with a mean age of 41.4 (±18.9 SD) years had 423,942 incident cancers. Incidence rate ratios (IRRs) of all-site cancer in patients with diabetes or hypertension were highest immediately following diagnosis of metabolic disorder. In women, cancer risk associated with diabetes continued to decline albeit remained significant (IRRs of 1.18–1.22 in years 1–8 following diagnosis). For diabetes in men, and hypertension, IRRs stabilized and remained significantly increased after about one year with IRRs of 1.10-1.13 in men for diabetes, and 1.07–1.14 for hypertension in both sexes. Conversely, no association was observed between hypercholesterolemia (treatment with statins) and cancer risk. The association between hypertension and cancer risk was strongest in young adults aged 20–34 and decreased with advancing age.
Conclusions
Diabetes and hypertension were associated with increased risk of all-site cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2122-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-016-2122-7
PMCID: PMC4762170  PMID: 26900131
Cancer; Metabolic; Diabetes; Hypertension; Hypercholesterolemia; Epidemiology
20.  Dialysis-Requiring Acute Kidney Injury in Denmark 2000-2012: Time Trends of Incidence and Prevalence of Risk Factors—A Nationwide Study 
PLoS ONE  2016;11(2):e0148809.
Introduction
Dialysis-requiring acute kidney injury is a severe illness associated with poor prognosis. However, information pertaining to incidence rates and prevalence of risk factors remains limited in spite of increasing focus. We evaluate time trends of incidence rates and changing patterns in prevalence of comorbidities, concurrent medication, and other risk factors in nationwide retrospective cohort study.
Materials and Methods
All patients with dialysis-requiring acute kidney injury were identified between January 1st 2000 and December 31st 2012. By cross-referencing data from national administrative registries, the association of changing patterns in dialysis treatment, comorbidity, concurrent medication and demographics with incidence of dialysis-requiring acute kidney injury was evaluated.
Results
A total of 18,561 adult patients with dialysis-requiring AKI were identified between 2000 and 2012. Crude incidence rate of dialysis-requiring AKI increased from 143 per million (95% confidence interval, 137–144) in 2000 to 366 per million (357–375) in 2006, and remained stable hereafter. Notably, incidence of continuous veno-venous hemodialysis (CRRT) and use of acute renal replacement therapy in elderly >75 years increased substantially from 23 per million (20–26) and 328 per million (300–355) in 2000, to 213 per million (206–220) and 1124 per million (1076–1172) in 2012, respectively. Simultaneously, patient characteristics and demographics shifted towards increased age and comorbidity.
Conclusions
Although growth in crude incidence rate of dialysis-requiring AKI stabilized in 2006, continuous growth in use of CRRT, and acute renal replacement therapy of elderly patients >75 years, was observed. Our results indicate an underlying shift in clinical paradigm, as opposed to unadulterated growth in incidence of dialysis-requiring AKI.
doi:10.1371/journal.pone.0148809
PMCID: PMC4749171  PMID: 26863015
21.  Danish register-based study on the association between specific cardiovascular drugs and fragility fractures 
BMJ Open  2015;5(12):e009522.
Objective
To determine whether drugs used in treatment of cardiovascular diseases (CVD-drugs), including hypertension, increase the risk of fragility fractures in individuals above the age of 65 years.
Design
Retrospective nationwide cohort study.
Setting
Danish nationwide national registers.
Participants
All individuals in Denmark ≥65 years who used specified CVD-drugs in the study period between 1999 and 2012.
Main outcomes measures
Time-dependent exposure to CVD-drugs (nitrates, digoxin, thiazides, furosemide, ACE inhibitors, angiotensin receptor antagonists, β-blockers, calcium antagonists and statins) was determined by prescription claims from pharmacies. The association between use of specific CVD-drugs and fragility fractures was assessed using multivariable Poisson regression models, and adjusted incidence rate ratios (IRRs) were calculated.
Results
Overall, 1 586 554 persons were included, of these 16.1% experienced a fall-related fracture. The multivariable Poisson regression analysis showed positive associations between fracture and treatment with furosemide, thiazide and digoxin. IRRs during the first 14 days of treatment were for furosemide IRR 1.74 (95% CI 1.61 to 1.89) and for thiazides IRR 1.41 (1.28 to 1.55); IRR during the first 30 days of treatment with digoxin was 1.18 (1.02 to 1.37).
Conclusions
Use of furosemide, thiazides and digoxin was associated with elevated rates of fragility fractures among elderly individuals. This may warrant consideration when considering diuretic treatment of hypertension in elderly individuals.
doi:10.1136/bmjopen-2015-009522
PMCID: PMC4710826  PMID: 26715481
accidental falls; fragility fractures; cardiovaslular drugs
22.  Pharmacogenetic Risk Stratification in Angiotensin-Converting Enzyme Inhibitor-Treated Patients with Congestive Heart Failure: A Retrospective Cohort Study 
PLoS ONE  2015;10(12):e0144195.
Background
Evidence for pharmacogenetic risk stratification of angiotensin-converting enzyme inhibitor (ACEI) treatment is limited. Therefore, in a cohort of ACEI-treated patients with congestive heart failure (CHF), we investigated the predictive value of two pharmacogenetic scores that previously were found to predict ACEI efficacy in patients with ischemic heart disease and hypertension, respectively. Score A combined single nucleotide polymorphisms (SNPs) of the angiotensin II receptor type 1 gene (rs275651 and rs5182) and the bradykinin receptor B1 gene (rs12050217). Score B combined SNPs of the angiotensin-converting enzyme gene (rs4343) and ABO blood group genes (rs495828 and rs8176746).
Methods
Danish patients with CHF enrolled in the previously reported Echocardiography and Heart Outcome Study were included. Subjects were genotyped and categorized according to pharmacogenetic scores A and B of ≤1, 2 and ≥3 each, and followed for up to 10 years. Difference in cumulative incidences of cardiovascular death and all-cause death were assessed by the cumulative incidence estimator. Survival was modeled by Cox proportional hazard analyses.
Results
We included 667 patients, of whom 80% were treated with ACEIs. Differences in cumulative incidences of cardiovascular death (P = 0.346 and P = 0.486) and all-cause death (P = 0.515 and P = 0.486) were not significant for score A and B, respectively. There was no difference in risk of cardiovascular death or all-cause death between subjects with score A ≤1 vs. 2 (HR 1.03 [95% CI 0.79–1.34] and HR 1.11 [95% CI 0.88–1.42]), score A ≤1 vs. ≥3 (HR 0.80 [95% CI 0.59–1.08] and HR 0.91 [95% CI 0.70–1.20]), score B ≤1 vs. 2 (HR 1.02 [95% CI 0.78–1.32] and HR 0.98 [95% CI 0.77–1.24]), and score B ≤1 vs. ≥3 (HR 1.03 [95% CI 0.75–1.41] and HR 1.05 [95% CI 0.79–1.40]), respectively.
Conclusions
We found no association between either of the analyzed pharmacogenetic scores and fatal outcomes in ACEI-treated patients with CHF.
doi:10.1371/journal.pone.0144195
PMCID: PMC4669156  PMID: 26633885
23.  Stroke and recurrent haemorrhage associated with antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation: nationwide cohort study 
The BMJ  2015;351:h5876.
Study question What are the risks of all cause mortality, thromboembolism, major bleeding, and recurrent gastrointestinal bleeding associated with restarting antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation?
Methods This Danish cohort study (1996-2012) included all patients with atrial fibrillation discharged from hospital after gastrointestinal bleeding while receiving antithrombotic treatment. Restarted treatment regimens were single or combined antithrombotic drugs with oral anticoagulation and antiplatelets. Follow-up started 90 days after discharge to avoid confounding from use of previously prescribed drugs on discharge. Risks of all cause mortality, thromboembolism, major bleeding, and recurrent gastrointestinal bleeding were estimated with competing risks models and time dependent multiple Cox regression models.
Study answer and limitations 4602 patients (mean age 78 years) were included. Within two years, 39.9% (95% confidence interval 38.4% to 41.3%, n=1745) of the patients had died, 12.0% (11.0% to 13.0%, n=526) had experienced thromboembolism, 17.7% (16.5% to 18.8%, n=788) major bleeding, and 12.1% (11.1% to 13.1%, n=546) recurrent gastrointestinal bleeding. 27.1% (n=924) of patients did not resume antithrombotic treatment. Compared with non-resumption of treatment, a reduced risk of all cause mortality was found in association with restart of oral anticoagulation (hazard ratio 0.39, 95% confidence interval 0.34 to 0.46), an antiplatelet agent (0.76, 0.68 to 0.86), and oral anticoagulation plus an antiplatelet agent (0.41, 0.32 to 0.52), and a reduced risk of thromboembolism was found in association with restart of oral anticoagulation (0.41, 0.31 to 0.54), an antiplatelet agent (0.76, 0.61 to 0.95), and oral anticoagulation plus an antiplatelet agent (0.54, 0.36 to 0.82). Restarting oral anticoagulation alone was the only regimen with an increased risk of major bleeding (1.37, 1.06 to 1.77) compared with non-resumption of treatment; however, the difference in risk of recurrent gastrointestinal bleeding was not significant between patients who restarted an antithrombotic treatment regimen and those who did not resume treatment.
What this study adds Among patients with atrial fibrillation who experience gastrointestinal bleeding while receiving antithrombotic treatment; subsequent restart of oral anticoagulation alone was associated with better outcomes for all cause mortality and thromboembolism compared with patients who did not resume treatment. This was despite an increased longitudinal associated risk of bleeding.
Funding, competing interests, data sharing This study was supported by a grant from Boehringer-Ingelheim. Competing interests are available in the full paper on bmj.com. The authors have no additional data to share.
doi:10.1136/bmj.h5876
PMCID: PMC4646074  PMID: 26572685
24.  Comparison of antiplatelet regimens in secondary stroke prevention: a nationwide cohort study 
BMC Neurology  2015;15:225.
Background
In patients with ischemic stroke of non-cardioembolic origin, acetylsalicylic acid, clopidogrel, or a combination of acetylsalicylic acid and dipyridamole are recommended for the prevention of a recurrent stroke. The purpose of this study was to examine the risk of bleeding or recurrent stroke associated with these three treatments.
Methods
Patients who were discharged with first-time ischemic stroke from 2007–2010, with no history of atrial fibrillation were identified from Danish nationwide registries. Hazard ratios (HRs) and 1-year risks of recurrent ischemic stroke and bleeding were calculated for each antiplatelet regimen.
Results
Among patients discharged after first-time ischemic stroke, 3043 patients were treated with acetylsalicylic acid, 12,295 with a combination of acetylsalicylic acid and dipyridamole, and 3885 with clopidogrel. Adjusted HRs for clopidogrel versus the combination of acetylsalicylic acid and dipyridamole were 1.02 (95 % confidence interval [CI]: 0.89–1.17) for ischemic stroke and 1.06 (95 % CI: 0.83–1.35) for bleeding. Adjusted HRs for acetylsalicylic acid versus the combination of acetylsalicylic acid and dipyridamole were 1.48 (95 % CI: 1.31–1.67) for stroke and 1.47 (95 % CI: 1.18–1.82) for bleeding. Clopidogrel versus acetylsalicylic acid yielded HRs of 0.69 (95 % CI: 0.59–0.81) and 0.72 (95 % CI: 0.55–0.96) for stroke and bleeding, respectively. The 1-year predicted risks associated with acetylsalicylic acid, the combination of acetylsalicylic acid and dipyridamole, and clopidogrel were 11.1 (95 % CI: 10.2–12.2), 7.7 (95 % CI: 7.3–8.3), and 8.0 (95 % CI: 6.9–8.7) for ischemic stroke, respectively; while, the risks for bleeding were 3.4 (95 % CI: 2.8–3.9), 2.4 (95 % CI: 2.1–2.7), and 2.4 (95 % CI: 1.9–2.9), respectively.
Conclusion
Clopidogrel and the combination of acetylsalicylic acid and dipyridamole were associated with similar risks for recurrent ischemic stroke and bleeding; whereas acetylsalicylic acid was associated with higher risks for both ischemic stroke and bleeding. The latter finding may partially be explained by selection bias.
doi:10.1186/s12883-015-0480-4
PMCID: PMC4630842  PMID: 26525411
Ischemic stroke; Secondary prevention; Antiplatelet; Epidemiology
25.  Cardioversion and Risk of Adverse Events with Dabigatran versus Warfarin—A Nationwide Cohort Study 
PLoS ONE  2015;10(10):e0141377.
Aim
Cardioversion can rapidly and effectively restore sinus rhythm in patients with persistent atrial fibrillation. Since 2011 dabigatran has been available as an alternative to warfarin to prevent thromboembolic events in patients with non-valvular atrial fibrillation undergoing cardioversion. We studied time to cardioversion, risk of adverse events, and risk of readmission with atrial fibrillation after cardioversion according to anticoagulation therapy.
Methods and Results
Through the nationwide Danish registries we included 1,230 oral anticoagulation naïve patients with first time non-valvular atrial fibrillation and first time cardioversion from 2011 to 2012; 37% in the dabigatran group (n = 456), and 63% in the warfarin group (n = 774). Median time to cardioversion was 4.0 (interquartile range [IQR] 2.9 to 6.5) and 6.9 (IQR 3.9 to 12.1) weeks in the dabigatran and warfarin groups respectively, and the adjusted odds ratio of cardioversion within the first 4 weeks was 2.3 (95% confidence interval [CI] 1.7 to 3.1) in favor of dabigatran. The cumulative incidence of composite endpoint of stroke, bleeding or death were 2.0% and 1.0% at 30 weeks in the warfarin and dabigatran groups respectively, with an adjusted hazard ratio of 1.33 (95% CI 0.33 to 5.42). Cumulative incidence of readmission with atrial fibrillation after 30 weeks were 9% and 11% in the warfarin and dabigatran groups, respectively, and an adjusted hazard ratio of 0.66 (95% CI 0.41 to 1.08).
Conclusion
Anticoagulation treatment with dabigatran allows shorter time to cardioversion for atrial fibrillation than warfarin, and appears to be an effective and safe alternative treatment strategy to warfarin.
doi:10.1371/journal.pone.0141377
PMCID: PMC4625957  PMID: 26513589

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