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1.  Underuse of an invasive strategy for patients with diabetes with acute coronary syndrome: a nationwide study 
Open Heart  2015;2(1):e000165.
Guidelines recommend an early invasive strategy for patients with diabetes with acute coronary syndromes (ACS). We investigated if patients with diabetes with ACS are offered coronary angiography (CAG) and revascularisation to the same extent as patients without diabetes.
Methods and results
The study is a nationwide cohort study linking Danish national registries containing information on healthcare. The study population comprises all patients hospitalised with first-time ACS in Denmark during 2005–2007 (N=24 952). Diabetes was defined as claiming of a prescription for insulin and/or oral hypoglycaemic agents within 6 months prior to the ACS event. Diabetes was present in 2813 (11%) patients. Compared with patients without diabetes, patients with diabetes were older (mean 69 vs 67 years, p<0.0001), less often males (60% vs 64%, p=0.0001) and had more comorbidity. Fewer patients with diabetes underwent CAG: cumulative incidence 64% vs 74% for patients without diabetes, HR=0.72 (95% CI 0.69 to 0.76, p<0.0001); adjusted for age, sex, previous revascularisation and comorbidity HR=0.78 (95% CI 0.74 to 0.82, p<0.0001). More patients with diabetes had CAG showing two-vessel or three-vessel disease (53% vs 38%, p<0.0001). However, revascularisation after CAG revealing multivessel disease was less likely in patients with diabetes (multivariable adjusted HR=0.76, 95% CI 0.68 to 0.85, p<0.0001).
In this nationwide cohort of patients with incident ACS, patients with diabetes were found to be less aggressively managed by an invasive treatment strategy. The factors underlying the decision to defer an invasive strategy in patients with diabetes are unclear and merit further investigation.
PMCID: PMC4322312
2.  Benefit of Clopidogrel Therapy in Patients With Myocardial Infarction and Chronic Kidney Disease—A Danish Nation‐Wide Cohort Study 
The aim of the present study was to evaluate clopidogrel treatment after incident myocardial infarction (MI) in patients with and without chronic kidney disease (CKD).
Methods and Results
By linking nation‐wide registries, information about patients admitted with incident MI was found. Primary endpoints were all‐cause and cardiovascular (CV) mortality, a composite of all‐cause mortality and recurrent MI, and a composite of fatal and nonfatal bleedings. Effect of clopidogrel use versus clopidogrel nonuse was estimated using an adjusted Cox's regression model stratified according to percutaneous coronary intervention (PCI) treatment.
A total of 69 082 incident MI patients in the period 2002–2011 were included. Clopidogrel treatment was associated with hazard ratios (HRs) for the combined endpoint of all‐cause mortality and recurrent MI in PCI‐treated patients of 0.90 (95% confidence interval [CI], 0.47 to 1.72) in renal replacement therapy (RRT) patients, 0.59 (95% CI: 0.40 to 0.88) in non‐end‐stage CKD patients and 0.69 (95% CI, 0.61 to 0.77) in patients without kidney disease (P for interaction=0.60). In patients not treated with PCI, HRs were 0.90 (95% CI, 0.68 to 1.21) in RRT patients, 0.86 (95% CI, 0.75 to 0.99) in non‐end‐stage CKD patients, and 0.91 (95% CI, 0.87 to 0.95) in patients without kidney disease (P for interaction=0.74). An increase in bleeding events (not significant) was noted for clopidogrel‐treated patients not undergoing PCI and for non‐end‐stage CKD patients undergoing PCI, whereas clopidogrel was associated with less bleedings in PCI‐treated RRT patients and patients without kidney disease.
During a 1‐year follow‐up, after MI, clopidogrel was associated with improved outcomes in patients with non‐end‐stage CKD. Even though no effect difference, compared to patients without CKD, was observed, the benefit associated with the use of clopidogrel after MI in patients requiring RRT is less clear.
PMCID: PMC4310409  PMID: 25146707
kidney; myocardial infarction; revascularization
3.  Lack of megalin expression in adult human terminal ileum suggests megalin‐independent cubilin/amnionless activity during vitamin B12 absorption 
Physiological Reports  2014;2(7):e12086.
Cubilin plays an essential role in terminal ileum and renal proximal tubules during absorption of vitamin B12 and ligands from the glomerular ultrafiltrate. Cubilin is coexpressed with amnionless, and cubilin and amnionless are mutually dependent on each other for correct processing to the plasma membrane upon synthesis. Patients with defects in either protein suffer from vitamin B12‐malabsorption and in some cases proteinuria. Cubilin lacks a transmembrane region and signals for endocytosis and is dependent on a transmembrane coreceptor during internalization. Amnionless has been shown to be able to mediate internalization of cubilin in a cell‐based model system. Cubilin has additionally been suggested to function together with megalin, and a recent study of megalin‐deficient patients indicates that uptake of cubilin ligands in the kidney is critically dependent on megalin. To further investigate the potential role of amnionless and megalin in relation to cubilin function in terminal ileum and vitamin B12 uptake, we initiated a study of CUBN/cubilin, AMN/amnionless, and LRP2/megalin expression in adult human terminal ileum. Our study is the first to reveal the expression pattern of cubilin, amnionless, and megalin in adult human terminal ileum, where cubilin and amnionless localize to the epithelial cells. Surprisingly, we did not detect any megalin protein in adult terminal ileum and consistently, only extremely low amounts of LRP2 mRNA. Our data therefore advocate that cubilin and amnionless act independently of megalin in adult terminal ileum and that the cubilin‐megalin interdependency accordingly should be considered as tissue and ligand specific.
Studies of human terminal ileum samples demonstrate lack of LRP2/megalin expression in adult terminal ileum and point to a megalin‐independent cubilin‐amnionless‐driven uptake mechanism for vitamin B12.
PMCID: PMC4187553  PMID: 25052491
Amnionless; cubilin; human terminal ileum; megalin; vitamin B12 absorption
4.  Measuring Large-Scale Social Networks with High Resolution 
PLoS ONE  2014;9(4):e95978.
This paper describes the deployment of a large-scale study designed to measure human interactions across a variety of communication channels, with high temporal resolution and spanning multiple years—the Copenhagen Networks Study. Specifically, we collect data on face-to-face interactions, telecommunication, social networks, location, and background information (personality, demographics, health, politics) for a densely connected population of 1 000 individuals, using state-of-the-art smartphones as social sensors. Here we provide an overview of the related work and describe the motivation and research agenda driving the study. Additionally, the paper details the data-types measured, and the technical infrastructure in terms of both backend and phone software, as well as an outline of the deployment procedures. We document the participant privacy procedures and their underlying principles. The paper is concluded with early results from data analysis, illustrating the importance of multi-channel high-resolution approach to data collection.
PMCID: PMC4000208  PMID: 24770359
5.  Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome 
BMC Medical Genetics  2013;14:111.
Imerslund-Gräsbeck Syndrome (IGS) is a rare genetic disorder characterised by juvenile megaloblastic anaemia. IGS is caused by mutations in either of the genes encoding the intestinal intrinsic factor-vitamin B12 receptor complex, cubam. The cubam receptor proteins cubilin and amnionless are both expressed in the small intestine as well as the proximal tubules of the kidney and exhibit an interdependent relationship for post-translational processing and trafficking. In the proximal tubules cubilin is involved in the reabsorption of several filtered plasma proteins including vitamin carriers and lipoproteins. Consistent with this, low-molecular-weight proteinuria has been observed in most patients with IGS. The aim of this study was to characterise novel disease-causing mutations and correlate novel and previously reported mutations with the presence of low-molecular-weight proteinuria.
Genetic screening was performed by direct sequencing of the CUBN and AMN genes and novel identified mutations were characterised by in silico and/or in vitro investigations. Urinary protein excretion was analysed by immunoblotting and high-resolution gel electrophoresis of collected urines from patients and healthy controls to determine renal phenotype.
Genetic characterisation of nine IGS patients identified two novel AMN frameshift mutations alongside a frequently reported AMN splice site mutation and two CUBN missense mutations; one novel and one previously reported in Finnish patients. The novel AMN mutations were predicted to result in functionally null AMN alleles with no cell-surface expression of cubilin. Also, the novel CUBN missense mutation was predicted to affect structural integrity of the IF-B12 binding site of cubilin and hereby most likely cubilin cell-surface expression. Analysis of urinary protein excretion in the patients and 20 healthy controls revealed increased urinary excretion of cubilin ligands including apolipoprotein A-I, transferrin, vitamin D-binding protein, and albumin. This was, however, only observed in patients where plasma membrane expression of cubilin was predicted to be perturbed.
In the present study, mutational characterisation of nine IGS patients coupled with analyses of urinary protein excretion provide additional evidence for a correlation between mutation type and presence of the characteristic low-molecular-weight proteinuria.
PMCID: PMC3826550  PMID: 24156255
Imerslund-Gräsbeck syndrome; Cubilin; Amnionless; Proximal tubules; Tubular proteinuria
6.  The importance of early referral for the treatment of chronic kidney disease: a Danish nationwide cohort study 
BMC Nephrology  2012;13:108.
Many patients with advanced chronic kidney disease are referred late to renal units. This is associated with negative aspects. The purpose of the present study was to characterize late versus early referrals for renal replacement therapy including their renal disease, health care contacts and medical treatment before renal replacement therapy (RRT) and the consequences for RRT modality and mortality.
Nationwide cohort study including 4495 RRT patients identified in the Danish Nephrology Registry 1999–2006. The cohort was followed to end 2007 by linkage to other national registries. Late referral: follow-up ≤16 weeks in renal unit before RRT start. Cox proportional hazards models were used to estimate the relative risk of mortality or waiting list status within 365 days in late referrals versus early referrals.
A total of 1727 (38%) incident RRT patients were referred late. Among these, 72% were treated in non-nephrology hospital departments and 91% in general practice 2 years to 16 weeks before RRT start. Fewer late referrals received recommended pre-RRT treatment as judged by renin-angiotensin-system blockade: 32% versus 57% or the D-vitamin analogue alfacalcidol: 5% versus 30% (P < .001). Primary RRT modality was peritoneal dialysis: 18% in late versus 32% in early referrals (P < .001), 7% versus 30%, respectively, had an arteriovenous dialysis-fistula (P < .001) and 0.2% versus 6% were on the waiting-list for renal transplantation (P < .001) before RRT start. One-year-mortality was higher in late referrals: hazard ratio 1.55 (CI 95% 1.35–1.78). In a subgroup, 30% (CI 95% 25–35%) late and 9% (CI 95% 6–12%) early referrals had plasma creatinine ≤150% of upper reference limit within 1 to 2 years before RRT start (P < .001).
Late nephrology referrals were well-known to the healthcare system before referral for RRT start and more often had near normal plasma creatinine levels within 2 years before RRT start. They infrequently received available treatment or optimal first RRT modality. An increased effort to identify these patients in the healthcare system in time for proper pre-dialysis care including preparation for RRT is needed.
PMCID: PMC3469388  PMID: 22963236
Chronic kidney failure; Epidemiology; Late diagnosis; Treatment; Renal replacement therapy
7.  Reperfusion delay in patients treated with primary percutaneous coronary intervention: insight from a real world Danish ST-segment elevation myocardial infarction population in the era of telemedicine 
Reperfusion delay in ST-segment elevation myocardial infarction (STEMI) predicts adverse outcome. We evaluated time from alarm call (system delay) and time from first medical contact (PCI-related delay), where fibrinolysis could be initiated, to balloon inflation in a pre-hospital organization with tele-transmitted electrocardiograms, field triage and direct transfer to a 24/7 primary percutaneous coronary intervention (PPCI) center.
Methods and results:
This was a single center cohort study with long-term follow-up in 472 patients. The PPCI center registry was linked by person identification number to emergency medical services (EMS) and National Board of Health databases in the period of 2005–2008. Patients were stratified according to transfer distances to PPCI into zone 1 (0–25 km), zone 2 (65–100 km) and zone 3 (101–185 km) and according to referral by pre-hospital triage. System delay was 86 minutes (interquartile range (IQR) 72–113) in zone 1, 133 (116–180) in zone 2 and 173 (145–215) in zone 3 (p<0.001). PCI-related delay in directly referred patients was 109 (92–121) minutes in zone 2, but exceeded recommendations in zone 3 (139 (121–160)) and for patients admitted via the local hospital (219 (171–250)). System delay was an independent predictor of mortality (p<0.001).
Pre-hospital triage is feasible in 73% of patients. PCI-related delay exceeded European Society of Cardiology (ESC) guidelines for patients living >100 km away and for non-directly referred patients. Sorting the PPCI centers catchment area into geographical zones identifies patients with long reperfusion delays. Possible solutions are pharmaco-invasive regiments, research in early ischemia detection, airborne transfer and EMS personnel education that ensures pre-hospital triage.
PMCID: PMC3760540  PMID: 24062908
Acute myocardial infarction; STEMI; primary PCI; pre-hospital triage; reperfusion delay; telemedicine
8.  The FIB-PPH trial: fibrinogen concentrate as initial treatment for postpartum haemorrhage: study protocol for a randomised controlled trial 
Trials  2012;13:110.
Postpartum haemorrhage (PPH) remains a leading cause of maternal mortality worldwide. In Denmark 2% of parturients receive blood transfusion. During the course of bleeding fibrinogen (coagulation factor I) may be depleted and fall to critically low levels, impairing haemostasis and thus worsening the ongoing bleeding. A plasma level of fibrinogen below 2 g/L in the early phase of postpartum haemorrhage is associated with subsequent development of severe haemorrhage. Use of fibrinogen concentrate allows high-dose substitution without the need for blood type crossmatch. So far no publications of randomised controlled trials involving acutely bleeding patients in the obstetrical setting have been published. This trial aims to investigate if early treatment with fibrinogen concentrate reduces the need for blood transfusion in women suffering severe PPH.
In this randomised placebo-controlled double-blind multicentre trial, parturients with primary PPH are eligible following vaginal delivery in case of: manual removal of placenta (blood loss ≥ 500 ml) or manual exploration of the uterus after the birth of placenta (blood loss ≥ 1000 ml). Caesarean sections are also eligible in case of perioperative blood loss ≥ 1000 ml. The exclusion criteria are known inherited haemostatic deficiencies, prepartum treatment with antithrombotics, pre-pregnancy weight <45 kg or refusal to receive blood transfusion. Following informed consent, patients are randomly allocated to either early treatment with 2 g fibrinogen concentrate or 100 ml isotonic saline (placebo). Haemostatic monitoring with standard laboratory coagulation tests and thromboelastography (TEG, functional fibrinogen and Rapid TEG) is performed during the initial 24 hours.
Primary outcome is the need for blood transfusion. To investigate a 33% reduction in the need for blood transfusion, a total of 245 patients will be included. Four university-affiliated public tertiary care hospitals will include patients during a two-year period. Adverse events including thrombosis are assessed in accordance with International Conference on Harmonisation (ICH) good clinical practice (GCP).
A widespread belief in the benefits of early fibrinogen substitution in cases of PPH has led to increased off-label use. The FIB-PPH trial is investigator-initiated and aims to provide an evidence-based platform for the recommendations of the early use of fibrinogen concentrate in PPH.
Trial registration NCT01359878.
PMCID: PMC3434105  PMID: 22805300
Postpartum haemorrhage; Haemostasis; Blood transfusion; Fibrinogen concentrate; Obstetrics; Thrombelastography; Coagulation
9.  AMN Directs Endocytosis of the Intrinsic Factor-Vitamin B12 Receptor Cubam by Engaging ARH or Dab2 
Traffic (Copenhagen, Denmark)  2010;11(5):706-720.
Cubam is a multi-ligand receptor involved in dietary uptake of intrinsic factor-vitamin B12 in the small intestine and reabsorption of various low-molecular-weight proteins (such as albumin, transferrin, apolipoprotein A-I and vitamin D-binding protein) in the kidney. Cubam is composed of two proteins: cubilin and amnionless. Cubilin harbors ligand binding capabilities, while amnionless provides membrane anchorage and potential endocytic capacity via two FXNPXF signals within the cytosolic domain. These signals are similar to the FXNPXY signals found in members of the low-density lipoprotein receptor superfamily, which associate with clathrin-associated sorting proteins, including Disabled-2 (Dab2) and autosomal recessive hypercholesterolemia (ARH), during endocytosis. We therefore investigated the functionality of each amnionless FXNPXF signal and their respective interaction with sorting proteins. By sequential mutation and expression of a panel of amnionless mutants combined with yeast two-hybrid analyses, we demonstrate that the signals are functionally redundant and both are able to mediate endocytosis of cubam through interaction with Dab2 and ARH.
PMCID: PMC2964065  PMID: 20088845
amnionless; ARH; clathrin; cubilin; Dab2; endocytosis; [FY]NPX[FY] sorting signal; internalization; receptor; vitamin B12
10.  Use of statins and beta‐blockers after acute myocardial infarction according to income and education 
To study the initiation of and long‐term refill persistency with statins and beta‐blockers after acute myocardial infarction (AMI) according to income and education.
Design and setting
Linkage of individuals through national registers of hospitalisations, drug dispensation, income and education.
30 078 patients aged 30–74 years surviving first hospitalisation for AMI in Denmark between 1995 and 2001.
Main outcome measures
Initiation of statin or beta‐blocker treatment (out‐patient claim of prescriptions within 6 months of discharge) and refill persistency (first break in treatment lasting at least 90 days, and re‐initiation of treatment after a break).
When simultaneously estimating the effect of income and education on initiation of treatment, the effect of education attenuated and a clear income gradient remained for both drugs. Among patients aged 30–64 years, high income (adjusted hazard ratio (HR) 1.27; 95% confidence interval (CI) 1.19–1.35) and medium income (HR 1.13; 95% CI 1.06–1.20) was associated with initiation of statin treatment compared with low income. The risk of break in statin treatment was lower for patients with high (HR 0.73; 95% CI 0.66–0.82) and medium (HR 0.82; 95% CI 0.74–0.92) income compared with low income, whereas there was a trend in the opposite direction concerning a break in beta‐blocker treatment. There was no gradient in re‐initiation of treatment.
Patients with low compared with high income less frequently initiated preventive treatment post‐AMI, had worse long‐term persistency with statins, but tended to have better persistency with beta‐blockers. Low income by itself seems not to be associated with poor long‐term refill persistency post‐AMI.
PMCID: PMC2465659  PMID: 18000133
acute myocardial infarction; statins; beta‐blockers; income and education; initiation and persistency
11.  Mortality after acute myocardial infarction according to income and education 
To study how income and educational level influence mortality after acute myocardial infarction (AMI).
Design and setting
Prospective analysis using individual level linkage of registries in Denmark.
All patients 30–74 years old hospitalised for the first time with AMI in Denmark in 1995–2002.
Main outcome measures
Relative risk (RR) of 30 day mortality and long term mortality (31 days until 31 December 2003) associated with income (adjusted for education) or educational level (adjusted for income) and further adjusted for sex, age, civil status, and comorbidity.
The study identified 21 391 patients 30–64 years old and 16 169 patients 65–74 years old. The 30 day mortality was 7.0% among patients 30–64 years old and 15.9% among those 65–74 years old. Among patients surviving the first 30 days, the long term mortality was 9.9% and 28.3%, respectively. The adjusted RR of 30 day mortality and long term mortality among younger patients with low compared with high income was 1.54 (95% confidence interval 1.36 to 1.79) and 1.65 (1.45 to 1.85), respectively. The RR of 30 day and long term mortality among younger patients with low compared with high education was 1.24 (1.03 to 1.50) and 1.33 (1.11 to 1.59), respectively. The RR of 30 day and long term mortality among older patients with low compared with high income was 1.27 (1.15 to 1.41) and 1.38 (1.27 to 1.50), respectively. Older high and low education patients did not differ in mortality.
This study shows that both educational level and income substantially and independently affect mortality after AMI, indicating that each indicator has specific effects on mortality and that these indicators are not interchangeable.
PMCID: PMC2566173  PMID: 16537354
education; income; acute myocardial infarction; mortality
12.  Design paper: The CapOpus trial: A randomized, parallel-group, observer-blinded clinical trial of specialized addiction treatment versus treatment as usual for young patients with cannabis abuse and psychosis 
Trials  2008;9:42.
A number of studies indicate a link between cannabis-use and psychosis as well as more severe psychosis in those with existing psychotic disorders. There is currently insufficient evidence to decide the optimal way to treat cannabis abuse among patients with psychosis.
The major objective for the CapOpus trial is to evaluate the additional effect on cannabis abuse of a specialized addiction treatment program adding group treatment and motivational interviewing to treatment as usual.
The trial is designed as a randomized, parallel-group, observer-blinded clinical trial. Patients are primarily recruited through early-psychosis detection teams, community mental health centers, and assertive community treatment teams. Patients are randomized to one of two treatment arms, both lasting six months: 1) specialized addiction treatment plus treatment as usual or 2) treatment as usual. The specialized addiction treatment is manualized and consists of both individual and group-based motivational interviewing and cognitive behavioral therapy, and incorporates both the family and the case manager of the patient.
The primary outcome measure will be changes in amount of cannabis consumption over time. Other outcome measures will be psychosis symptoms, cognitive functioning, quality of life, social functioning, and cost-benefit analyses.
Trial registration NCT00484302.
PMCID: PMC2475529  PMID: 18620563
13.  Dwarfism and Impaired Gut Development in Insulin-Like Growth Factor II mRNA-Binding Protein 1-Deficient Mice 
Molecular and Cellular Biology  2004;24(10):4448-4464.
Insulin-like growth factor II mRNA-binding protein 1 (IMP1) belongs to a family of RNA-binding proteins implicated in mRNA localization, turnover, and translational control. Mouse IMP1 is expressed during early development, and an increase in expression occurs around embryonic day 12.5 (E12.5). To characterize the physiological role of IMP1, we generated IMP1-deficient mice carrying a gene trap insertion in the Imp1 gene. Imp1−/− mice were on average 40% smaller than wild-type and heterozygous sex-matched littermates. Growth retardation was apparent from E17.5 and remained permanent into adult life. Moreover, Imp1−/− mice exhibited high perinatal mortality, and only 50% were alive 3 days after birth. In contrast to most other organs, intestinal epithelial cells continue to express IMP1 postnatally, and Imp1−/− mice exhibited impaired development of the intestine, with small and misshapen villi and twisted colon crypts. Analysis of target mRNAs and global expression profiling at E12.5 indicated that Igf2 translation was downregulated, whereas the postnatal intestine showed reduced expression of transcripts encoding extracellular matrix components, such as galectin- 1, lumican, tenascin-C, procollagen transcripts, and the Hsp47 procollagen chaperone. Taken together, the results demonstrate that IMP1 is essential for normal growth and development. Moreover, IMP1 may facilitate intestinal morphogenesis via regulation of extracellular matrix formation.
PMCID: PMC400488  PMID: 15121863
14.  Activation Control of pur Gene Expression in Lactococcus lactis: Proposal for a Consensus Activator Binding Sequence Based on Deletion Analysis and Site-Directed Mutagenesis of purC and purD Promoter Regions 
Journal of Bacteriology  1998;180(15):3900-3906.
A comparison of the purC and purD upstream regions from Lactococcus lactis revealed the presence of a conserved ACCGAACAAT decanucleotide sequence located precisely between −79 and −70 nucleotides upstream from the transcriptional start sites. Both promoters have well-defined −10 regions but lack sequences resembling −35 regions for ς70 promoters. Fusion studies indicated the importance of the conserved sequence in purine-mediated regulation. Adjacent to the conserved sequence in purC is a second and similar region required for high-level expression of the gene. A consensus PurBox sequence (AWWWCCGAACWWT) could be proposed for the three regions. By site-directed mutagenesis we found that mutation of the central G in the PurBox sequence to C resulted in low levels of transcription and the loss of purine-mediated regulation at the purC and purD promoters. Deletion analysis also showed that the nucleotides before the central CCGAAC core in the PurBox sequence are important. All results support the idea that purC and purD transcription is regulated by a transcriptional activator binding to the PurBox sequence.
PMCID: PMC107374  PMID: 9683487

Results 1-14 (14)