Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke: A Randomized Placebo-Controlled Trial.

BACKGROUND AND PURPOSE: Delayed recanalization increases the risk of infarct growth and poor clinical outcome in acute ischemic stroke. The vasoactive agent theophylline has shown neuroprotective effects in animal stroke models but inconclusive results in case series and randomized clinical trials. The primary objective of this study was to evaluate whether theophylline, as an add-on to thrombolytic therapy, is safe and effective in acute ischemic stroke patients. METHODS: The TEA-Stroke trial (The Theophylline in Acute Ischemic Stroke) was an investigator-initiated 2-center, proof-of-concept, phase II clinical study with a randomized, double-blinded, placebo-controlled design. The main inclusion criteria were magnetic resonance imaging-verified acute ischemic stroke, moderate to severe neurological deficit (National Institutes of Health Stroke Scale score of ≥4), and treatment with thrombolysis within 4.5 hours of onset. Participants were randomly assigned in the ratio 1:1 to either 220 mg of intravenous theophylline or placebo. The co-primary outcomes were early clinical improvement on the National Institutes of Health Stroke Scale score and infarct growth on magnetic resonance imaging at 24-hour follow-up. RESULTS: Theophylline as an add-on to thrombolytic therapy improved the National Institutes of Health Stroke Scale score at 24 hours by mean 4.7 points (SD, 5.6) compared with an improvement of 1.3 points (SD, 7.5) in the control group (P=0.044). Mean infarct growth was 141.6% (SD, 126.5) and 104.1% (SD, 62.5) in the theophylline and control groups, respectively (P=0.146). Functional independence at 90 days was 61% in the theophylline group and 58% in the control group (P=0.802). CONCLUSIONS: This proof-of-concept trial investigated theophylline administration as an add-on to thrombolytic therapy in acute ischemic stroke. The co-primary end points early clinical improvement and infarct growth at 24-hour follow-up were not significantly different after post hoc correction for multiplicity (Bonferroni technique). The small study size precludes a conclusion as to whether theophylline has a neuroprotective effect but provides a promising clinical signal that may support a future clinical trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: EudraCT number 2013-001989-42.

Influence of socioeconomic status on the referral process to cardiac rehabilitation following acute coronary syndrome: a cross-sectional study.

OBJECTIVE: To evaluate the association between socioeconomic status (SES) and referral to cardiac rehabilitation (CR) after incident acute coronary syndrome (ACS) by dividing the referral process into three phases: (1) informed about CR, (2) willingness to participate in CR, (3) and assigned CR setting. DESIGN: Cross-sectional study. SETTING: Department of Cardiology at a Danish University Hospital from 1 January 2011 to 31 December 2014. PARTICIPANTS: A total of 1229 patients assessed for CR during hospitalisation with ACS were prospectively registered in the Rehab-North Register from 2011 to 2014. SES was assessed using data from national registers, concerning: personal income, occupational status, educational level and civil status. Patients were excluded if one of the following criteria was fulfilled: (1) missing data on SES, or (2) acceptable reason for not informing patients about CR (treatment with coronary artery bypass grafting, transfer to another hospital, still under treatment or death). MAIN OUTCOME MEASURES: Outcomes were defined by dividing the referral process into three phases: (1) informed about CR, (2) willingness to participate, and (3) assigned CR setting (in-hospital/community centre) after ACS. RESULTS: A total of 854 (69.5 %) patients were referred to CR. After adjustment for age, gender, ACS diagnosis (ST-elevated myocardial infarction, non-ST-elevated myocardial infarction, unstable angina pectoris) and comorbidity, high income had the strongest association of referral to CR in all three phases (informed about CR: OR 2.17, 95% CI 1.01 to 4.64; willingness to participate in CR: OR 1.55, 95% CI 1.02 to 2.35; assigned in-hospital CR: OR 1.47, 95% CI 0.91 to 2.36). Educational level showed similar tendencies, however not statistically significant. The results did not vary according to gender. CONCLUSION: This is the first study to investigate the referral process to CR using a three-phase structure. It suggests income and education to influence all phases in the referral process to CR after ACS.

Arrhythmias in Patients on Maintenance Dialysis: A Cross-sectional Study.

RATIONALE & OBJECTIVE: Patients with kidney failure treated with maintenance dialysis experience a high rate of mortality, in part due to sudden cardiac death caused by arrhythmias. The prevalence of arrhythmias, including the subset that are clinically significant, is not well known. This study sought to estimate the prevalence of arrhythmias, characterize the pattern of arrhythmic events in relation to dialysis treatments, and identify associated clinical characteristics. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 152 patients with kidney failure treated with maintenance dialysis in Denmark. EXPOSURES: Dialysis treatment; clinical characteristics; cardiac output and preload defined using echocardiography. OUTCOMES: Prevalence and pattern of arrhythmias on 48-hour Holter monitoring; odds ratios for arrhythmias. ANALYTICAL APPROACH: Descriptive analysis of the prevalence of arrhythmias. Pattern of arrhythmias described using a repeated-measures negative binomial regression model. Associations between clinical characteristics and echocardiographic findings with arrhythmias were assessed using logistic regression. RESULTS: Among the 152 patients studied, 83.6% were treated with in-center dialysis; 10.5%, with home hemodialysis; and 5.9%, with peritoneal dialysis. Premature atrial and ventricular complexes were seen in nearly all patients and 41% had paroxysmal supraventricular tachycardia. Clinically significant arrhythmias included persistent atrial fibrillation observed among 8.6% of patients, paroxysmal atrial fibrillation among 3.9%, nonsustained ventricular tachycardia among 19.7%, bradycardia among 4.6%, advanced second-degree atrioventricular block among 1.3%, and third-degree atrioventricular block among 2.6%. Premature ventricular complexes were more common on dialysis days, while tachyarrhythmias were more often observed during dialysis and in the immediate postdialytic period. Older age (OR per 10 years older, 1.53; 95% CI, 1.15-2.03; P=0.003), elevated preload (OR, 4.02; 95% CI, 1.05-15.35; P=0.04), and lower cardiac output (OR per 1L/min greater, 0.66; 95% CI, 0.44-1.00; P=0.05) were independently associated with clinically significant arrhythmias. LIMITATIONS: Arrhythmia monitoring limited to 48 hours; small sample size; heterogeneous nature of the population, risk for residual confounding. CONCLUSIONS: Arrhythmias, including clinically significant abnormal rhythms, were common. Tachyarrhythmias were more frequent during dialysis and the immediate postdialytic period. The relevance of these findings to clinical outcomes requires additional study.

Dose-Response Association Between Level of Physical Activity and Mortality in Normal, Elevated, and High Blood Pressure.

It has been a challenge to verify the dose of exercise that will produce the maximum health benefits in hypertension. This study aimed to explore the association between level of daily physical activity, all-cause mortality and cardiovascular outcome at different blood pressure levels. A random sample of 18 974 white men and women aged 20 to 98 years were examined in a prospective cardiovascular population study. Self-reported activity level in leisure-time was drawn from the Physical Activity Questionnaire (level I: inactivity; II: light activity; and III: moderate/high-level activity). Blood pressure was defined as normal blood pressure: <120/<80 mm Hg; Prehypertension: 120-139/80-89 mm Hg; Stage I hypertension: 140-159/90-99 mm Hg; Stage II hypertension ≥160/≥100 mm Hg. The mean follow-up time was 23.4±11.7 years. At all levels of blood pressure, higher levels of physical activity were associated with lower all-cause mortality in a dose-response pattern. The pattern remained unchanged after adjustment for following confounders: sex, age, smoking status, education, diabetes mellitus, previous cardiovascular disease, body mass index, and calendar time. Compared with inactivity, following hazard ratios were found for stage I hypertension: light activity, hazard ratio 0.78 (0.72-0.84; P<0.001), moderate/high-level activity, hazard ratio 0.69 (0.63-0.75; P<0.001). At all levels of blood pressure, the risk of cardiovascular events was significantly reduced independent of the level of physical activity. In conclusion, the association between physical activity and all-cause mortality was present in an inverse dose-response pattern at all levels of blood pressure. Physical activity was associated with reduction in cardiovascular events independent of the level of physical activity.

Does socially differentiated cardiac rehabilitation affect the use of healthcare services after myocardial infarction? A 10-year follow-up study.

OBJECTIVE: To examine the long-term effect of a socially differentiated cardiac rehabilitation (CR) intervention tailored to reduce social inequalities in health regarding use of healthcare services in general practice and hospital among socially vulnerable patients admitted with first-episode myocardial infarction (MI). DESIGN: A prospective cohort study with 10 years' follow-up. SETTING: Department of cardiology at a university hospital in Denmark between 2000 and 2004. PARTICIPANTS: Patients <70 years admitted with first-episode MI categorised as socially vulnerable (n=208) or non-socially vulnerable (n=171) based on educational level and social network. INTERVENTION: A socially differentiated CR intervention. The intervention consisted of standard CR and expanded CR with focus on cross-sectional collaboration. MAIN OUTCOME MEASURES: Participation in annual chronic care consultations in general practice, contacts to general practice, all-cause hospitalisations and cardiovascular readmissions. RESULTS: At 2-year and 5-year follow-up, socially vulnerable patients receiving expanded CR participated significantly more in annual chronic care consultations (p=0.02 and p<0.01) but at 10-year follow-up, there were no significant differences in annual chronic care consultations (p=0.13). At 10-year follow-up, socially vulnerable patients receiving standard CR had significantly more contacts to general practice (p=0.03). At 10-year follow-up, there were no significant differences in the proportion of socially vulnerable patients receiving expanded CR in the mean number of all-cause hospitalisations and cardiovascular readmissions (p>0.05). CONCLUSIONS: The present study found no persistent association between the socially differentiated CR intervention and use of healthcare services in general practice and hospital in patients admitted with first-episode MI during a 10-year follow-up.

Echocardiographic global longitudinal strain is associated with infarct size assessed by cardiac magnetic resonance in acute myocardial infarction.

The aim of this study was to investigate if there was an association between infarct size (IS) measured by cardiac magnetic resonance (CMR) and echocardiographic global longitudinal strain (GLS) in the early stage of acute myocardial infarction in patients with preserved left ventricular ejection fraction (LVEF). Patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention were assessed with CMR and transthoracic echocardiogram within 1 week of hospital admission. Two-dimensional speckle tracking was performed using a semi-automatic algorithm (EchoPac, GE Healthcare). Longitudinal strain curves were generated in a 17-segment model covering the entire left ventricular myocardium. GLS was calculated automatically. LVEF was measured by auto-LVEF in EchoPac. IS was measured by late gadolinium enhancement CMR in short-axis views covering the left ventricle. The study population consisted of 49 patients (age 60.4 ± 9.7 years; 92% male). The study population had preserved echocardiographic LVEF with a mean of 45.8 ± 8.7%. For each percent increase of IS, we found an impairment in GLS by 1.59% (95% CI 0.57-2.61), P = 0.02, after adjustment for sex, age and LVEF. No significant association between IS and echocardiographic LVEF was found: -0.25 (95% CI: -0.61 to 0.11), P = 0.51. At the segmental level, the strongest association between IS and longitudinal strain was found in the apical part of the LV: impairment of 1.69% (95% CI: 1.14-2.23), P < 0.001, for each percent increase in IS. In conclusion, GLS was significantly associated with IS in the early stage of acute myocardial infarction in patients with preserved LVEF, and this association was strongest in the apical part of the LV. No association between IS and LVEF was found.

Medication adherence, biological and lifestyle risk factors in patients with myocardial infarction: a ten-year follow-up on socially differentiated cardiac rehabilitation.

Objective: There is strong evidence that medication adherence and lifestyle changes are essential in patients undergoing secondary cardiovascular disease prevention. Cardiac rehabilitation (CR) increases medication adherence and improves lifestyle changes. Patients with cardiac diseases and a low educational level and patients with little social support are less responsive to improve medication adherence and to adapt lifestyle changes. The aim of the present study was to investigate the long-term effects of a socially differentiated CR intervention on medication adherence as well as changes in biological and lifestyle risk factors at two- five- and ten-year follow-up. Design: A prospective cohort study. Setting: The cardiac ward at Aarhus University Hospital, Denmark. Intervention: A socially differentiated CR intervention in addition to the standard CR program. Subjects: Patients admitted with first-episode myocardial infarction between 2000 and 2004, N = 379. Patients were defined as socially vulnerable or non-socially vulnerable according to their educational level and extent of social network. Main outcome measures: Primary outcome was medication adherence to antithrombotics, beta-blockers, statins and angiotensin-converting enzyme inhibitors. Secondary outcomes were biological and lifestyle risk factors defined as; total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, glycated hemoglobin, blood pressure and smoking status. Results: No significant long-term effect of the intervention was found. Conclusions: The results indicate a non-significant effect of the intervention. However, it was found that equality in health was improved in the study population except concerning smoking. General practitioners manage to support the long-term secondary cardiovascular disease prevention in all patients regardless of social status. Key points The socially differentiated intervention did not significantly improve medication adherence or biological and lifestyle risk factors. Despite the non-significant effect of the intervention, equality in health was improved except concerning smoking. General practitioners managed to support the long-term secondary cardiovascular disease prevention in all patients regardless of social status.

Coronary Artery Calcification and Mortality Risk in Patients With Severe Mental Illness.

Background Cardiovascular mortality is the leading contributor to the shortened life expectancy in patients with severe mental illness (SMI), but efforts to predict cardiovascular outcomes in these patients have been lacking. In this study, we aimed to determine the severity of coronary artery calcification (CAC), and its effect on mortality rates in patients with SMI, compared with the general population. Methods All individuals with a registered cardiac computed tomography for calcium scoring in the Western Denmark Heart Registry, from January 1, 2008 to December 31, 2016, were included. We identified patients diagnosed with SMI ( International Classification of Diseases, Tenth Revision: F20, F30, F31), whereas the remaining individuals were used as a comparison group. Results Among 48 757 individuals, including 564 patients with SMI (1.2%), we found no difference in CAC score between patients with SMI and the comparison group. SMI patients with CAC >100 had an increased mortality rate (hazard ratio, 3.16; 95% CI, 1.41-7.06), as well as SMI patients with CAC <100 (hazard ratio, 3.95; 95% CI, 2.36-6.62), compared with the comparison group with CAC <100 as reference, adjusted for age, sex, and calendar period. Conclusions Patients with SMI have increased cardiovascular risks, but show no difference in CAC score, compared with the comparison group. Mortality rates were increased in patients with SMI, independent of CAC severity; however, the relatively large number of noncardiovascular causes of death in this sample might indicate other contributing factors to death than coronary artery disease in this sample of SMI patients.

Educational level and living arrangements are associated with dietary intake of red meat and fruit/vegetables: A Danish cross-sectional study.

Aims: To evaluate the association between education and living arrangements and the intake of fish, red meat and fruit and vegetables.Methods: The study design was cross-sectional and conducted in Denmark in 2013. Participants filled in questionnaires about their educational level and living arrangements (living alone or with others) and dietary intake including fish, red meat, fruit and vegetables. Regression analyses were performed to assess the associations within 85,456 randomly sampled healthy men and women who were at least 25 years old.Results: Length of education was statistically significant and positively associated with the intake of fruit and vegetables and negatively associated with the intake of red meat for both men and women. Men with a high level of education had a 187g/week (95% confidence interval: 199-175g/week) lower intake of red meat and a 109g/day (95% confidence interval: 102-117g/day) higher intake of fruit and vegetables than men with a low level of education. Women with a high level of education had a 175g/week (95% confidence interval: 186-164g/week) lower intake of red meat and a 106g/day (95% confidence interval: 97-114g/day) higher intake of fruit and vegetables than women with a low level of education. Living with others was statistically significant and positively associated with the intake of red meat, and fruit and vegetables. There were no clear associations between education, living arrangements and intake of fish.Conclusions: Men and women with a high educational level ate more fruit and vegetables but less red meat than men and women with a low educational level. Men and women living with others ate more red meat, fruit and vegetables than men and women living alone.

Positive predictive value of first-time rheumatoid arthritis diagnoses and their serological subtypes in the Danish National Patient Registry.

PURPOSES: To assess whether the positive predictive value (PPV) of first-time rheumatoid arthritis (RA) diagnosis registration in the Danish National Patient Registry increases when data are linked to the RA treatment codes and to assess the PPV of first-time RA diagnoses according to RA serological subtypes. METHODS: Participants from the Danish Diet, Cancer, and Health cohort with at least one RA diagnosis, registered at one of the Central Denmark Region hospitals in the Danish National Patient Registry during the period 1977-2016, were identified. Register-based RA diagnoses were verified by scrutinizing medical records against RA classification criteria or clinical case RA. PPVs for overall RA, seropositive RA, and other RA were calculated for two models: first-time RA diagnosis registration ever in the Danish National Patient Registry and first-time RA diagnosis registration ever where subsequently a prescription had been redeemed for a synthetic disease-modifying antirheumatic drug. RESULTS: Overall, 205 of 311 first-time register-based RA diagnoses were verified (PPV: 61.9%; 95% CI: 56.9-67.0). Regarding RA serological subtypes, 93 of 150 register-based seropositive RA (PPV: 62.0; 95% CI: 53.9-69.5) and 36 of 144 other RA (PPV: 25.0; 95% CI: 18.5-32.8) were confirmed. When register-based RA diagnosis codes were linked to RA treatment codes, the PPVs increased substantially: the PPV for overall RA was 87.7% (95% CI: 82.5-91.5), the PPV for seropositive RA was 80.2% (95% CI: 71.6-86.7), and the PPV for other RA was 41.1% (95% CI: 30.2-52.9). CONCLUSION: The first-time RA diagnoses in the Danish National Patient Registry should be used with caution in epidemiology research. However, linking registry-based RA diagnoses to the subsequent RA treatment codes increases the probability of identifying true RA diagnoses, especially overall RA and seropositive RA.

Explaining trends in coronary heart disease mortality in different socioeconomic groups in Denmark 1991-2007 using the IMPACTSEC model.

AIM: To quantify the contribution of changes in different risk factors population levels and treatment uptake on the decline in CHD mortality in Denmark from 1991 to 2007 in different socioeconomic groups. DESIGN: We used IMPACTSEC, a previously validated policy model using data from different population registries. PARTICIPANTS: All adults aged 25-84 years living in Denmark in 1991 and 2007. MAIN OUTCOME MEASURE: Deaths prevented or postponed (DPP). RESULTS: There were approximately 11,000 fewer CHD deaths in Denmark in 2007 than would be expected if the 1991 mortality rates had persisted. Higher mortality rates were observed in the lowest socioeconomic quintile. The highest absolute reduction in CHD mortality was seen in this group but the highest relative reduction was in the most affluent socioeconomic quintile. Overall, the IMPACTSEC model explained nearly two thirds of the decline in. Improved treatments accounted for approximately 25% with the least relative mortality reduction in the most deprived quintile. Risk factor improvements accounted for approximately 40% of the mortality decrease with similar gains across all socio-economic groups. The 36% gap in explaining all DPPs may reflect inaccurate data or risk factors not quantified in the current model. CONCLUSIONS: According to the IMPACTSEC model, the largest contribution to the CHD mortality decline in Denmark from 1991 to 2007 was from improvements in risk factors, with similar gains across all socio-economic groups. However, we found a clear socioeconomic trend for the treatment contribution favouring the most affluent groups.

A simple transformation independent method for outlier definition.

BACKGROUND: Definition and elimination of outliers is a key element for medical laboratories establishing or verifying reference intervals (RIs). Especially as inclusion of just a few outlying observations may seriously affect the determination of the reference limits. Many methods have been developed for definition of outliers. Several of these methods are developed for the normal distribution and often data require transformation before outlier elimination. METHODS: We have developed a non-parametric transformation independent outlier definition. The new method relies on drawing reproducible histograms. This is done by using defined bin sizes above and below the median. The method is compared to the method recommended by CLSI/IFCC, which uses Box-Cox transformation (BCT) and Tukey's fences for outlier definition. The comparison is done on eight simulated distributions and an indirect clinical datasets. RESULTS: The comparison on simulated distributions shows that without outliers added the recommended method in general defines fewer outliers. However, when outliers are added on one side the proposed method often produces better results. With outliers on both sides the methods are equally good. Furthermore, it is found that the presence of outliers affects the BCT, and subsequently affects the determined limits of current recommended methods. This is especially seen in skewed distributions. The proposed outlier definition reproduced current RI limits on clinical data containing outliers. CONCLUSIONS: We find our simple transformation independent outlier detection method as good as or better than the currently recommended methods.

Long-term outcome after normal myocardial perfusion imaging in suspected ischaemic heart disease
.

INTRODUCTION: Ischaemic heart disease (IHD) is the leading cause of mortality in the Western world. Therefore, to focus on those at risk of having IHD while at the same time avoiding unnecessary patient concern, it is important to have diagnostic tools capable of refuting an IHD diagnosis. Within the past 30 years, myocardial perfusion imaging (MPI) has been used increasingly to detect myocardial perfusion defects. MPI is a safe and non-invasive method with a sensitivity and specificity of > 90%. The aim of this study was to evaluate the long-term prognostic outcome after a normal MPI. 
Methods: The study population comprised patients referred for MPI from one single department of cardiology with invasive facilities, from 2008 to 2009. The patients' demographics and the results of the MPIs were collected from their medical records. Only patients without known IHD and with a normal MPI were included. After a follow-up period of 7.8 years (range: 6.8-8.8 years), a retrospective database search was performed. The major outcomes were all-cause mortality, cardiac events defined as nonfatal myocardial infarct or coronary revascularisation by percutaneous coron-ary intervention or coronary artery bypass grafting. 
Results: The risk of a cardiac event or death following a normal MPI was 9.6% during long-term follow-up, with an estimated annual death rate of 1.4% per year (95% confidence interval: 0.8-2.5%). This was not different from the background population. 
Conclusion: A normal MPI predicts a favourable long-term prognostic outcome. 
Funding: none.
 Trial registration: FSEID-00002257.

The prognostic efficacy of cell-free DNA hypermethylation in colorectal cancer.

Epigenetic alterations in colorectal cancer (CRC) cause important differences in the underlying tumor biology and aggressiveness. DNA hypermethylation is central for the development of CRC but the prognostic impact remains elusive. We aimed to assess the association between cell-free hypermethylated DNA and stage and survival in colorectal cancer (CRC). We analyzed pre-treatment plasma samples from 193 patients with CRC. Thirty gene-promoter regions were analyzed using methylation specific PCR. We compared the median number (range) of hypermethylated promoter regions with CRC stage, and constructed a multivariable Cox-regression model adjusted for stage, to evaluate the added prognostic information. The median number of hypermethylated promoter regions was nine (0-28) in patients with distant metastasis compared to five (0-19) in patients without metastatic disease (p < 0.0001). The majority of the hypermethylated promoter regions inferred a poor prognosis. Cox-regression analysis adjusted for patient age, sex, pre-treatment CEA-levels, and disease stage, showed that RARB (HR = 1.99, 95% CI [1.07, 3.72]) and RASSF1A (HR = 3.35, 95% CI [1.76, 6.38]) hypermethylation inferred a significant effect on survival. The risk of metastasis increase with the number of cell-free hypermethylated promoter regions. The presence of RARB and RASSF1A hypermethylation indicated aggressive disease, regardless of stage at the time of diagnosis.

Cell-free DNA promoter hypermethylation in plasma as a predictive marker for survival of patients with pancreatic adenocarcinoma.

INTRODUCTION: Few prognostic biomarkers are available for pancreatic cancer. The aim of this study is to examine the correlation between the survival of pancreatic adenocarcinoma patients and hypermethylated genes in plasma-derived cell-free DNA. METHODS: Consecutive patients with pancreatic adenocarcinoma were prospectively included and staged according to the TNM classification. Methylation-specific PCR of 28 genes was conducted. A survival prediction model independent of cancer stage and stage-specific survival prediction models were developed by multivariable Cox regression analysis using backward stepwise selection. RESULTS: Ninety-five patients with pancreatic adenocarcinoma were included. Patients with more than 10 hypermethylated genes had a HR of 2.03 (95% CI; 1.15-3.57) compared to patients with fewer hypermethylated genes. Three survival prediction models were developed: Total group; (American Society of Anesthesiologists score (ASA)=3, GSTP1, SFRP2, BNC1, SFRP1, TFPI2, and WNT5A) Risk groups 2, 3 and 4 had a HR of 2.65 (95% CI; 1.24-5.66), 4.34 (95% CI; 1.98-9.51) and 21.19 (95% CI; 8.61-52.15), respectively, compared to risk group 1. Stage I-II; (ASA=3, SFRP2, and MESTv2) Risk groups 2, 3 and 4 had a HR of 4.83 (95% CI; 2.01-11.57), 9.12 (95% CI; 2.18-38.25) and 70.90 (95% CI; 12.63-397.96), respectively, compared to risk group 1. Stage IV; (BMP3, NPTX2, SFRP1, and MGMT) Risk group 2 had a HR of 5.23 (95% CI; 2.13-12.82) compared to risk group 1. CONCLUSION: Prediction models based on cell-free DNA hypermethylation stratified pancreatic adenocarcinoma patients into risk groups according to survival. The models have the potential to work as prognostic biomarkers. However, further validation of the results is required to substantiate the findings.

Social inequality and barriers to cardiac rehabilitation in the rehab-North register.

AIM: Barriers to participation in cardiac rehabilitation (CR) may occur at three levels of the referral process (lack of information, declining to participate, and referral to appropriate CR programme). The aim is to analyse the impact of socioeconomic status on barriers to CR and investigate whether such barriers influenced the choice of referral. METHODS: The Rehab-North Register, a cross-sectional study, enrolled 5455 patients hospitalised at Aalborg University Hospital with myocardial infarction (MI) during 2011-2014. Patients hospitalised with ST-elevated MI and complicated non-ST-elevated MI were to be sent to specialized CR, whereas patients with uncomplicated non-ST-elevated MI and unstable angina pectoris were to be sent to community-based CR. Detailed selected socioeconomic information was gathered from statistical registries in Statistics Denmark. Data was assessed using logistic regression. RESULTS: Patients being retired, low educated, and/or with an annual gross income <27.000 Euro/yr were significantly less informed about cardiac rehabilitation programmes. Patients being older than 70 years, retired, low educated and/or with an annual gross income <27.000 Euro were significantly less willing to participate in CR. Further, this patient population were to a higher extent referred to community-based CR. CONCLUSION: Patients with low socioeconomic status received less information about and were less willing to participate in cardiac rehabilitation. The same patient population was to a higher extent referred to community-based CR. Knowledge about barriers at different levels and the impact of social inequality may help in tailoring a better approach in the referral process to CR.

Promoter hypermethylation in plasma-derived cell-free DNA as a prognostic marker for pancreatic adenocarcinoma staging.

Correct staging of pancreatic cancer is paramount, as treatment is stage specific. However, minimally invasive tools to facilitate staging are lacking. DNA promoter hypermethylation is a hallmark of cancer. The aim of this study is to evaluate promoter hypermethylation in cell-free DNA as a prognostic marker for stage classification of pancreatic adenocarcinoma. Consecutive patients with pancreatic adenocarcinoma were prospectively included. Plasma samples were obtained before diagnostic work-up and treatment. Patients were staged according to the TNM classification. Methylation-specific PCR of 28 genes was performed. Prognostic prediction models for staging of pancreatic adenocarcinoma were developed by multivariable logistic regression analysis using stepwise backwards elimination. Ninety-five patients with pancreatic adenocarcinoma were included. The mean number of hypermethylated genes was identical for stage I, II and III disease (7.09 (95% CI; 5.51-8.66), 7.00 (95% CI; 5.93-8.07) and 6.77 (95% CI; 5.08-8.46)), respectively, and highly significantly different from stage IV disease (10.24 (95% CI; 8.88-11.60)). The prediction model (SEPT9v2, SST, ALX4, CDKN2B, HIC1, MLH1, NEUROG1, and BNC1) enabled the differentiation of stage IV from stage I-III disease (AUC of 0.87 (cut point 0.55; sensitivity 74%, specificity 87%)). Model (MLH1, SEPT9v2, BNC1, ALX4, CDKN2B, NEUROG1, WNT5A, and TFPI2) enabled the differentiation of stage I-II from stage III-IV disease (AUC of 0.82 (cut point 0.66; sensitivity 73%, specificity 80%)). Cell-free DNA promoter hypermethylation has the potential to be blood-based prognostic markers for pancreatic adenocarcinoma, as panels of hypermethylated genes enables the differentiation according to cancer stage. However, further validation is required.

Hypermethylated DNA, a circulating biomarker for colorectal cancer detection.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers in the western world. Screening is an efficient method of reducing cancer-related mortality. Molecular biomarkers for cancer in general and CRC in particular have been proposed, and hypermethylated DNA from stool or blood samples are already implemented as biomarkers for CRC screening. We aimed to evaluate the performance of proven hypermethylated DNA promoter regions as plasma based biomarkers for CRC detection. METHODS: We conducted a cross-sectional case-control study of 193 CRC patients and 102 colonoscopy-verified healthy controls. Using methylation specific polymerase chain reaction, we evaluated 30 DNA promoter regions previously found to be CRC specific. We used multivariable logistic regression with stepwise backwards selection, and subsequent leave-pair-out cross validation, to calculate the optimism corrected area under the receiver operating characteristics curve (AUC) for all stage as well as early stage CRC. RESULTS: None of the individual DNA promoter regions provided an overall sensitivity above 30% at a reasonable specificity. However, seven hypermethylated promoter regions (ALX4, BMP3, NPTX2, RARB, SDC2, SEPT9, and VIM) along with the covariates sex and age yielded an optimism corrected AUC of 0.86 for all stage CRC and 0.85 for early stage CRC. Overall sensitivity for CRC detection was 90.7% at 72.5% specificity using a cut point value of 0.5. CONCLUSIONS: Individual hypermethylated DNA promoter regions have limited value as CRC screening markers. However, a panel of seven hypermethylated promoter regions show great promise as a model for CRC detection.

Assessment of enthesitis in patients with psoriatic arthritis using clinical examination and ultrasound.

BACKGROUND: Enthesitis is a major feature of psoriatic arthritis. However, clinical assessment of enthesitis is known to lack accuracy and have poor interobserver reliability. OBJECTIVE: To determine effect of training on clinical assessment of enthesitis and to compare ultrasonography with clinical examination for the detection of entheseal abnormalities. METHODS: 20 rheumatologists performed repeated assessment of enthesitis in patients with established psoriatic arthritis before and after a 2-hour training session in standardised enthesitis count according to Leeds Enthesitis Index (LEI) and Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC). Moreover, 20 patients underwent clinical and ultrasonographic examination of entheses to evaluate consensus-based elementary lesions of enthesitis. RESULTS: Training significantly increased Intra-class Correlation Coefficient for LEI from 0.18 to 0.82 and for SPARCC from 0.38 to 0.67. Ultrasound examination showed high associations between hypoechogenicity and increased thickness of the entheses and clinical examination. There was no correlation between erosions and enthesophytes found by ultrasound and clinical assessments. CONCLUSION: Training in standardised enthesitis scoring systems significantly improved clinical assessments of enthesitis and should be performed before use in daily clinical practice. Ultrasound revealed more advanced stages of enthesitis, such as enthesophytes and erosions, which were not detected with clinical examination.

The effect of marine n-3 polyunsaturated fatty acids on cardiac autonomic and hemodynamic function in patients with psoriatic arthritis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The aim of this study was to investigate the effect of marine n-3 polyunsaturated fatty acids (PUFA) on cardiac autonomic function and vascular function in patients with psoriatic arthritis. METHODS: The study was conducted as a randomized, double-blind, placebo-controlled trial, where 145 patients with psoriatic arthritis were supplemented with 3 g of n-3 PUFA or olive oil (control) daily for 24 weeks. Blood pressure, heart rate, heart rate variability (HRV), central blood pressure, pulse wave velocity (PWV) and fatty acid composition of granulocytes, were determined at baseline and after supplementation. RESULTS: At baseline we found a significant difference in the mean of all normal RR intervals (inverse of heart rate, vary from beat to beat) when comparing subjects with the highest vs the lowest fish intake (p = 0.03). After supplementation for 24 weeks there was a trend towards an increase in RR (p = 0.13) and decrease in heart rate (p = 0.12) comparing the n-3 PUFA group with the control group. However, per-protocol analysis showed significantly increased RR (p = 0.01) and lowered heart rate (p = 0.01) in the n-3 PUFA supplemented patients compared with controls. Blood pressure, PWV and Central blood pressure did not change after supplementation with n-3 PUFA. Adjustment for disease activity and conventional cardiovascular risk factors did not change the results. CONCLUSIONS: Marine n-3 PUFA increased RR intervals in patients with psoriatic arthritis which may suggest a protective effect of n-3 PUFA against cardiovascular disease in this population. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01818804.