Søren Nymand Lophaven

A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults

The efficacy of vortioxetine 10 and 20 mg/d vs. placebo on cognitive function and depression in adults with recurrent moderate-to-severe major depressive disorder (MDD) was evaluated. Patients (18–65 yr, N = 602) were randomized (1:1:1) to vortioxetine 10 or 20 mg/d or placebo for 8 wk in a double-blind multi-national study. Cognitive function was assessed with objective neuropsychological tests of executive function, processing speed, attention and learning and memory, and a subjective cognitive measure. The primary outcome measure was change from baseline to week 8 in a composite z-score comprising the Digit Symbol Substitution Test (DSST) and Rey Auditory Verbal Learning Test (RAVLT) scores. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). In the pre-defined primary efficacy analysis, both doses of vortioxetine were significantly better than placebo, with mean treatment differences vs. placebo of 0.36 (vortioxetine 10 mg, p < 0.0001) and 0.33 (vortioxetine 20 mg, p < 0.0001) on the composite cognition score. Significant improvement vs. placebo was observed for vortioxetine on most of the secondary objectives and subjective patient-reported cognitive measures. The differences to placebo in the MADRS total score at week 8 were −4.7 (10 mg: p < 0.0001) and −6.7 (20 mg: p < 0.0001). Path and subgroup analyses indicate that the beneficial effect of vortioxetine on cognition is largely a direct treatment effect. No safety concern emerged with vortioxetine. Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent MDD and these effects were largely independent of its effect on improving depressive symptoms.

The incidence of inflammatory bowel disease in Denmark 1980–2013: a nationwide cohort study

Globally, the incidence rates of inflammatory bowel disease (IBD) are increasing; however, data from high‐incidence areas are conflicting. Previous studies in Denmark have assessed incidence rates of Crohns disease (CD) and ulcerative colitis (UC) using short observation periods.

Which Cognitive Domains are Improved by Treatment with Vortioxetine

Background: These post hoc analyses evaluated vortioxetine efficacy on cognitive dysfunction in depression. Data were from a double-blind, randomized, fixed-dose, placebo-controlled, 8-week depression study in adults aged 18–65 years (n = 602) with DSM-IV–defined major depressive disorder (MDD). Subjects were randomized (1:1:1) to vortioxetine 10mg/day or 20mg/day or placebo. Methods: Cognitive function was assessed at baseline, Week 1 (10mg/day only) and Week 8 using Digit Symbol Substitution Test (DSST) number of correct symbols, Rey Auditory Verbal Learning Test, Trail Making Test, Stroop test, Simple Reaction Time, and Choice Reaction Time tests. The cognition variables were standardized and used for constructing composite Z-scores for the cognitive domains of executive function, attention/speed of processing, and memory. Results: At Week 1, vortioxetine 10mg/day separated from placebo for attention/speed of processing (standardized composite Z-score = 0.21; p = 0.0238) and DSST number of correct symbols (standardized effect size = 0.18; p = 0.0458) and for executive function (standardized composite Z-score = 0.20; p = 0.0274). At Week 8, vortioxetine 10mg/day and 20mg/day separated from placebo for executive function and attention/speed of processing, with standardized composite Z-scores ranging from 0.35 to 0.49 (all p < 0.01). Standardized composite Z-scores for memory were 0.31 (p = 0.0036, 10mg/day) and 0.22 (p = 0.0349, 20mg/day). Standardized effect sizes for DSST were 0.51 (p < 0.0001, 10mg/day) and 0.52 (p < 0.0001, 20mg/day). Results are limited by the post hoc nature of the analyses and the absence of an active reference in the original study. Conclusions: Vortioxetine (10 and 20mg/day) had a multi-domain beneficial effect on cognitive performance, as evidenced by improvements in measures of executive function, attention/speed of processing, and memory. The effect on the DSST may be due to improvements in several cognitive skills.

Inflammatory bowel diseases in Faroese-born Danish residents and their offspring: further evidence of the dominant role of environmental factors in IBD development

The incidence of inflammatory bowel disease (IBD) is record high in the Faroe Islands, and many Faroese emigrate to Denmark, where the IBD incidence is considerably lower.

Benefit-to-harm ratio of the Danish breast cancer screening programme

The primary aim of breast cancer screening is to reduce breast cancer mortality, but screening also has negative side‐effects as overdiagnosis. To evaluate a screening programme, both benefits and harms should be considered. Published estimates of the benefit‐to‐harm ratio, the number of breast cancer deaths prevented divided by the number of overdiagnosed breast cancer cases, varied considerably. The objective of the study was to estimate the benefit‐to‐harm ratio of breast cancer screening in Denmark. The numbers of breast cancer deaths prevented and overdiagnosed cases [invasive and ductal carcinoma in situ (DCIS)] were estimated per 1,000 women aged 50–79, using national published estimates for breast cancer mortality and overdiagnosis, and national incidence and mortality rates. Estimations were made for both invited and screened women. Among 1,000 women invited to screening from age 50 to age 69 and followed until age 79, we estimated that 5.4 breast cancer deaths would be prevented and 2.1 cases overdiagnosed, under the observed scenario in Denmark of a breast cancer mortality reduction of 23.4% and 2.3% of the breast cancer cases being overdiagnosed. The estimated benefit‐to‐harm ratio was 2.6 for invited women and 2.5 for screened women. Hence, 2–3 women would be prevented from dying from breast cancer for every woman overdiagnosed with invasive breast cancer or DCIS. The difference between the previous published ratios and 2.6 for Denmark is probably more a reflection of the accuracy of the underlying estimates than of the actual screening programmes. Therefore, benefit‐to‐harm ratios should be used cautiously.

OP XI – 1 Long-term exposure to road traffic noise and incidence of myocardial infarction. a danish nurse cohort study

Background/aim Exposure to road traffic noise has been linked to adverse health effects, including cardiovascular diseases (CVD), however, evidence is inconsistent. In this study we examined the association between long-term exposure to road traffic noise and incidence of myocardial infarction (MI). Methods We used the data from a nationwide Danish Nurse Cohort on 22 438 female nurses (age >44 years) who at recruitment in 1993 or 1999 reported information on CVD risk factors. We obtained data on incidence of MI from the Danish National Patient Register until end of 2014. Road traffic noise levels at the nurses’ residences between 1970 and 2014 were estimated using The Nord2000 as the annual mean of a weighted 24 hour average (Lden). We used time-varying Cox regression models to examine the association between 24-, 10-, and 1 year running mean of Lden and MI incidence, in a crude model (adjusted for age and time of cohort enrolment) and in a fully adjusted model (adjusted for age, enrolment year, physical activity, alcohol, smoking, marital status, fruit consumption and use of hormone therapy). Results Of the 22 438 women, 590 developed MI during a mean follow-up of 18.3 years. Residential road traffic noise levels ranged from 5–82.7 dB at the year of cohort baseline. We found no association between exposure to road traffic noise and MI in crude (hazard ratio; 95% confidence interval: 0.94; 0.83–1.05) or fully (0.92; 0.82–1.04) adjusted model, for each 10 dB increase in 24 year mean road traffic noise levels. Similar results were found with 10 year and 1 year exposure windows. We observed a possible trend of increased risk, although statistically non-significant, in nurses living in urban areas (1.29; 0.84–2.00), and none in those living in provincial (0.98; 0.77–1.23) or rural (0.91; 0.77–1.07) areas (p for interaction 0.38). Conclusion We found no association between long-term exposure to road traffic noise and MI in the total population of Danish nurses. We present novel finding that nurses living in urban areas may be more susceptible to the effects of exposure to road traffic noise with respect to MI.

BMI at school age and incident asthma admissions in early adulthood: a prospective study of 310,211 children

Background Excess body weight in adulthood is associated with risk for asthma admission (AA). Our aim was to investigate if this association also applies to the relation between body mass index (BMI) in childhood and AAs in early adulthood (age 20–45 years). Methods This was a prospective study of 310,211 schoolchildren (born 1930–1989) from the Copenhagen School Health Records Register. Height and weight were measured annually, and generated BMI z-scores were categorized as low (lower quartile), normal (interquartile) and high (upper quartile). Associations between BMI at ages 7–13 and AA were estimated by Cox regressions, and presented as hazard ratios (HRs) and 95% confidence intervals (CI). Main outcome was incident hospital AAs (extracted from the Danish National Patient Register) in early adulthood. Results During 4,708,607 person-years of follow-up, 1,813 incident AAs were observed. Nonlinear associations were detected between childhood BMI and AAs. The risk of AA increased for females in the highest BMI category in childhood, with the highest HR of 1.3 (95% CI 1.16–1.55) at the age of 13 years. By contrast, males in the low BMI category had a higher risk of AA in early adulthood, with the highest HR of 1.24 (95% CI 1.03–1.51) at the age of 12 years. Females with an increase in BMI between ages 7 and 13 years had an increased risk of AA compared with females with stable BMI (HR 1.28, 95% CI 1.10–1.50). Conclusion The association between childhood BMI and AA in early adulthood is non-linear. High BMI increases the risk of AA in females, whereas low BMI increases the risk in males.

Letter: determining the dominant role of environmental factors in UC development―Authors' reply

generations had not been taken into account in the data analysis, which was confirmed to be an important factor in the UC development. In the authors’ previous study on the trend of IBD prevalence in Faroe islands, they found a rapid increasement over time in UC prevalence while a modest increasement in CD prevalence, which suggests that age is also an important factor affecting UC prevalence. In this study, the data on Faroese-born Danish residents and their children were retrieved from the Danish Central Population Register between 1980-2014. There was significant difference among the ages of the first-, secondand third-generation immigrants (Table 1). The secondand third-generation immigrants involved in this study were much younger than the first-generation immigrants. The result that the UC prelavences of secondand thirdgeneration immigrants were no more than that of the native Danes maybe ascribed to more younger subjects involved in the secondand third-generations. So the conclusion lacked strong evidence. We think age-matched analysis will improve the reliability of the results.

Impact of assumptions – the example of the Welch-analysis of mammography screening effectiveness

blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis. Cancer Immunol Immunother. 2016;65:951–959. [16] Mozzillo N, Simeone E, Benedetto L, et al. Assessing a novel immuno-oncology-based combination therapy: ipilimumab plus electrochemotherapy. Oncoimmunology. 2015;4:e1008842. [17] Mir LM, Gehl J, Sersa G, et al. Standard operating procedures of the electrochemotherapy: instructions for the use of bleomycin or cisplatin administered either systemically or locally and electric pulses delivered by the Cliniporator (TM) by means of invasive or non-invasive electrodes. EJC Suppl. 2006;4:14–25. [18] Kalialis LV, Drzewiecki KT, Klyver H. Spontaneous regression of metastases from melanoma: review of the literature. Melanoma Res. 2009;19:275–282. [19] Kuriyama S, Mitoro A, Tsujinoue H, et al. Electrochemotherapy can eradicate established colorectal carcinoma and leaves a systemic protective memory in mice. Int J Oncol. 2000;16:979–985. [20] Miyazaki S, Gunji Y, Matsubara H, et al. Possible involvement of antitumor immunity in the eradication of colon 26 induced by low-voltage electrochemotherapy with bleomycin. Surg Today. 2003;33:39–44. [21] Di Gennaro P, Gerlini G, Urso C, et al. CD4þ FOXP3þ T regulatory cells decrease and CD3þCD8þ T cells recruitment in TILs from melanoma metastases after electrochemotherapy. Clin Exp Metastasis. 2016;33:787–798. [22] Daud AI, DeConti RC, Andrews S, et al. Phase I trial of interleukin12 plasmid electroporation in patients with metastatic melanoma. J Clin Oncol. 2008;26:5896–5903. [23] Teulings HE, Limpens J, Jansen SN, et al. Vitiligo-like depigmentation in patients with stage III–IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol. 2015;33:773–781. [24] Frandsen SK, Gibot L, Madi M, et al. Calcium electroporation: evidence for differential effects in normal and malignant cell lines, evaluated in a 3D spheroid model. PLoS One. 2015;10:e0144028. [25] Frandsen SK, Gissel H, Hojman P, et al. Direct therapeutic applications of calcium electroporation to effectively induce tumor necrosis. Cancer Res. 2012;72:1336–1341. [26] National Institute for Health and Care Excellence (NICE). Electrochemotherapy for metastases in the skin from tumours of non-skin origin and melanoma. [Internet]. United Kingdom: National Institute for Health and Excellence; 2013 [cited 2017 Jan 10]. Available from: https://www.nice.org.uk/guidance/ipg446