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Navaratnam K.,University of Liverpool | Alfirevic Z.,University of Liverpool | Baker P.N.,Keele University | Gluud C.,Copenhagen Trial Unit | And 4 more authors.
BMC Pregnancy and Childbirth | Year: 2013

Background: 5% of first time pregnancies are complicated by pre-eclampsia, the leading cause of maternal death in Europe. No clinically useful screening test exists; consequentially clinicians are unable to offer targeted surveillance or preventative strategies. IMPROvED Consortium members have pioneered a personalised medicine approach to identifying blood-borne biomarkers through recent technological advancements, involving mapping of the blood metabolome and proteome. The key objective is to develop a sensitive, specific, high-throughput and economically viable early pregnancy screening test for pre-eclampsia.Methods/Design: We report the design of a multicentre, phase IIa clinical study aiming to recruit 5000 low risk primiparous women to assess and refine innovative prototype tests based on emerging metabolomic and proteomic technologies. Participation involves maternal phlebotomy at 15 and 20 weeks' gestation, with optional testing and biobanking at 11 and 34 weeks. Blood samples will be analysed using two innovative, proprietary prototype platforms; one metabolomic based and one proteomic based, both of which outperform current biomarker based screening tests at comparable gestations. Analytical and clinical data will be collated and analysed via the Copenhagen Trials Unit.Discussion: The IMPROvED study is expected to refine proteomic and metabolomic panels, combined with clinical parameters, and evaluate clinical applicability as an early pregnancy predictive test for pre-eclampsia. If 'at risk' patients can be identified, this will allow stratified care with personalised fetal and maternal surveillance, early diagnosis, timely intervention, and significant health economic savings. The IMPROvED biobank will be accessible to the European scientific community for high quality research into the cause and prevention of adverse pregnancy outcome.Trial registration: Trial registration number NCT01891240. The IMPROvED project is funded by the seventh framework programme for Research and Technological development of the EU. http://www.fp7-improved.eu/. © 2013 Navaratnam et al.; licensee BioMed Central Ltd.


Hansen M.S.,Rigshospitalet | Wetterslev J.,Copenhagen Trial Unit | Pipper C.B.,Copenhagen University | Ostervig R.,Rigshospitalet | And 2 more authors.
PLoS ONE | Year: 2016

Introduction: Clinical pain models can be applied when investigating basic physiologic pain responses in healthy volunteers. Several pain models exist; however, only few have been adequately validated. Our primary aim with this prospective study was to investigate the intra- and interindividual variation in secondary hyperalgesia elicited by brief thermal sensitization (45°C for 3 min) in healthy volunteers. Material and Methods: Fifty healthy volunteers were included. Areas of secondary hyperalgesia following brief thermal sensitization were investigated by 2 observers on 4 experimental days, with a minimum interval of 7 days. Additionally, heat pain detection threshold and pain during thermal stimulation (45°C for 1 min.), and the psychological tests Pain Catastrophizing Scale and Hospital Anxiety and Depression Score were applied. Results: For areas of secondary hyperalgesia, an intra-observer intra-person correlation of 0.85, 95% CI [0.78, 0.90], an intra-observer inter-person correlation of 0.03, 95% CI [0.00, 0.16], and a coefficient of variation of 0.17, 95% CI [0.14, 0.21] was demonstrated. Four percent of the study population had areas of secondary hyperalgesia both below the 1st and above the 3rd quartile considering all included participants. Heat pain detection threshold predicted area of secondary hyperalgesia with an adjusted R2 of 0.20 (P = 0.0006). Conclusions: We have demonstrated a low intra-individual, and a high inter-individual variation in thermally induced secondary hyperalgesia. We conclude that brief thermal sensitization produce secondary hyperalgesia with a high level of reproducibility, which can be applied to investigate different phenotypes related to secondary hyperalgesia in healthy volunteers. Trial Registration: clinicaltrials.gov NCT02166164. © 2016 Hansen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Wikkelsoe A.J.,Copenhagen University | Afshari A.,Review Centre | Wetterslev J.,Copenhagen Trial Unit | Brok J.,Hvidovre Hospital | And 2 more authors.
Acta Anaesthesiologica Scandinavica | Year: 2011

Background Thrombelastography (TEG) and Thrombelastometry (ROTEM) are viscoelastic whole-blood assays evaluating the haemostatic capacity of blood. These devices are used in algorithms to guide transfusion of haemostatic blood components. Methods The methods used for this study were systematic reviews with meta-analyses and trial sequential analyses of randomised clinical trials (RCTs) of TEG/ROTEM-based algorithm compared with standard treatment in patients with bleeding. Primary outcome was all-cause mortality. We searched the literature in seven databases (up to 31 October 2010), reference lists, registers of ongoing trials, and contacted authors and experts. We extracted data from included studies related to study methods, interventions, outcomes, bias risk and adverse events using Cochrane methodology. All trials irrespective of blinding or language status were included. Results Nine trials involving 776 participants were included. Eight trials involved cardiac surgery with an average blood loss of 390-960ml, and one trial investigated liver transplantations. One trial was classified as low-risk-of-bias trial. We found two ongoing trials. No impact was identified on mortality, amount of blood transfused, incidence of surgical reinterventions, time to extubation, or length of stay in hospital and intensive care unit. We identified a significant reduction in blood loss favouring the use of TEG/ROTEM {85ml [95% confidence interval (CI) 29.4-140.7]} and in the proportion of patients receiving freshly frozen plasma and platelets [relative risk 0.39 (95%CI 0.27-0.57)]. Conclusion There is currently weak evidence to support the use of TEG/ROTEM as a tool to guide transfusion in patients with severe bleeding. Further studies need to address other clinical settings and with larger blood losses. © 2011 The Acta Anaesthesiologica Scandinavica Foundation.


PubMed | Rigshospitalet, Copenhagen Trial Unit, Copenhagen University and Bispebjerg and Frederiksberg Hospitals
Type: Journal Article | Journal: PloS one | Year: 2016

Clinical pain models can be applied when investigating basic physiologic pain responses in healthy volunteers. Several pain models exist; however, only few have been adequately validated. Our primary aim with this prospective study was to investigate the intra- and inter-individual variation in secondary hyperalgesia elicited by brief thermal sensitization (45C for 3 min) in healthy volunteers.Fifty healthy volunteers were included. Areas of secondary hyperalgesia following brief thermal sensitization were investigated by 2 observers on 4 experimental days, with a minimum interval of 7 days. Additionally, heat pain detection threshold and pain during thermal stimulation (45C for 1 min.), and the psychological tests Pain Catastrophizing Scale and Hospital Anxiety and Depression Score were applied.For areas of secondary hyperalgesia, an intra-observer intra-person correlation of 0.85, 95% CI [0.78, 0.90], an intra-observer inter-person correlation of 0.03, 95% CI [0.00, 0.16], and a coefficient of variation of 0.17, 95% CI [0.14, 0.21] was demonstrated. Four percent of the study population had areas of secondary hyperalgesia both below the 1st and above the 3rd quartile considering all included participants. Heat pain detection threshold predicted area of secondary hyperalgesia with an adjusted R2 of 0.20 (P = 0.0006).We have demonstrated a low intra-individual, and a high inter-individual variation in thermally induced secondary hyperalgesia. We conclude that brief thermal sensitization produce secondary hyperalgesia with a high level of reproducibility, which can be applied to investigate different phenotypes related to secondary hyperalgesia in healthy volunteers.clinicaltrials.gov NCT02166164.


Hansen M.S.,Rigshospitalet | Petersen E.E.,Copenhagen Trial Unit | Dahl J.B.,Bispebjerg Hospital | Wetterslev J.,Copenhagen Trial Unit
Acta Anaesthesiologica Scandinavica | Year: 2016

Background: The number of surgical procedures is increasing, and knowledge of surgical risk factors, post-operative mortality and serious adverse events (SAE) is essential. The aim with our study was to determine the risk of a composite outcome of post-operative: death; myocardial infarction; pulmonary embolism; stroke; gastrointestinal bleeding; dialysis or reoperation. Methods: Data of surgical procedures in the period from January 1, 2012 to June 30, 2012 were retrieved from the Danish Anaesthesia Database (DAD). Follow-up of all patients undergoing hip or knee replacement, abdominal or gynaecological surgery was conducted retrieving data from The Danish Civil Registration System and the National Patient Register. Total observation time was from January 1, 2012 to June 6, 2013. Results: A total7449 adult patients were included in the final analysis. The risk of the composite outcome during a follow-up until 342 days after inclusion of the last patient was estimated to 8.3%, 95% Confidence Intervals (CI) (7.8–9.0), with a median observation time of 437 days (IQR 387–485, range 0–522). The risk of the composite outcome within 90- and 180-day follow-up of each patient was 4.8% (4.4–5.3) and 5.9% (5.4–6.5), respectively. Mortality within longest follow-up as well as 90 and 180 days post-operatively was 3.6% (3.1–4.0), 1.7% (1.4–2.0), and 2.2% (1.9–2.6), respectively. Conclusion: We found a risk of one or more events in the composite outcome within 342 days after inclusion of the last patients of 8.3% (7.8–9.0). The results are applicable in estimations of adequate sample sizes in future clinical trials investigating effects of interventions on SAEs. © 2016 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd


PubMed | Rigshospitalet, Copenhagen Trial Unit and Bispebjerg Hospital
Type: Journal Article | Journal: Acta anaesthesiologica Scandinavica | Year: 2016

The number of surgical procedures is increasing, and knowledge of surgical risk factors, post-operative mortality and serious adverse events (SAE) is essential. The aim with our study was to determine the risk of a composite outcome of post-operative: death; myocardial infarction; pulmonary embolism; stroke; gastrointestinal bleeding; dialysis or reoperation.Data of surgical procedures in the period from January 1, 2012 to June 30, 2012 were retrieved from the Danish Anaesthesia Database (DAD). Follow-up of all patients undergoing hip or knee replacement, abdominal or gynaecological surgery was conducted retrieving data from The Danish Civil Registration System and the National Patient Register. Total observation time was from January 1, 2012 to June 6, 2013.A total7449 adult patients were included in the final analysis. The risk of the composite outcome during a follow-up until 342days after inclusion of the last patient was estimated to 8.3%, 95% Confidence Intervals (CI) (7.8-9.0), with a median observation time of 437days (IQR 387-485, range 0-522). The risk of the composite outcome within 90- and 180-day follow-up of each patient was 4.8% (4.4-5.3) and 5.9% (5.4-6.5), respectively. Mortality within longest follow-up as well as 90 and 180days post-operatively was 3.6% (3.1-4.0), 1.7% (1.4-2.0), and 2.2% (1.9-2.6), respectively.We found a risk of one or more events in the composite outcome within 342days after inclusion of the last patients of 8.3% (7.8-9.0). The results are applicable in estimations of adequate sample sizes in future clinical trials investigating effects of interventions on SAEs.


Dahl R.M.,Copenhagen University | Wetterslev J.,Copenhagen Trial Unit | Jorgensen L.N.,Copenhagen University | Rasmussen L.S.,Copenhagen University | And 2 more authors.
Acta Anaesthesiologica Scandinavica | Year: 2014

Background A number of perioperative risk factors may suppress the immune system and contribute to the development of post-operative complications. The association between surgical site infection (SSI) and other wound-related complications resulting from immunosuppression through either perioperative administration of dexamethasone, pre-operative smoking or alcohol abuse is, however, uncertain. Methods This study was a post hoc analysis of data from the PROXI randomized trial in 1386 patients who underwent emergency or elective laparotomy. We assessed the associations of use of dexamethasone, smoking status and alcohol abuse with the primary outcome, being a composite of SSI, anastomotic leak, wound dehiscence, burst abdomen and 30-day mortality. Results The primary outcome occurred in 21% of patients receiving dexamethasone versus 28% of patients not receiving dexamethasone, and this was not statistically significant when adjusting for stratification variables originally used in the PROXI trial [OR 0.90, 95% CI (0.65-1.24)]. In smokers, the primary outcome occurred in 32%, compared with 23% of non-smokers (P = 0.0001). Smokers also had a higher frequency of SSI (25% vs 17%, P < 0.0001) and burst abdomen (3.8% vs 2.4%, P = 0.04). In alcohol abusers, the primary outcome occurred in 48%, compared with 25% in patients who did not abuse alcohol (P = 0.0006). Burst abdomen occurred more commonly in alcohol abusers (15% vs 2.3%, P < 0.0001). Conclusion Perioperative administration of dexamethasone was not significantly associated with SSI or other wound-related complications. Conversely, smoking and alcohol abuse were both significant predictors of the primary outcome consisting of wound-related complications and mortality. © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.


Hogdal N.,Copenhagen University | Juhl C.,University of Southern Denmark | Juhl C.,Copenhagen University | Aadahl M.,Research Center for Prevention and Health | Gluud C.,Copenhagen Trial Unit
Acta Oncologica | Year: 2015

Purpose. In head and neck cancer patients undergoing curative radiotherapy, we investigated the benefits and harms of an early exercise regime on trismus. Material and methods. Patients with head and neck cancer undergoing radiotherapy were centrally randomised to exercises 5-6 times for 45 minutes during and after radiotherapy supervised by a physiotherapist in addition to usual care versus usual care alone. The primary outcome was change in maximal interincisor distance (MID) measured at 5 and 12 months. Secondary outcomes were change in cervical ranges of motion, tissue tightness, and health-related quality of life. Mixed model analysis of repeated measures adjusted for tumour size and operation was conducted to assess the effect of early preventive exercises across time periods. Results. Of the 100 patients included, two patients withdrew and one died before the onset of radiotherapy. The unadjusted mean difference in MID at 12 months after having completed radiotherapy was 0.83 mm (95% confidence interval (CI) -3.64-5.29, p = 0.71) in the exercise intervention group compared with the control group. When adjusted for operation and tumour size, the effect of the exercise intervention on mean MID from baseline to 12-month follow-up was 5.92 mm (95% CI -0.48-12.33, p = 0.07). Of the secondary outcomes, cervical rotation showed a statistically significant deterioration in the exercise group compared with the control group (p = 0.01). No significant effects were observed on the other secondary outcomes. Conclusions. In patients with cancer in the oral cavity or oropharynx, early supervised exercises combined with self-care treatment focusing on mobility exercises to reduce trismus do not seem to provide additional beneficial effects compared with usual care during curative radiotherapy. © 2015 Informa Healthcare.


PubMed | Copenhagen Trial Unit and Copenhagen University
Type: Journal Article | Journal: Acta anaesthesiologica Scandinavica | Year: 2016

Using a restrictive transfusion strategy appears to be safe in sepsis, but there may be subgroups of patients who benefit from transfusion at a higher haemoglobin level. We explored if subgroups of patients with septic shock and anaemia had better outcome when transfused at a higher vs. a lower haemoglobin threshold.In post-hoc analyses of the full trial population of 998 patients from the Transfusion Requirements in Septic Shock (TRISS) trial, we investigated the intervention effect on 90-day mortality in patients with severe comorbidity (chronic lung disease, haematological malignancy or metastatic cancer), in patients who had undergone surgery (elective or acute) and in patients with septic shock as defined by the new consensus definition: lactate above 2 mmol/l and the need for vasopressors to maintain a mean arterial pressure above 65 mmHg.The baseline characteristics were mostly similar between the two intervention groups in the different subgroups. There were no differences in the intervention effect on 90-day mortality in patients with chronic lung disease (test of interaction P = 0.31), haematological malignancy (P = 0.47), metastatic cancer (P = 0.51), in those who had undergone surgery (P = 0.99) or in patients with septic shock by the new definition (P = 0.20).In exploratory analyses of a randomized trial in patients with septic shock and anaemia, we observed no survival benefit in any subgroups of transfusion at a haemoglobin threshold of 90 g/l vs. 70 g/l.


Bjelakovic G.,Cochrane Hepato Biliary Group | Nikolova D.,Cochrane Hepato Biliary Group | Gluud C.,Cochrane Hepato Biliary Group | Gluud C.,Copenhagen Trial Unit
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2014

PURPOSE OF REVIEW: Oxidative damage to cells and tissues is considered involved in the aging process and in the development of chronic diseases in humans, including cancer and cardiovascular diseases, the leading causes of death in high-income countries. This has stimulated interest in the preventive potential of antioxidant supplements. Today, more than one half of adults in high-income countries ingest antioxidant supplements hoping to improve their health, oppose unhealthy behaviors, and counteract the ravages of aging. RECENT FINDINGS: Older observational studies and some randomized clinical trials with high risks of systematic errors ('bias') have suggested that antioxidant supplements may improve health and prolong life. A number of randomized clinical trials with adequate methodologies observed neutral or negative results of antioxidant supplements. Recently completed large randomized clinical trials with low risks of bias and systematic reviews of randomized clinical trials taking systematic errors ('bias') and risks of random errors ('play of chance') into account have shown that antioxidant supplements do not seem to prevent cancer, cardiovascular diseases, or death. Even more, beta-carotene, vitamin A, and vitamin E may increase mortality. Some recent large observational studies now support these findings. According to recent dietary guidelines, there is no evidence to support the use of antioxidant supplements in the primary prevention of chronic diseases or mortality. SUMMARY: Antioxidant supplements do not possess preventive effects and may be harmful with unwanted consequences to our health, especially in well-nourished populations. The optimal source of antioxidants seems to come from our diet, not from antioxidant supplements in pills or tablets. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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