Holbæk, Denmark
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Wetterslev Jo.,Copenhagen University | Jakobsen J.C.,Copenhagen University | Jakobsen J.C.,Holbaek Hospital | Gluud C.,Copenhagen University
BMC Medical Research Methodology | Year: 2017

Background: Most meta-analyses in systematic reviews, including Cochrane ones, do not have sufficient statistical power to detect or refute even large intervention effects. This is why a meta-analysis ought to be regarded as an interim analysis on its way towards a required information size. The results of the meta-analyses should relate the total number of randomised participants to the estimated required meta-analytic information size accounting for statistical diversity. When the number of participants and the corresponding number of trials in a meta-analysis are insufficient, the use of the traditional 95% confidence interval or the 5% statistical significance threshold will lead to too many false positive conclusions (type I errors) and too many false negative conclusions (type II errors). Methods: We developed a methodology for interpreting meta-analysis results, using generally accepted, valid evidence on how to adjust thresholds for significance in randomised clinical trials when the required sample size has not been reached. Results: The Lan-DeMets trial sequential monitoring boundaries in Trial Sequential Analysis offer adjusted confidence intervals and restricted thresholds for statistical significance when the diversity-adjusted required information size and the corresponding number of required trials for the meta-analysis have not been reached. Trial Sequential Analysis provides a frequentistic approach to control both type I and type II errors. We define the required information size and the corresponding number of required trials in a meta-analysis and the diversity (D2) measure of heterogeneity. We explain the reasons for using Trial Sequential Analysis of meta-analysis when the actual information size fails to reach the required information size. We present examples drawn from traditional meta-analyses using unadjusted naïve 95% confidence intervals and 5% thresholds for statistical significance. Spurious conclusions in systematic reviews with traditional meta-analyses can be reduced using Trial Sequential Analysis. Several empirical studies have demonstrated that the Trial Sequential Analysis provides better control of type I errors and of type II errors than the traditional naïve meta-analysis. Conclusions: Trial Sequential Analysis represents analysis of meta-analytic data, with transparent assumptions, and better control of type I and type II errors than the traditional meta-analysis using naïve unadjusted confidence intervals. © 2017 The Author(s).

Risum N.,Copenhagen University | Tayal B.,University of Pittsburgh | Tayal B.,University of Aalborg | Hansen T.F.,Gentofte University Hospital | And 8 more authors.
Journal of the American College of Cardiology | Year: 2015

Background Current guidelines suggest that patients with left bundle branch block (LBBB) be treated with cardiac resynchronization therapy (CRT); however, one-third do not have a significant activation delay, which can result in nonresponse. By identifying characteristic opposing wall contraction, 2-dimensional strain echocardiography (2DSE) may detect true LBBB activation. Objectives This study sought to investigate whether the absence of a typical LBBB mechanical activation pattern by 2DSE was associated with unfavorable long-term outcome and if this is additive to electrocardiographic (ECG) morphology and duration. Methods From 2 centers, 208 CRT candidates (New York Heart Association classes II to IV, ejection fraction ≤35%, QRS duration ≥120 ms) with LBBB by ECG were prospectively included. Before CRT implantation, longitudinal strain in the apical 4-chamber view determined whether typical LBBB contraction was present. The pre-defined outcome was freedom from death, left ventricular assist device, or heart transplantation over 4 years. Results Two-thirds of patients (63%) had a typical LBBB contraction pattern. During 4 years, 48 patients (23%) reached the primary endpoint. Absence of a typical LBBB contraction was independently associated with increased risk of adverse outcome after adjustment for ischemic heart disease and QRS width (hazard ratio [HR]: 3.1; 95% CI: 1.64 to 5.88; p < 0.005). Adding pattern assessment to a risk prediction model including QRS duration and ischemic heart disease significantly improved the net reclassification index to 0.14 (p = 0.04) and improved the C-statistics (0.63 [95% CI: 0.54 to 0.72] vs. 0.71 [95% CI: 0.63 to 0.80]; p = 0.02). Use of strict LBBB ECG criteria was not independently associated with outcome in the multivariate model (HR: 1.72; 95% CI: 0.89 to 3.33; p = 0.11. Assessment of LBBB contraction pattern was superior to time-to-peak indexes of dyssynchrony (p ;lt& 0.01 for all). Conclusions Contraction pattern assessment to identify true LBBB activation provided important prognostic information in CRT candidates. © 2015 American College of Cardiology Foundation.

Jorgensen M.E.,Steno Diabetes Center | Borch-Johnsen K.,Holbaek Hospital | Stolk R.,University of Groningen | Bjerregaard P.,University of Southern Denmark
Diabetes Care | Year: 2013

OBJECTIVE A high amount of subcutaneous fat is suggested to explain the observation of lower obesity-associated metabolic risk among Inuit than among Europeans. We examined the association between measures of obesity (visceral adipose tissue [VAT], subcutaneous adipose tissue [SAT], BMI, waist circumference [WC], and percentage of body fat) and the indices of glucose metabolism (fasting and 2-h glucose levels, insulin resistance per homeostasis model assessment [HOMA-IR], and the insulin sensitivity index [ISI0,120]) among Greenland Inuit. RESEARCH DESIGN AND METHODSdA total of 3,108 adult Inuit participated in a population-based study. The examination included a 75-g oral glucose tolerance test and anthropometric measurements. VAT and SAT were measured by ultrasound according to a validated protocol. Information on sociodemographic characteristics and health behaviors was obtained by interview. RESULTSdMean SATs were 1.8 and 3.5 cm in men and women, respectively. Mean VATs were 7.0 and 6.3 cminmen and women, respectively. The total prevalence of type 2 diabetes was 9%. Percentage of body fat generally was most strongly associated with all outcomes. Both SAT and VAT were significantly associated with glucose intolerance, fasting and 2-h plasma glucose levels, HOMA-IR, and ISI0,120. VAT was more strongly associated with all outcomes than was SAT. After further adjustment for BMI orWC, VAT was associated with glucose intolerance and insulin resistance, whereas there was a trend toward a negative or no association with SAT. CONCLUSIONSdHigh mean values of SAT may to a large extent explain the high WC in Inuit populations, and this is suggested to contribute to the lower observed metabolic risk for a given level of obesity. © 2013 by the American Diabetes Association.

Humaidan P.,Skive Regional Hospital | Humaidan P.,University of Aarhus | Polyzos N.P.,Free University of Brussels | Alsbjerg B.,Skive Regional Hospital | And 5 more authors.
Human Reproduction | Year: 2013

STUDY QUESTIONDoes a GnRH agonist (GnRHa) trigger followed by a bolus of 1.500 IU hCG in a group of patients at risk of ovarian hyperstimulation syndrome (OHSS) reduce the OHSS incidence compared with hCG trigger?SUMMARY ANSWERA GnRHa trigger followed by early luteal hCG support with one bolus of 1.500 IU hCG appears to reduce OHSS in patients at risk of OHSS; however, in a low-risk group a second bolus of 1.500 IU hCG induced two cases of late onset OHSS.WHAT IS KNOWN ALREADYA GnRHa trigger is an alternative to hCG in GnRH antagonist co-treated cycles.STUDY DESIGN, SIZE, DURATIONTwo RCTs were performed in four Danish IVF units. A total of 446 patients were assessed for eligibility and 390 patients were enrolled in the study from January 2009 until December 2011. The primary outcome of the study was OHSS incidence in the group at risk of OHSS.PARTICIPANTS/MATERIALS, SETTING, METHODSPatients received a fixed dose of recombinant human FSH for the first 4 days. On the day of triggering, patients were assessed for their risk of OHSS based on the total number of follicles ≥11 mm diameter, and were classified as being at risk of OHSS when the total number of follicles ≥11 mm was between 15 and 25 and at low risk of OHSS when the total number of follicles ≥11 mm was ≤14. Two separate randomization lists were used for each of the OHSS risk groups. Women at risk of OHSS were allocated (RCT 1) to either: Group A (n = 60), ovulation triggering with a bolus of 0.5 mg buserelin (GnRHa) s.c. followed by a single bolus of 1.500 IU hCG s.c. after the oocyte retrieval - or: Group B (n = 58): 5.000 IU hCG. Similarly, women at low risk of OHSS were allocated (RCT 2) to receive either: Group C (n = 125), a bolus of 0.5 mg buserelin s.c., followed by a bolus of 1.500 IU hCG s.c. after oocyte retrieval and a second bolus of 1.500 IU hCG on the day of oocyte retrieval +5 - or: Group D (n = 141), 5.000 IU hCG. Groups C and D were included in order to obtain preliminary data.MAIN RESULTS AND THE ROLE OF CHANCEIn women at risk of OHSS (RCT 1) (15-25 follicles) no OHSS case was seen in Group A (GnRHa trigger and one bolus of 1.500 IU hCG), whereas two cases of moderate late-onset OHSS occurred in group B (3.4%), (P = 0.24). In contrast, in women at a low risk of OHSS (RCT 2) (≤14 follicles) two cases of late-onset OHSS occurred in Group C (GnRHa trigger and two boluses of 1.500 IU hCG), whereas no OHSS case was encountered in Group D (P = 0.22).LIMITATIONS, REASONS FOR CAUTIONAlthough the first RCT was powered to include 168 patients at risk of OHSS (15-25 follicles ≥11 mm) randomized to either GnRHa trigger or hCG trigger, the trial was prematurely discontinued when a total of 118 patients at risk of OHSS were randomized. In addition the second RCT in the OHSS low-risk group was designed as a feasibility study to assess the incidence of OHSS after GnRHa trigger and dual hCG administration versus 5.000 IU hCG. No power calculation was performed for this trial. In addition, there was a lack of blinding in the RCTs.WIDER IMPLICATIONS OF THE FINDINGSAlthough a non-significant result, one bolus of 1.500 IU hCG after GnRHa trigger tended to reduce the OHSS rate in patients with 15-25 follicles ≥11 mm as well as secure the ongoing pregnancy rate. In contrast, in patients at low risk of OHSS the administration of two boluses of 1.500 IU hCG after GnRHa trigger should be avoided as it may induce OHSS. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Sorensen M.V.,Aarhus University Hospital | Pedersen S.,Holbaek Hospital | Mogelvang R.,Holbaek Hospital | Skov-Jensen J.,Holbaek Hospital | And 2 more authors.
JACC: Cardiovascular Interventions | Year: 2011

Objectives: We evaluated the potential association between plasma high-mobility group box 1 (HMGB1) levels and outcome in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention. Background: The positive effect of reperfusion after STEMI may be compromised by ischemic/reperfusion injury. HMGB1 is released by necrotic cells and, in pre-clinical studies, has been implicated to play a role in myocardial ischemic/reperfusion injury. Methods: The study included 141 STEMI patients, with acute occlusion of the left anterior descending coronary artery successfully treated with percutaneous coronary intervention. Plasma HMGB1 levels were measured by enzyme-linked immunoadsorbent assay at admission. Forty-two healthy individuals served as control subjects. Results: After a median of 10 months of follow-up, 13 STEMI patients died. There were no significant differences with regard to baseline variables between the group of patients who survived and those who died. Baseline HMGB1 levels were increased in STEMI patients when compared with control subjects. Furthermore, the STEMI patients who died had higher HMGB1 levels than those who survived. After adjusting for age, sex, troponin I, and creatine kinase-myocardial band, we found that a doubling of HMGB1 concentrations increased the risk of mortality by 75% (hazard ratio: 1.75; 95% confidence interval: 1.1 to 2.8). Conclusions: Plasma HMGB1 levels are elevated in STEMI patients compared with healthy control subjects. Furthermore, after a follow-up period of 10 months, plasma HMGB1 levels are shown to be independently associated with increased mortality in STEMI patients treated with PCI. These data suggest that plasma HMGB1 may be used as a new prognostic biomarker in STEMI patients. © 2011 American College of Cardiology Foundation.

Tvede M.,Copenhagen University | Tinggaard M.,Holbaek Hospital | Helms M.,Copenhagen University
Clinical Microbiology and Infection | Year: 2015

Clostridium difficile infection is one of the most common nosocomial infections. Among other alternatives to standard treatment with vancomycin for recurrent infection are faecal microbiota transplantation and rectal bacteriotherapy with a fixed mixture of intestinal bacterial strains isolated from faeces of healthy persons to mimic a theoretical normal microflora. Developed by Dr. Tvede and Dr. Rask-Madsen, the latter method has been in use for selected patients during the last 25 years in Denmark. In this study we reviewed the medical records of patients treated with rectal bacteriotherapy for relapsing C. difficile in Denmark, 2000-2012. The primary end point was recurrent diarrhoea within 30 days after treatment. A total of 55 patients were included in this case series. Thirty-five patients (64%) had no recurrence within 30 days of bacteriotherapy. Patients with recurrence tended to be older (75.8 years vs. 61.3 years; p 0.26), and more often have preexisting gastrointestinal illness and longer duration of time from the first CDI to bacteriotherapy (221.6 days vs. 175.3 days; p 0.18). Treatment success was 80% in the subgroup of patients with no known gastrointestinal illness and first C. difficile episode less than 6 months before bacteriotherapy. The most common adverse events were abdominal pain (10.9%) and worsening diarrhoea (4.3%). One patient was hospitalized 10 days after treatment with appendicitis, fever, and Escherichia coli bacteremia. The results from this study indicate that rectal bacteriotherapy is a viable alternative to faecal microbiota transplantation in patients with relapsing C. difficile-associated diarrhoea. © 2014 European Society of Clinical Microbiology and Infectious Diseases.

Jakobsen J.C.,Copenhagen University | Jakobsen J.C.,Holbaek Hospital | Gluud C.,Copenhagen University | Winkel P.,Copenhagen University | And 2 more authors.
BMC Medical Research Methodology | Year: 2014

Background: Thresholds for statistical significance are insufficiently demonstrated by 95% confidence intervals or P-values when assessing results from randomised clinical trials. First, a P-value only shows the probability of getting a result assuming that the null hypothesis is true and does not reflect the probability of getting a result assuming an alternative hypothesis to the null hypothesis is true. Second, a confidence interval or a P-value showing significance may be caused by multiplicity. Third, statistical significance does not necessarily result in clinical significance. Therefore, assessment of intervention effects in randomised clinical trials deserves more rigour in order to become more valid. Methods. Several methodologies for assessing the statistical and clinical significance of intervention effects in randomised clinical trials were considered. Balancing simplicity and comprehensiveness, a simple five-step procedure was developed. Results: For a more valid assessment of results from a randomised clinical trial we propose the following five-steps: (1) report the confidence intervals and the exact P-values; (2) report Bayes factor for the primary outcome, being the ratio of the probability that a given trial result is compatible with a 'null' effect (corresponding to the P-value) divided by the probability that the trial result is compatible with the intervention effect hypothesised in the sample size calculation; (3) adjust the confidence intervals and the statistical significance threshold if the trial is stopped early or if interim analyses have been conducted; (4) adjust the confidence intervals and the P-values for multiplicity due to number of outcome comparisons; and (5) assess clinical significance of the trial results. Conclusions: If the proposed five-step procedure is followed, this may increase the validity of assessments of intervention effects in randomised clinical trials. © 2014 Jakobsen et al.; licensee BioMed Central Ltd.

Humaidan P.,Skive Regional Hospital | Ejdrup Bredkjaer H.,Holbaek Hospital | Westergaard L.G.,University of Southern Denmark | Yding Andersen C.,Copenhagen University
Fertility and Sterility | Year: 2010

Objective: To prospectively assess the reproductive outcome with a small bolus of hCG administered on the day of oocyte retrieval after ovulation induction with a GnRH agonist (GnRHa). Design: Prospective, randomized trial. Setting: Three hospital-based IVF clinics. Patient(s): Three hundred five IVF/intracytoplasmic sperm injection patients after a GnRH antagonist protocol. Intervention(s): Ovulation induction was performed with either 10,000 IU hCG or 0.5 mg GnRHa (buserelin) supplemented with 1,500 IU hCG on the day of oocyte retrieval. Main Outcome Measure(s): Reproductive outcome in the two groups. Result(s): No significant differences were seen regarding positive hCG/ET rate (48% and 48%), ongoing pregnancy rate (26% and 33%), delivery rate (24% and 31%), and rate of early pregnancy loss (21% and 17%) between the GnRHa and 10,000 IU hCG groups, respectively. Conclusion(s): A small bolus of hCG in the GnRHa group secured the luteal phase, resulting in a comparable reproductive outcome in the two groups. However, a nonsignificant difference of 7% in delivery rates justifies further studies to refine the use of GnRHa for ovulation induction. © 2010 American Society for Reproductive Medicine.

Trollegaard A.M.,Holbaek Hospital | Aarby N.S.,Holbaek Hospital | Hellberg S.,Holbaek Hospital
Journal of Bone and Joint Surgery - Series B | Year: 2010

Between 1993 and 2008, 41 patients underwent total coccygectomy for coccydynia which had failed to respond to six months of conservative management. Of these, 40 patients were available for clinical review and 39 completed a questionnaire giving their evaluation of the effect of the operation. Excellent or good results were obtained in 33 of the 41 patients, comprising 18 of the 21 patients with coccydynia due to trauma, five of the eight patients with symptoms following childbirth and ten of 12 idiopathic onset. In eight patients the results were moderate or poor, although none described worse pain after the operation. The only post-operative complication was superficial wound infection which occurred in five patients and which settled fully with antibiotic treatment. One patient required re-operation for excision of the distal cornua of the sacrum. Total coccygectomy offered satisfactory relief of pain in the majority of patients regardless of the cause of their symptoms. ©2010 British Editorial Society of Bone and Joint Surgery.

Sehested L.T.,Holbaek Hospital | Pedersen P.,Holbaek Hospital
Danish Medical Journal | Year: 2014

Introduction: Intrauterine growth retardation (IUGR) is the term describing a foetus that has not reached its genetic growth potential. There is no international consensus on the definition of IUGR. The aim of this study was to describe a cohort of weight-restricted neonates and their mothers focusing on risk factors, catch up and neonatal outcome. MATERIAL AND METHODS: This was a retrospective descript ive study of IUGR neonates with a birth weight below 70% of the expected whose mothers were admitted to the Neonatal Ward at Hvidovre Hospital during 2007-2009. Obstetrical and maternal risk factors and neonatal growth and outcome at six weeks, five months and 12 months of age were collected. RESULTS: A total of 73 neonates and their mothers were included. Caesarean delivery was given in 78% of the cases. Maternal risk factors included gestational hypertension (33%), smoking (24%) and placental infarction (17%). Hypo-glycaemic episodes developed in 31% of the neonates. At 12 months, 90% had caught up growth and 7% had a neuro-logically poor outcome. No infants died. CONCLUSION: Maternal smoking and gestational hypertension are important risk factors for the development of IUGR. Special attention must be given to reducing the risk of hy-poglycaemia. More studies are needed. Our purpose was to underline the need for a consensus on the definition of IUGR, catch-up and follow-up programmes in order to compare results in the future.

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