Christian Gluud

Hepatic effects of dietary weight loss in morbidly obese subjects

This prospective study was carried out in order to evaluate the influence on liver morphology and function of a very-low-calorie formula diet. Fourty-one morbidly obese, non-alcoholic subjects had liver biopsy performed before and after a median weight loss of 34 kg. Fatty change improved (p less than 0.001), but 24% of the patients developed slight portal inflammation (p = 0.039) or slight portal fibrosis (p = 0.063). Patients developing portal fibrosis had a higher degree of fatty change at entry (p = 0.029), a more pronounced reduction of fatty change (p = 0.014) and a faster weight loss (p = 0.026). Liver biochemistry, which was of no individual diagnostic value, improved. It is concluded that morbidly obese subjects with a high degree of hepatic fatty change are at risk of developing portal inflammation and fibrosis when undergoing very fast dietary weight reductions.

Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324 168 participants from randomised trials

BACKGROUND The risk of cancer from antihypertensive drugs has been much debated, with a recent analysis showing increased risk with angiotensin-receptor blockers (ARBs). We assessed the association between antihypertensive drugs and cancer risk in a comprehensive analysis of data from randomised clinical trials. METHODS We undertook traditional direct comparison meta-analyses, multiple comparisons (network) meta-analyses, and trial sequential analyses. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from 1950, to August, 2010, for randomised clinical trials of antihypertensive therapy (ARBs, angiotensin-converting-enzyme inhibitors [ACEi], β blockers, calcium-channel blockers [CCBs], or diuretics) with follow-up of at least 1 year. Our primary outcomes were cancer and cancer-related deaths. FINDINGS We identified 70 randomised controlled trials (148 comparator groups) with 324,168 participants. In the network meta-analysis (fixed-effect model), we recorded no difference in the risk of cancer with ARBs (proportion with cancer 2·04%; odds ratio 1·01, 95% CI 0·93-1·09), ACEi (2·03%; 1·00, 0·92-1·09), β blockers (1·97%; 0·97, 0·88-1·07), CCBs (2·11%; 1·05, 0·96-1·13), diuretics (2·02%; 1·00, 0·90-1·11), or other controls (1·95%, 0·97, 0·74-1·24) versus placebo (2·02%). There was an increased risk with the combination of ACEi plus ARBs (2·30%, 1·14, 1·02-1·28); however, this risk was not apparent in the random-effects model (odds ratio 1·15, 95% CI 0·92-1·38). No differences were detected in cancer-related mortality for ARBs (death rate 1·33%; odds ratio 1·00, 95% CI 0·87-1·15), ACEi (1·25%; 0·95, 0·81-1·10), β blockers (1·23%; 0·93, 0·80-1·08), CCBs (1·27%; 0·96, 0·82-1·11), diuretics (1·30%; 0·98, 0·84-1·13), other controls (1·43%; 1·08, 0·78-1·46), and ACEi plus ARBs (1·45%; 1·10, 0·90-1·32). In direct comparison meta-analyses, similar results were recorded for all antihypertensive classes, except for an increased risk of cancer with ACEi and ARB combination (OR 1·14, 95% CI 1·04-1·24; p=0·004) and with CCBs (1·06, 1·01-1·12; p=0·02). However, we noted no significant differences in cancer-related mortality. On the basis of trial sequential analysis, our results suggest no evidence of even a 5-10% relative risk (RR) increase of cancer and cancer-related deaths with any individual class of antihypertensive drugs studied. However, for the ACEi and ARB combination, the cumulative Z curve crossed the trial sequential monitoring boundary, suggesting firm evidence for at least a 10% RR increase in cancer risk. INTERPRETATION Our analysis refutes a 5·0-10·0% relative increase in the risk of cancer or cancer-related death with the use of ARBs, ACEi, β blockers, diuretics, and CCBs. However, increased risk of cancer with the combination of ACEi and ARBs cannot be ruled out.

Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial

BACKGROUND Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma. METHODS This double-blind, randomised, phase 3 trial was undertaken at 37 clinics in Denmark, Norway, and Sweden. Patients with multiple myeloma who were starting antimyeloma treatment were randomly assigned in a 1:1 ratio to receive one of two doses of pamidronate (30 mg or 90 mg) given by intravenous infusion once a month for at least 3 years. Randomisation was done by use of a central, computerised minimisation system. Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (scale 0-100). All patients who returned questionnaires at 12 months and were still on study treatment were included in the analysis of the primary endpoint. This study is registered with ClinicalTrials.gov, number NCT00376883. FINDINGS From January, 2001, until August, 2005, 504 patients were randomly assigned to pamidronate 30 mg or 90 mg (252 in each group). 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis. Mean physical function at 12 months was 66 points (95% CI 62·9-70·0) in the 90 mg group and 68 points (64·6-71·4) in the 30 mg group (95% CI of difference -6·6 to 3·3; p=0·52). Median time to first skeletal-related event in patients who had such an event was 9·2 months (8·1-10·7) in the 90 mg group and 10·2 months (7·3-14·0) in the 30 mg group (p=0·63). In a retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group. INTERPRETATION Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma. FUNDING Nordic Cancer Union and Novartis Healthcare.

Robustness assessments are needed to reduce bias in meta-analyses that include zero-event randomized trials.

OBJECTIVES:Meta-analysis of randomized trials with binary data can use a variety of statistical methods. Zero-event trials may create analytic problems. We explored how different methods may impact inferences from meta-analyses containing zero-event trials.METHODS:Five levels of statistical methods are identified for meta-analysis with zero-event trials, leading to numerous data analyses. We used the binary outcomes from our Cochrane review of randomized trials of laparoscopic vs. small-incision cholecystectomy for patients with symptomatic cholecystolithiasis to illustrate the influence of statistical method on inference.RESULTS:In seven meta-analyses of seven outcomes from 15 trials, there were zero-event trials in 0 to 71.4% of the trials. We found inconsistency in significance in one of seven outcomes (14%; 95% confidence limit 0.4%–57.9%). There was also considerable variability in the confidence limits, the intervention-effect estimates, and heterogeneity for all outcomes.CONCLUSIONS:The statistical method may influence the inference drawn from a meta-analysis that includes zero-event trials. Robustness assessments are needed to reduce bias in meta-analyses that include zero-event trials.

Prevalence of hepatobiliary dysfunction in a regional group of patients with chronic inflammatory bowel disease.

A regional group of outpatients with chronic inflammatory bowel disease (ulcerative colitis, n = 396, and Crohns disease, n = 125) was biochemically screened to estimate the prevalence of hepatobiliary dysfunction. Among the 396 patients with ulcerative colitis, 69 (17%; 95% confidence limits, 14-22%) had at least 1 abnormal laboratory value. Serum bilirubin was elevated in 5%, alkaline phosphatases in 8%, aspartate aminotransferases in 4%, and alanine aminotransferases in 8% of the patients. Two per cent had decreased plasma coagulation factors (2.7 and 10) and serum albumin. Further diagnositc evaluation consisting of ultrasonography, liver biopsy, and endoscopic retrograde cholangiography was performed in patients who had biochemical values more than twice the upper normal limit in two consecutive blood tests within a fortnight. Six patients (1%) fulfilled this criterion. Three patients had primary sclerosing cholangitis, of whom two were primarily diagnosed; one patient had cholangiocarcinoma also primarily diagnosed; and two patients were found to have alcoholic hepatic damage. Among the 125 patients with Crohns disease, 38 (30%; 95% confidence limits, 23-38%) had at least 1 abnormal laboratory value. Serum bilirubin was elevated in 2%, alkaline phosphatases in 18%, asparetate aminotransferases in 3%, and alanine aminotransferases in 10% of the patients. One per cent had decreased plasma coagulation factors (2.7 and 10) and serum albumin concentrations. Three patients (2%) fulfilled the criteria for further evaluation as described above. One patient appeared to have epithelioid granuloma in the liver and one patient had alcoholic liver disease, whereas one patient refused further examination.(ABSTRACT TRUNCATED AT 250 WORDS)

The SafeBoosC Phase II Randomised Clinical Trial: A Treatment Guideline for Targeted Near-Infrared-Derived Cerebral Tissue Oxygenation versus Standard Treatment in Extremely Preterm Infants

Near-infrared spectroscopy-derived regional tissue oxygen saturation of haemoglobin (rStO2) reflects venous oxygen saturation. If cerebral metabolism is stable, rStO2 can be used as an estimate of cerebral oxygen delivery. The SafeBoosC phase II randomised clinical trial hypothesises that the burden of hypo- and hyperoxia can be reduced by the combined use of close monitoring of the cerebral rStO2 and a treatment guideline to correct deviations in rStO2 outside a predefined target range. Aims: To describe the rationale for and content of this treatment guideline. Methods: Review of the literature and assessment of the quality of evidence and the grade of recommendation for each of the interventions. Results and Conclusions: A clinical intervention algorithm based on the main determinants of cerebral perfusion-oxygenation changes during the first hours after birth was generated. The treatment guideline is presented to assist neonatologists in making decisions in relation to cerebral oximetry readings in preterm infants within the SafeBoosC phase II randomised clinical trial. The evidence grades were relatively low and the guideline cannot be recommended outside a research setting.

The SafeBoosC II randomized trial : Treatment guided by near-infrared spectroscopy reduces cerebral hypoxia without changing early biomarkers of brain injury

Background:The SafeBoosC phase II multicentre randomized clinical trial investigated the benefits and harms of monitoring cerebral oxygenation by near-infrared spectroscopy (NIRS) combined with an evidence-based treatment guideline vs. no NIRS data and treatment as usual in the control group during the first 72 h of life. The trial demonstrated a significant reduction in the burden of cerebral hypoxia in the experimental group. We now report the blindly assessed and analyzed treatment effects on electroencephalographic (EEG) outcomes (burst rate and spectral edge frequency 95% (SEF95)) and blood biomarkers of brain injury (S100β, brain fatty acid-binding protein, and neuroketal).Methods:One hundred and sixty-six extremely preterm infants were randomized to either experimental or control group. EEG was recorded at 64 h of age and blood samples were collected at 6 and 64 h of age.Results:One hundred and thirty-three EEGs were evaluated. The two groups did not differ regarding burst rates (experimental 7.2 vs. control 7.7 burst/min) or SEF95 (experimental 18.1 vs. control 18.0 Hz). The two groups did not differ regarding blood S100β, brain fatty acid-binding protein, and neuroketal concentrations at 6 and 64 h (n = 123 participants).Conclusion:Treatment guided by NIRS reduced the cerebral burden of hypoxia without affecting EEG or the selected blood biomarkers.

Simulation-based multiprofessional obstetric anaesthesia training conducted in situ versus off-site leads to similar individual and team outcomes: a randomised educational trial

Objective To investigate the effect of in situ simulation (ISS) versus off-site simulation (OSS) on knowledge, patient safety attitude, stress, motivation, perceptions of simulation, team performance and organisational impact. Design Investigator-initiated single-centre randomised superiority educational trial. Setting Obstetrics and anaesthesiology departments, Rigshospitalet, University of Copenhagen, Denmark. Participants 100 participants in teams of 10, comprising midwives, specialised midwives, auxiliary nurses, nurse anaesthetists, operating theatre nurses, and consultant doctors and trainees in obstetrics and anaesthesiology. Interventions Two multiprofessional simulations (clinical management of an emergency caesarean section and a postpartum haemorrhage scenario) were conducted in teams of 10 in the ISS versus the OSS setting. Primary outcome Knowledge assessed by a multiple choice question test. Exploratory outcomes Individual outcomes: scores on the Safety Attitudes Questionnaire, stress measurements (State-Trait Anxiety Inventory, cognitive appraisal and salivary cortisol), Intrinsic Motivation Inventory and perceptions of simulations. Team outcome: video assessment of team performance. Organisational impact: suggestions for organisational changes. Results The trial was conducted from April to June 2013. No differences between the two groups were found for the multiple choice question test, patient safety attitude, stress measurements, motivation or the evaluation of the simulations. The participants in the ISS group scored the authenticity of the simulation significantly higher than did the participants in the OSS group. Expert video assessment of team performance showed no differences between the ISS versus the OSS group. The ISS group provided more ideas and suggestions for changes at the organisational level. Conclusions In this randomised trial, no significant differences were found regarding knowledge, patient safety attitude, motivation or stress measurements when comparing ISS versus OSS. Although participant perception of the authenticity of ISS versus OSS differed significantly, there were no differences in other outcomes between the groups except that the ISS group generated more suggestions for organisational changes. Trial registration number NCT01792674.

Autoantibodies and Immunoglobulins in Patients with Alcoholic Cirrhosis

In order to evaluate the possible relation between hepatic function and hemodynamics and the increased humoral immune response of cirrhotic patients, titres of antinuclear antibodies (ANA) and smooth muscle antibodies (SMA) and concentrations of immunoglobulin (Ig) G, A and M were determined in 74 consecutive patients with alcoholic liver cirrhosis. Patients showed significantly (p less than 0.05) increased prevalences of ANA and SMA and concentrations of Ig G, A and M when compared to controls. No significant correlations were found between titres of ANA or SMA and hepatic scan score, galactose elimination capacity, indocyanine green clearance, hepatic blood flow and wedged-to-free hepatic vein pressure. Hepatic scan score correlated directly (rho = 0.38, p less than 0.05) to IgA concentrations; wedged-to-free hepatic vein pressure correlated directly to IgG concentrations (rho = 0.35, p less than 0.05) and to IgM concentrations (rho = 0.42, p less than 0.01). No other significant correlations were found between Ig concentrations and variables of hepatic function or hemodynamics.

Instructor feedback versus no instructor feedback on performance in a laparoscopic virtual reality simulator: a randomized educational trial

BackgroundSeveral studies have found a positive effect on the learning curve as well as the improvement of basic psychomotor skills in the operating room after virtual reality training. Despite this, the majority of surgical and gynecological departments encounter hurdles when implementing this form of training. This is mainly due to lack of knowledge concerning the time and human resources needed to train novice surgeons to an adequate level. The purpose of this trial is to investigate the impact of instructor feedback regarding time, repetitions and self-perception when training complex operational tasks on a virtual reality simulator.Methods/DesignThe study population consists of medical students on their 4th to 6th year without prior laparoscopic experience. The study is conducted in a skills laboratory at a centralized university hospital. Based on a sample size estimation 98 participants will be randomized to an intervention group or a control group. Both groups have to achieve a predefined proficiency level when conducting a laparoscopic salpingectomy using a surgical virtual reality simulator. The intervention group receives standardized instructor feedback of 10 to 12 min a maximum of three times. The control group receives no instructor feedback. Both groups receive the automated feedback generated by the virtual reality simulator. The study follows the CONSORT Statement for randomized trials. Main outcome measures are time and repetitions to reach the predefined proficiency level on the simulator. We include focus on potential sex differences, computer gaming experience and self-perception.DiscussionThe findings will contribute to a better understanding of optimal training methods in surgical education.Trial RegistrationNCT01497782