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Gotzsche P.C.,Rigshospitalet
Cochrane database of systematic reviews (Online) | Year: 2011

A variety of estimates of the benefits and harms of mammographic screening for breast cancer have been published and national policies vary. To assess the effect of screening for breast cancer with mammography on mortality and morbidity. We searched PubMed (November 2008). Randomised trials comparing mammographic screening with no mammographic screening. Both authors independently extracted data. Study authors were contacted for additional information. Eight eligible trials were identified. We excluded a biased trial and included 600,000 women in the analyses. Three trials with adequate randomisation did not show a significant reduction in breast cancer mortality at 13 years (relative risk (RR) 0.90, 95% confidence interval (CI) 0.79 to 1.02); four trials with suboptimal randomisation showed a significant reduction in breast cancer mortality with an RR of 0.75 (95% CI 0.67 to 0.83). The RR for all seven trials combined was 0.81 (95% CI 0.74 to 0.87). We found that breast cancer mortality was an unreliable outcome that was biased in favour of screening, mainly because of differential misclassification of cause of death. The trials with adequate randomisation did not find an effect of screening on cancer mortality, including breast cancer, after 10 years (RR 1.02, 95% CI 0.95 to 1.10) or on all-cause mortality after 13 years (RR 0.99, 95% CI 0.95 to 1.03).Numbers of lumpectomies and mastectomies were significantly larger in the screened groups (RR 1.31, 95% CI 1.22 to 1.42) for the two adequately randomised trials that measured this outcome; the use of radiotherapy was similarly increased. Screening is likely to reduce breast cancer mortality. As the effect was lowest in the adequately randomised trials, a reasonable estimate is a 15% reduction corresponding to an absolute risk reduction of 0.05%. Screening led to 30% overdiagnosis and overtreatment, or an absolute risk increase of 0.5%. This means that for every 2000 women invited for screening throughout 10 years, one will have her life prolonged and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress for many months because of false positive findings. It is thus not clear whether screening does more good than harm. To help ensure that the women are fully informed of both benefits and harms before they decide whether or not to attend screening, we have written an evidence-based leaflet for lay people that is available in several languages on www.cochrane.dk.


Lundh A.,Rigshospitalet
Cochrane database of systematic reviews (Online) | Year: 2012

Clinical research affecting how doctors practice medicine is increasingly sponsored by companies that make drugs and medical devices. Previous systematic reviews have found that pharmaceutical industry sponsored studies are more often favorable to the sponsor's product compared with studies with other sources of sponsorship. This review is an update using more stringent methodology and also investigating sponsorship of device studies. To investigate whether industry sponsored drug and device studies have more favorable outcomes and differ in risk of bias, compared with studies having other sources of sponsorship. We searched MEDLINE (1948 to September 2010), EMBASE (1980 to September 2010), the Cochrane Methodology Register (Issue 4, 2010) and Web of Science (August 2011). In addition, we searched reference lists of included papers, previous systematic reviews and author files. Cross-sectional studies, cohort studies, systematic reviews and meta-analyses that quantitatively compared primary research studies of drugs or medical devices sponsored by industry with studies with other sources of sponsorship. We had no language restrictions. Two assessors identified potentially relevant papers, and a decision about final inclusion was made by all authors. Two assessors extracted data, and we contacted authors of included papers for additional unpublished data. Outcomes included favorable results, favorable conclusions, effect size, risk of bias and whether the conclusions agreed with the study results. Two assessors assessed risk of bias of included papers. We calculated pooled risk ratios (RR) for dichotomous data (with 95% confidence intervals). Forty-eight papers were included. Industry sponsored studies more often had favorable efficacy results, risk ratio (RR): 1.24 (95% confidence interval (CI): 1.14 to 1.35), harms results RR: 1.87 (95% CI: 1.54 to 2.27) and conclusions RR: 1.31 (95% CI: 1.20 to 1.44) compared with non-industry sponsored studies. Ten papers reported on sponsorship and effect size, but could not be pooled due to differences in their reporting of data. The results were heterogeneous; five papers found larger effect sizes in industry sponsored studies compared with non-industry sponsored studies and five papers did not find a difference in effect size. Only two papers (including 120 device studies) reported separate data for devices and we did not find a difference between drug and device studies on the association between sponsorship and conclusions (test for interaction, P = 0.23). Comparing industry and non-industry sponsored studies, we did not find a difference in risk of bias from sequence generation, allocation concealment and follow-up. However, industry sponsored studies more often had low risk of bias from blinding, RR: 1.32 (95% CI: 1.05 to 1.65), compared with non-industry sponsored studies. In industry sponsored studies, there was less agreement between the results and the conclusions than in non-industry sponsored studies, RR: 0.84 (95% CI: 0.70 to 1.01). Sponsorship of drug and device studies by the manufacturing company leads to more favorable results and conclusions than sponsorship by other sources. Our analyses suggest the existence of an industry bias that cannot be explained by standard 'Risk of bias' assessments.


Afshari A.,Rigshospitalet
Cochrane database of systematic reviews (Online) | Year: 2011

Severe bleeding and coagulopathy as a result of massive transfusion are serious clinical conditions that are associated with high mortality. Thromboelastography (TEG) and thromboelastometry (ROTEM) are increasingly used to guide transfusion strategy but their roles remain disputed. To systematically assess the benefits and harms of a TEG or ROTEM guided transfusion strategy in randomized trials involving patients with severe bleeding. Randomized clinical trials (RCTs) were identified from electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 9); MEDLINE; EMBASE; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; and the Chinese Biomedical Literature Database (up to 31st October 2010). We contacted trial authors, authors of previous reviews, and manufacturers in the field. We included all RCTs, irrespective of blinding or language, that compared transfusion guided by TEG or ROTEM to transfusion guided by clinical judgement and standard laboratory tests, or both. Two authors independently abstracted data; they resolved any disagreements by discussion. We presented pooled estimates of the intervention effects on dichotomous outcomes as relative risks (RR) and on continuous outcomes as mean differences, with 95% confidence intervals (CI). Our primary outcome measure was all cause mortality. We performed subgroup and sensitivity analyses to assess the effect of TEG or ROTEM in adults and children on various clinical and physiological outcomes. We assessed the risk of bias through assessment of trial methodological components and the risk of random error through trial sequential analysis. We included nine RCTs with a total of 776 participants; only one trial had a low risk of bias. We found two ongoing trials but were unable to retrieve any data from them. Compared with standard treatment, TEG or ROTEM showed no statistically significant effect on overall mortality (3.78% versus 5.11%, RR 0.77, 95% CI 0.35 to 1.72; I(2) = 0%) but only five trials provided data on mortality. Our analyses demonstrated a statistically significant effect of TEG or ROTEM on the amount of bleeding (MD -85.05 ml, 95% CI -140.68 to -29.42; I(2) = 26%) but failed to show any statistically significant effect on other predefined outcomes. There is an absence of evidence that TEG or ROTEM improves morbidity or mortality in patients with severe bleeding. Application of a TEG or ROTEM guided transfusion strategy seems to reduce the amount of bleeding but whether this has implications for the clinical condition of patients is still uncertain. More research is needed.


Krogsboll L.T.,Rigshospitalet
Cochrane database of systematic reviews (Online) | Year: 2012

General health checks are common elements of health care in some countries. These aim to detect disease and risk factors for disease with the purpose of reducing morbidity and mortality. Most of the commonly used screening tests offered in general health checks have been incompletely studied. Also, screening leads to increased use of diagnostic and therapeutic interventions, which can be harmful as well as beneficial. It is, therefore, important to assess whether general health checks do more good than harm. We aimed to quantify the benefits and harms of general health checks with an emphasis on patient-relevant outcomes such as morbidity and mortality rather than on surrogate outcomes such as blood pressure and serum cholesterol levels. We searched The Cochrane Library, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Effective Practice and Organisation of Care (EPOC) Trials Register, MEDLINE, EMBASE, Healthstar, CINAHL, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) to July 2012. Two authors screened titles and abstracts, assessed papers for eligibility and read reference lists. One author used citation tracking (Web of Knowledge) and asked trialists about additional studies. We included randomised trials comparing health checks with no health checks in adults unselected for disease or risk factors. We did not include geriatric trials. We defined health checks as screening general populations for more than one disease or risk factor in more than one organ system. Two authors independently extracted data and assessed the risk of bias in the trials. We contacted authors for additional outcomes or trial details when necessary. For mortality outcomes we analysed the results with random-effects model meta-analysis, and for other outcomes we did a qualitative synthesis as meta-analysis was not feasible. We included 16 trials, 14 of which had available outcome data (182,880 participants). Nine trials provided data on total mortality (155,899 participants, 11,940 deaths), median follow-up time nine years, giving a risk ratio of 0.99 (95% confidence interval (CI) 0.95 to 1.03). Eight trials provided data on cardiovascular mortality (152,435 participants, 4567 deaths), risk ratio 1.03 (95% CI 0.91 to 1.17) and eight trials on cancer mortality (139,290 participants, 3663 deaths), risk ratio 1.01 (95% CI 0.92 to 1.12). Subgroup and sensitivity analyses did not alter these findings.We did not find an effect on clinical events or other measures of morbidity but one trial found an increased occurrence of hypertension and hypercholesterolaemia with screening and one trial found an increased occurence of self-reported chronic disease. One trial found a 20% increase in the total number of new diagnoses per participant over six years compared to the control group. No trials compared the total number of prescriptions, but two out of four trials found an increased number of people using antihypertensive drugs. Two out of four trials found small beneficial effects on self-reported health, but this could be due to reporting bias as the trials were not blinded. We did not find an effect on admission to hospital, disability, worry, additional visits to the physician, or absence from work, but most of these outcomes were poorly studied. We did not find useful results on the number of referrals to specialists, the number of follow-up tests after positive screening results, or the amount of surgery. General health checks did not reduce morbidity or mortality, neither overall nor for cardiovascular or cancer causes, although the number of new diagnoses was increased. Important harmful outcomes, such as the number of follow-up diagnostic procedures or short term psychological effects, were often not studied or reported and many trials had methodological problems. With the large number of participants and deaths included, the long follow-up periods used, and considering that cardiovascular and cancer mortality were not reduced, general health checks are unlikely to be beneficial.


Ronsholt F.F.,Rigshospitalet
Journal of acquired immune deficiency syndromes (1999) | Year: 2012

Residual immune activation and skewed T cell maturation may contribute to excess comorbidity and mortality in successfully treated HIV-infected patients, and long-term effects of combination antiretroviral therapy (cART) on immune reconstitution remain a debated issue. Quantitative T cell reconstitution and activation and its association with residual viremia in patients with 12 years of viremic suppression were investigated. Blood samples collected cross-sectionally from 71 HIV-infected patients with cART-induced viremic suppression through 12 years were compared with samples from 16 healthy controls. Several different subsets of naive, memory, and activated T cells were analyzed in fresh whole blood by 6-color flowcytometry, and ultrasensitive quantification of HIV RNA was performed. HIV-infected patients had lower absolute and relative CD4 T cell counts and higher absolute and relative CD8 T cell counts than controls. HIV-infected patients had lower concentrations of naive CD4 cells than controls, but proportions were similar. HIV-infected patients had higher concentrations of CD8 T cells than controls in all the examined subsets but only a higher proportion of CD8 cells in the intermediately differentiated and activated subsets. Residual viremia did not correlate to proportions of naive CD4, CD4 recent thymic emigrants, or activated CD8 T cells. This study demonstrated some degree of T cell imbalance even after 12 years of successful cART. Large longitudinal studies are needed to establish whether these discrete changes have clinical relevance.


Jeppesen P.B.,Rigshospitalet
Current Opinion in Gastroenterology | Year: 2014

PURPOSE OF REVIEW: Teduglutide, a recombinant analog of human glucagon-like peptide 2, has recently been approved in the US and Europe (Gattex and Revestive, respectively) as the first targeted treatment of short bowel syndrome-associated intestinal failure (SBS-IF). Glucagon-like peptide 2 improves structural and functional intestinal adaptation following intestinal resection by decelerating a rapid gastric emptying, by decreasing gastric hypersecretion, by increasing intestinal blood flow and by promoting intestinal growth. This review summarizes the findings from phase 2 and 3 studies preceding the US Food and Drug Administration and the European Medicines Agency approval of subcutaneous teduglutide for this orphan condition. RECENT FINDINGS: In a 3-week, phase 2, metabolic balance study, teduglutide increased intestinal wet weight absorption by approximately 700 g/day and reduced fecal energy losses by approximately 0.8 MJ/day (∼200 kcal/day). In two subsequent 24-week, phase 3 studies, teduglutide reduced the need for parenteral support in the same magnitude. Teduglutide had an acceptable tolerability profile, where adverse events generally were of gastrointestinal origin consistent with the known mechanism of action. SUMMARY: Teduglutide will add incremental benefit to the limited medical treatment armamentarium in SBS patients by maximizing intestinal absorption, decreasing fecal losses, thereby decreasing or even eliminating the need for parenteral support. Future research should target and implement other key hormones with similar and possible additive or synergistic effects, thereby further promoting structural and functional adaptation and intestinal rehabilitation in these severely disabled SBS patients. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Jeppesen P.B.,Rigshospitalet
JPEN. Journal of parenteral and enteral nutrition | Year: 2014

Short bowel syndrome (SBS) refers to the malabsorptive state caused by physical or functional loss of portions of the small intestine, most commonly following extensive intestinal resection. Such resections hinder absorption of adequate amounts of macronutrients, micronutrients, electrolytes, and water, resulting in malnutrition, diarrhea, and dehydration. Clinical features of SBS vary along a continuum, depending on the extent and anatomy of intestine lost and the ability of the patient and the remaining intestine to compensate for the loss. The impact of SBS can be extensive, leading to diminished health-related quality of life because of its many physical and psychological effects on patients. SBS is associated with decreased survival; risk factors for SBS-related mortality include very short remnant small bowel, end-jejunal remnant anatomy, and arterial mesenteric infarction as primary cause. Although parenteral nutrition and/or intravenous fluid (PN/IV) is a life-saving measure for many patients with SBS, patients with the most severe malabsorption (ie, dependent on PN/IV) are at risk for severe, chronic complications and death. Patients' treatment needs vary depending on disease severity and resection type; thus, each patient should be individually managed. This review discusses the spectrum of disease in patients with SBS and presents common complications encountered by these patients to highlight the importance of individualized management and treatment.


Thomsen T.,Rigshospitalet
The Cochrane database of systematic reviews | Year: 2014

Smokers have a substantially increased risk of postoperative complications. Preoperative smoking intervention may be effective in decreasing this incidence, and surgery may constitute a unique opportunity for smoking cessation interventions. The objectives of this review are to assess the effect of preoperative smoking intervention on smoking cessation at the time of surgery and 12 months postoperatively, and on the incidence of postoperative complications. We searched the Cochrane Tobacco Addiction Group Specialized Register in January 2014. Randomized controlled trials that recruited people who smoked prior to surgery, offered a smoking cessation intervention, and measured preoperative and long-term abstinence from smoking or the incidence of postoperative complications or both outcomes. The review authors independently assessed studies to determine eligibility, and discussed the results between them. Thirteen trials enrolling 2010 participants met the inclusion criteria. One trial did not report cessation as an outcome. Seven reported some measure of postoperative morbidity. Most studies were judged to be at low risk of bias but the overall quality of evidence was moderate due to the small number of studies contributing to each comparison.Ten trials evaluated the effect of behavioural support on cessation at the time of surgery; nicotine replacement therapy (NRT) was offered or recommended to some or all participants in eight of these. Two trials initiated multisession face-to-face counselling at least four weeks before surgery and were classified as intensive interventions, whilst seven used a brief intervention. One further study provided an intensive intervention to both groups, with the intervention group additionally receiving a computer-based scheduled reduced smoking intervention. One placebo-controlled trial examined the effect of varenicline administered one week preoperatively followed by 11 weeks postoperative treatment, and one placebo-controlled trial examined the effect of nicotine lozenges from the night before surgery as an adjunct to brief counselling at the preoperative evaluation. There was evidence of heterogeneity between the effects of trials using intensive and brief interventions, so we pooled these separately. An effect on cessation at the time of surgery was apparent in both subgroups, but the effect was larger for intensive intervention (pooled risk ratio (RR) 10.76; 95% confidence interval (CI) 4.55 to 25.46, two trials, 210 participants) than for brief interventions (RR 1.30; 95% CI 1.16 to 1.46, 7 trials, 1141 participants). A single trial did not show evidence of benefit of a scheduled reduced smoking intervention. Neither nicotine lozenges nor varenicline were shown to increase cessation at the time of surgery but both had wide confidence intervals (RR 1.34; 95% CI 0.86 to 2.10 (1 trial, 46 participants) and RR 1.49; 95% CI 0.98 to 2.26 (1 trial, 286 participants) respectively). Four of these trials evaluated long-term smoking cessation and only the intensive intervention retained a significant effect (RR 2.96; 95% CI 1.57 to 5.55, 2 trials, 209 participants), whilst there was no evidence of a long-term effect following a brief intervention (RR 1.09; 95% CI 0.68 to 1.75, 2 trials, 341 participants). The trial of varenicline did show a significant effect on long-term smoking cessation (RR 1.45; 95% CI 1.01 to 2.07, 1 trial, 286 participants).Seven trials examined the effect of smoking intervention on postoperative complications. As with smoking outcomes, there was evidence of heterogeneity between intensive and brief behavioural interventions. In subgroup analyses there was a significant effect of intensive intervention on any complications (RR 0.42; 95% CI 0.27 to 0.65, 2 trials, 210 participants) and on wound complications (RR 0.31; 95% CI 0.16 to 0.62, 2 trials, 210 participants). For brief interventions, where the impact on smoking had been smaller, there was no evidence of a reduction in complications (RR 0.92; 95% CI 0.72 to 1.19, 4 trials, 493 participants) for any complication (RR 0.99; 95% CI 0.70 to 1.40, 3 trials, 325 participants) for wound complications. The trial of varenicline did not detect an effect on postoperative complications (RR 0.94; 95% CI 0.52 to 1.72, 1 trial, 286 participants). There is evidence that preoperative smoking interventions providing behavioural support and offering NRT increase short-term smoking cessation and may reduce postoperative morbidity. One trial of varenicline begun shortly before surgery has shown a benefit on long-term cessation but did not detect an effect on early abstinence or on postoperative complications. The optimal preoperative intervention intensity remains unknown. Based on indirect comparisons and evidence from two small trials, interventions that begin four to eight weeks before surgery, include weekly counselling and use NRT are more likely to have an impact on complications and on long-term smoking cessation.


The present invention relates to a novel use and methods of treatment using sympathicomimetic agonists with pro-hemostatic activity.


Patent
Rigshospitalet and Technical University of Denmark | Date: 2015-12-14

The present invention is directed to the technical field of imaging compositions useful for diagnosing cancer and other diseases in a subject. In particular, the invention relates to a class of diagnostic compounds comprising a novel liposome composition with encapsulated metal entities such as radionuclides, for example ^(61)Cu and ^(64)Cu copper isotopes. The invention further relates to a novel method for loading delivery systems, such as liposome compositions, with metal entities such as radionuclides, and the use of liposomes for targeted diagnosis and treatment of a target site, such as cancerous tissue and, in general, pathological conditions associated with leaky blood vessels. The present invention provides a new diagnostic tool for the utilization of positron emission tomography (PET) imaging technique.

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