Variability in pain response to a non-pharmacological intervention across repeated routine pain exposure in preterm infants: a feasibility study

AIM: To explore the variability in pain response in preterm infants across time who received sucrose during routine heel stick. METHOD: Single group, exploratory repeated measures design. SETTING: Two tertiary level neonatal intensive care units (NICU) in Switzerland. SUBJECTS: Nine preterm infants born between 28 2/7 and 31 4/7 weeks of gestation during their first 14 days of life. MEASUREMENTS: Pain was assessed by the Bernese Pain Scale for Neonates (BPSN), the Premature Infant Pain Profile (PIPP) and the Visual Analogue Scale (VAS). Salivary cortisol was analysed. RESULTS: 72-94% of the variability was within-subject variability, indicating inconsistency of pain responses across the 5 heel sticks. Interrater agreement was highest during heel sticks 1-3 and decreased during heel stick 4 and 5, indicating a possible alteration of pain patterns. No significant differences in the amount of cortisol could be detected before and after the heel sticks (p = 0.55), indicating no stress-induced peak after the painful intervention. However, a general gradual decrease of cortisol levels across time could be detected. CONCLUSION: A high variability in pain response among preterm neonates across time could be described. Consistency of cortisol levels before and after the heel sticks could indicate the effectiveness of sucrose across time.

Psychosocial interventions for smoking cessation in patients with coronary heart disease

BACKGROUND: Quitting smoking improves prognosis after a cardiac event, but many patients continue to smoke, and improved cessation aids are urgently required. OBJECTIVES: To assess the effectiveness of psychosocial interventions such as behavioural therapeutic intervention, telephone support and self-help interventions in helping people with coronary heart disease (CHD) to quit smoking. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (issue 2 2003), MEDLINE, EMBASE, PsycINFO and PSYNDEX were searched from the start of the database to August 2003. Results were supplemented by cross-checking references, and handsearches in selected journals and systematic reviews. SELECTION CRITERIA: Randomised controlled studies (RCTs) in patients with CHD with a minimum follow-up of 6 months. After initial selection of the studies three trials with methodological flaws (e.g. high drop out) were excluded. DATA COLLECTION AND ANALYSIS: Abstinence rates were computed according to an intention to treat analysis if possible, or if not on follow-up results only. MAIN RESULTS: We found 16 RCTs meeting inclusion criteria. Interventions consist of behavioural therapeutic approaches, telephone support and self-help material and were either focused on smoking cessation alone or addressed several risk factors. The trials mostly included older male patients with CHD, predominantly myocardial infarction. Overall there was a positive effect of interventions on abstinence after 6 to 12 months (odds ratio (OR) 1.66, 95% confidence interval (CI) 1.25 to 2.22), but substantial heterogeneity between trials. Studies with validated assessment of smoking status at follow-up had lower efficacy (OR 1.44, 95% CI 0.99 to 2.11) than non-validated trials (OR 1.92, 95% CI 1.26 to 2.93). Studies were clustered by intervention strategy and intensity of the intervention. Clustering reduced heterogeneity, although many trials used more than one type of intervention. The ORs for different strategies were similar (behavioural therapies OR 1.69, 95% CI 1.33 to 2.14; telephone support OR 1.58, 95% CI 1.28 to 1.97; self-help OR 1.48, 95% CI 1.11 to 1.96). More intense interventions showed increased quit rates (OR 1.98, 95% CI 1.49 to 2.65) whereas brief interventions did not appear effective (OR 0.92, 95% CI 0.70 to 1.22). Two trials had longer term follow-up, and did not show any benefits after 5 years. AUTHORS' CONCLUSIONS: Psychosocial smoking cessation interventions are effective in promoting abstinence at 1 year, provided they are of sufficient duration. Further studies, with longer follow-up, should compare different psychosocial intervention strategies, or the addition of a psychosocial intervention strategy to pharmacological therapy (e.g. nicotine replacement therapy) compared with pharmacological treatment alone.

Publication and non-publication of clinical trials: longitudinal study of applications submitted to a research ethics committee

BACKGROUND: Not all clinical trials are published, which may distort the evidence that is available in the literature. We studied the publication rate of a cohort of clinical trials and identified factors associated with publication and nonpublication of results. METHODS: We analysed the protocols of randomized clinical trials of drug interventions submitted to the research ethics committee of University Hospital (Inselspital) Bern, Switzerland from 1988 to 1998. We identified full articles published up to 2006 by searching the Cochrane CENTRAL database (issue 02/2006) and by contacting investigators. We analyzed factors associated with the publication of trials using descriptive statistics and logistic regression models. RESULTS: 451 study protocols and 375 corresponding articles were analyzed. 233 protocols resulted in at least one publication, a publication rate of 52%. A total of 366 (81%) trials were commercially funded, 47 (10%) had non-commercial funding. 346 trials (77%) were multi-centre studies and 272 of these (79%) were international collaborations. In the adjusted logistic regression model non-commercial funding (Odds Ratio [OR] 2.42, 95% CI 1.14-5.17), multi-centre status (OR 2.09, 95% CI 1.03-4.24), international collaboration (OR 1.87, 95% CI 0.99-3.55) and a sample size above the median of 236 participants (OR 2.04, 95% CI 1.23-3.39) were associated with full publication. CONCLUSIONS: In this cohort of applications to an ethics committee in Switzerland, only about half of clinical drug trials were published. Large multi-centre trials with non-commercial funding were more likely to be published than other trials, but most trials were funded by industry.

Multidimensional preventive home visit programs for community-dwelling older adults: a systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Multidimensional preventive home visit programs aim at maintaining health and autonomy of older adults and preventing disability and subsequent nursing home admission, but results of randomized controlled trials (RCTs) have been inconsistent. Our objective was to systematically review RCTs examining the effect of home visit programs on mortality, nursing home admissions, and functional status decline. METHODS: Data sources were MEDLINE, EMBASE, Cochrane CENTRAL database, and references. Studies were reviewed to identify RCTs that compared outcome data of older participants in preventive home visit programs with control group outcome data. Publications reporting 21 trials were included. Data on study population, intervention characteristics, outcomes, and trial quality were double-extracted. We conducted random effects meta-analyses. RESULTS: Pooled effects estimates revealed statistically nonsignificant favorable, and heterogeneous effects on mortality (odds ratio [OR] 0.92, 95% confidence interval [CI], 0.80-1.05), functional status decline (OR 0.89, 95% CI, 0.77-1.03), and nursing home admission (OR 0.86, 95% CI, 0.68-1.10). A beneficial effect on mortality was seen in younger study populations (OR 0.74, 95% CI, 0.58-0.94) but not in older populations (OR 1.14, 95% CI, 0.90-1.43). Functional decline was reduced in programs including a clinical examination in the initial assessment (OR 0.64, 95% CI, 0.48-0.87) but not in other trials (OR 1.00, 95% CI, 0.88-1.14). There was no single factor explaining the heterogenous effects of trials on nursing home admissions. CONCLUSION: Multidimensional preventive home visits have the potential to reduce disability burden among older adults when based on multidimensional assessment with clinical examination. Effects on nursing home admissions are heterogeneous and likely depend on multiple factors including population factors, program characteristics, and health care setting.

Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study

OBJECTIVE: To examine whether the association of inadequate or unclear allocation concealment and lack of blinding with biased estimates of intervention effects varies with the nature of the intervention or outcome. DESIGN: Combined analysis of data from three meta-epidemiological studies based on collections of meta-analyses. DATA SOURCES: 146 meta-analyses including 1346 trials examining a wide range of interventions and outcomes. MAIN OUTCOME MEASURES: Ratios of odds ratios quantifying the degree of bias associated with inadequate or unclear allocation concealment, and lack of blinding, for trials with different types of intervention and outcome. A ratio of odds ratios <1 implies that inadequately concealed or non-blinded trials exaggerate intervention effect estimates. RESULTS: In trials with subjective outcomes effect estimates were exaggerated when there was inadequate or unclear allocation concealment (ratio of odds ratios 0.69 (95% CI 0.59 to 0.82)) or lack of blinding (0.75 (0.61 to 0.93)). In contrast, there was little evidence of bias in trials with objective outcomes: ratios of odds ratios 0.91 (0.80 to 1.03) for inadequate or unclear allocation concealment and 1.01 (0.92 to 1.10) for lack of blinding. There was little evidence for a difference between trials of drug and non-drug interventions. Except for trials with all cause mortality as the outcome, the magnitude of bias varied between meta-analyses. CONCLUSIONS: The average bias associated with defects in the conduct of randomised trials varies with the type of outcome. Systematic reviewers should routinely assess the risk of bias in the results of trials, and should report meta-analyses restricted to trials at low risk of bias either as the primary analysis or in conjunction with less restrictive analyses.

Selective pharmacological targeting of a DEAD box RNA helicase

RNA helicases represent a large family of proteins implicated in many biological processes including ribosome biogenesis, splicing, translation and mRNA degradation. However, these proteins have little substrate specificity, making inhibition of selected helicases a challenging problem. The prototypical DEAD box RNA helicase, eIF4A, works in conjunction with other translation factors to prepare mRNA templates for ribosome recruitment during translation initiation. Herein, we provide insight into the selectivity of a small molecule inhibitor of eIF4A, hippuristanol. This coral-derived natural product binds to amino acids adjacent to, and overlapping with, two conserved motifs present in the carboxy-terminal domain of eIF4A. Mutagenesis of amino acids within this region allowed us to alter the hippuristanol-sensitivity of eIF4A and undertake structure/function studies. Our results provide an understanding into how selective targeting of RNA helicases for pharmacological intervention can be achieved.

Survival and cardiac remodeling benefits in patients undergoing late percutaneous coronary intervention of the infarct-related artery: evidence from a meta-analysis of randomized controlled trials

Our purpose was to perform a systematic review and meta-analysis of randomized trials comparing percutaneous coronary intervention (PCI) of the infarct-related artery (IRA) with medical therapy in patients randomized >12 h after acute myocardial infarction (AMI).

Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: Meta-analysis of randomized trials

Uncertainty persists concerning the effect of improved long-term glycemic control on macrovascular disease in diabetes mellitus (DM).

Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials

BACKGROUND: Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer. METHODS: Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups. FINDINGS: Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42). INTERPRETATION: Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits. FUNDING: German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).

The importance of allocation concealment and patient blinding in osteoarthritis trials: a meta-epidemiologic study

OBJECTIVE: To evaluate the association of adequate allocation concealment and patient blinding with estimates of treatment benefits in osteoarthritis trials. METHODS: We performed a meta-epidemiologic study of 16 meta-analyses with 175 trials that compared therapeutic interventions with placebo or nonintervention control in patients with hip or knee osteoarthritis. We calculated effect sizes from the differences in means of pain intensity between groups at the end of followup divided by the pooled SD and compared effect sizes between trials with and trials without adequate methodology. RESULTS: Effect sizes tended to be less beneficial in 46 trials with adequate allocation concealment compared with 112 trials with inadequate or unclear concealment of allocation (difference -0.15; 95% confidence interval [95% CI] -0.31, 0.02). Selection bias associated with inadequate or unclear concealment of allocation was most pronounced in meta-analyses with large estimated treatment benefits (P for interaction < 0.001), meta-analyses with high between-trial heterogeneity (P = 0.009), and meta-analyses of complementary medicine (P = 0.019). Effect sizes tended to be less beneficial in 64 trials with adequate blinding of patients compared with 58 trials without (difference -0.15; 95% CI -0.39, 0.09), but differences were less consistent and disappeared after accounting for allocation concealment. Detection bias associated with a lack of adequate patient blinding was most pronounced for nonpharmacologic interventions (P for interaction < 0.001). CONCLUSION: Results of osteoarthritis trials may be affected by selection and detection bias. Adequate concealment of allocation and attempts to blind patients will minimize these biases.

The effects of excluding patients from the analysis in randomised controlled trials: meta-epidemiological study

OBJECTIVE: To examine whether excluding patients from the analysis of randomised trials are associated with biased estimates of treatment effects and higher heterogeneity between trials. DESIGN: Meta-epidemiological study based on a collection of meta-analyses of randomised trials. DATA SOURCES: 14 meta-analyses including 167 trials that compared therapeutic interventions with placebo or non-intervention control in patients with osteoarthritis of the hip or knee and used patient reported pain as an outcome. METHODS: Effect sizes were calculated from differences in means of pain intensity between groups at the end of follow-up, divided by the pooled standard deviation. Trials were combined by using random effects meta-analysis. Estimates of treatment effects were compared between trials with and trials without exclusions from the analysis, and the impact of restricting meta-analyses to trials without exclusions was assessed. RESULTS: 39 trials (23%) had included all patients in the analysis. In 128 trials (77%) some patients were excluded from the analysis. Effect sizes from trials with exclusions tended to be more beneficial than those from trials without exclusions (difference -0.13, 95% confidence interval -0.29 to 0.04). However, estimates of bias between individual meta-analyses varied considerably (tau(2)=0.07). Tests of interaction between exclusions from the analysis and estimates of treatment effects were positive in five meta-analyses. Stratified analyses indicated that differences in effect sizes between trials with and trials without exclusions were more pronounced in meta-analyses with high between trial heterogeneity, in meta-analyses with large estimated treatment benefits, and in meta-analyses of complementary medicine. Restriction of meta-analyses to trials without exclusions resulted in smaller estimated treatment benefits, larger P values, and considerable decreases in between trial heterogeneity. CONCLUSION: Excluding patients from the analysis in randomised trials often results in biased estimates of treatment effects, but the extent and direction of bias is unpredictable. Results from intention to treat analyses should always be described in reports of randomised trials. In systematic reviews, the influence of exclusions from the analysis on estimated treatment effects should routinely be assessed.

Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis

The vitronectin receptor integrin alphavbeta3 promotes angiogenesis by mediating migration and proliferation of endothelial cells, but also drives fibrogenic activation of hepatic stellate cells (HSCs) in vitro. Expecting antifibrotic synergism, we studied the effect of alphavbeta3 inhibition in two in vivo models of liver fibrogenesis. Liver fibrosis was induced in rats by way of bile duct ligation (BDL) for 6 weeks or thioacetamide (TAA) injections for 12 weeks. A specific alphavbeta3 (alphavbeta5) inhibitor (Cilengitide) was given intraperitoneally twice daily at 15 mg/kg during BDL or after TAA administration. Liver collagen was determined as hydroxyproline, and gene expression was quantified by way of quantitative polymerase chain reaction. Liver angiogenesis, macrophage infiltration, and hypoxia were assessed by way of CD31, CD68 and hypoxia-inducible factor-1alpha immunostaining. Cilengitide decreased overall vessel formation. This was significant in portal areas of BDL and septal areas of TAA fibrotic rats and was associated with a significant increase of liver collagen by 31% (BDL) and 27% (TAA), and up-regulation of profibrogenic genes and matrix metalloproteinase-13. Treatment increased gamma glutamyl transpeptidase in both models, while other serum markers remained unchanged. alphavbeta3 inhibition resulted in mild liver hypoxia, as evidenced by up-regulation of hypoxia-inducible genes. Liver infiltration by macrophages/Kupffer cells was not affected, although increases in tumor necrosis factor alpha, interleukin-18, and cyclooxygenase-2 messenger RNA indicated modest macrophage activation. CONCLUSION: Specific inhibition of integrin alphavbeta3 (alphavbeta5) in vivo decreased angiogenesis but worsened biliary (BDL) and septal (TAA) fibrosis, despite its antifibrogenic effect on HSCs in vitro. Angiogenesis inhibitors should be used with caution in patients with hepatic fibrosis.