Comparative efficacy of pharmacological and non-pharmacological interventions in fibromyalgia syndrome: network meta-analysis

OBJECTIVES To synthesise the available evidence on pharmacological and non-pharmacological interventions recommended for fibromyalgia syndrome (FMS). METHODS Electronic databases including MEDLINE, PsycINFO, Scopus, the Cochrane Controlled Trials Registry and the Cochrane Library were searched for randomised controlled trials comparing any therapeutic approach as recommended in FMS guidelines (except complementary and alternative medicine) with control interventions in patients with FMS. Primary outcomes were pain and quality of life. Data extraction was done using standardised forms. RESULTS 102 trials in 14 982 patients and eight active interventions (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors (SNRIs), the gamma-amino butyric acid analogue pregabalin, aerobic exercise, balneotherapy, cognitive behavioural therapy (CBT), multicomponent therapy) were included. Most of the trials were small and hampered by methodological quality, introducing heterogeneity and inconsistency in the network. When restricted to large trials with ≥100 patients per group, heterogeneity was low and benefits for SNRIs and pregabalin compared with placebo were statistically significant, but small and not clinically relevant. For non-pharmacological interventions, only one large trial of CBT was available. In medium-sized trials with ≥50 patients per group, multicomponent therapy showed small to moderate benefits over placebo, followed by aerobic exercise and CBT. CONCLUSIONS Benefits of pharmacological treatments in FMS are of questionable clinical relevance and evidence for benefits of non-pharmacological interventions is limited. A combination of pregabalin or SNRIs as pharmacological interventions and multicomponent therapy, aerobic exercise and CBT as non-pharmacological interventions seems most promising for the management of FMS.

Comparative efficacy of seven psychotherapeutic interventions for patients with depression: a network meta-analysis

BACKGROUND Previous meta-analyses comparing the efficacy of psychotherapeutic interventions for depression were clouded by a limited number of within-study treatment comparisons. This study used network meta-analysis, a novel methodological approach that integrates direct and indirect evidence from randomised controlled studies, to re-examine the comparative efficacy of seven psychotherapeutic interventions for adult depression. METHODS AND FINDINGS We conducted systematic literature searches in PubMed, PsycINFO, and Embase up to November 2012, and identified additional studies through earlier meta-analyses and the references of included studies. We identified 198 studies, including 15,118 adult patients with depression, and coded moderator variables. Each of the seven psychotherapeutic interventions was superior to a waitlist control condition with moderate to large effects (range d = -0.62 to d = -0.92). Relative effects of different psychotherapeutic interventions on depressive symptoms were absent to small (range d = 0.01 to d = -0.30). Interpersonal therapy was significantly more effective than supportive therapy (d = -0.30, 95% credibility interval [CrI] [-0.54 to -0.05]). Moderator analysis showed that patient characteristics had no influence on treatment effects, but identified aspects of study quality and sample size as effect modifiers. Smaller effects were found in studies of at least moderate (Δd = 0.29 [-0.01 to 0.58]; p = 0.063) and large size (Δd = 0.33 [0.08 to 0.61]; p = 0.012) and those that had adequate outcome assessment (Δd = 0.38 [-0.06 to 0.87]; p = 0.100). Stepwise restriction of analyses by sample size showed robust effects for cognitive-behavioural therapy, interpersonal therapy, and problem-solving therapy (all d>0.46) compared to waitlist. Empirical evidence from large studies was unavailable or limited for other psychotherapeutic interventions. CONCLUSIONS Overall our results are consistent with the notion that different psychotherapeutic interventions for depression have comparable benefits. However, the robustness of the evidence varies considerably between different psychotherapeutic treatments.

3G network traffic sources measurement and analysis

In this paper, we show statistical analyses of several types of traffic sources in a 3G network, namely voice, video and data sources. For each traffic source type, measurements were collected in order to, on the one hand, gain better understanding of the statistical characteristics of the sources and, on the other hand, enable forecasting traffic behaviour in the network. The latter can be used to estimate service times and quality of service parameters. The probability density function, mean, variance, mean square deviation, skewness and kurtosis of the interarrival times are estimated by Wolfram Mathematica and Crystal Ball statistical tools. Based on evaluation of packet interarrival times, we show how the gamma distribution can be used in network simulations and in evaluation of available capacity in opportunistic systems. As a result, from our analyses, shape and scale parameters of gamma distribution are generated. Data can be applied also in dynamic network configuration in order to avoid potential network congestions or overflows. Copyright © 2013 John Wiley & Sons, Ltd.

Why participate in an online social network: an empirical analysis

Despite their enormous success the motivation behind user participation in Online Social Networks is still little understood. This study explores a variety of possible incentives and provides an empirical evaluation of their subjective relevance. The analysis is based on survey data from 129 test subjects. Using Structural Equation Modeling, we identified that the satisfaction of the needs for belongingness and the esteem needs through self-presentation together with peer pressure are the main drivers of participation. The analysis of a sub-sample of active users pointed out the satisfaction of the cognitive needs as an additional participation determinant. Based on these findings, recommendations for online social network providers are made.

Bifurcation and singularity analysis of a molecular network for the induction of long-term memory.

Withdrawal reflexes of the mollusk Aplysia exhibit sensitization, a simple form of long-term memory (LTM). Sensitization is due, in part, to long-term facilitation (LTF) of sensorimotor neuron synapses. LTF is induced by the modulatory actions of serotonin (5-HT). Pettigrew et al. developed a computational model of the nonlinear intracellular signaling and gene network that underlies the induction of 5-HT-induced LTF. The model simulated empirical observations that repeated applications of 5-HT induce persistent activation of protein kinase A (PKA) and that this persistent activation requires a suprathreshold exposure of 5-HT. This study extends the analysis of the Pettigrew model by applying bifurcation analysis, singularity theory, and numerical simulation. Using singularity theory, classification diagrams of parameter space were constructed, identifying regions with qualitatively different steady-state behaviors. The graphical representation of these regions illustrates the robustness of these regions to changes in model parameters. Because persistent protein kinase A (PKA) activity correlates with Aplysia LTM, the analysis focuses on a positive feedback loop in the model that tends to maintain PKA activity. In this loop, PKA phosphorylates a transcription factor (TF-1), thereby increasing the expression of an ubiquitin hydrolase (Ap-Uch). Ap-Uch then acts to increase PKA activity, closing the loop. This positive feedback loop manifests multiple, coexisting steady states, or multiplicity, which provides a mechanism for a bistable switch in PKA activity. After the removal of 5-HT, the PKA activity either returns to its basal level (reversible switch) or remains at a high level (irreversible switch). Such an irreversible switch might be a mechanism that contributes to the persistence of LTM. The classification diagrams also identify parameters and processes that might be manipulated, perhaps pharmacologically, to enhance the induction of memory. Rational drug design, to affect complex processes such as memory formation, can benefit from this type of analysis.

Epileptic seizures as condensed sleep: an analysis of network dynamics from electroencephalogram signals

Both deepening sleep and evolving epileptic seizures are associated with increasing slow-wave activity. Larger-scale functional networks derived from electroencephalogram indicate that in both transitions dramatic changes of communication between brain areas occur. During seizures these changes seem to be 'condensed', because they evolve more rapidly than during deepening sleep. Here we set out to assess quantitatively functional network dynamics derived from electroencephalogram signals during seizures and normal sleep. Functional networks were derived from electroencephalogram signals from wakefulness, light and deep sleep of 12 volunteers, and from pre-seizure, seizure and post-seizure time periods of 10 patients suffering from focal onset pharmaco-resistant epilepsy. Nodes of the functional network represented electrical signals recorded by single electrodes and were linked if there was non-random cross-correlation between the two corresponding electroencephalogram signals. Network dynamics were then characterized by the evolution of global efficiency, which measures ease of information transmission. Global efficiency was compared with relative delta power. Global efficiency significantly decreased both between light and deep sleep, and between pre-seizure, seizure and post-seizure time periods. The decrease of global efficiency was due to a loss of functional links. While global efficiency decreased significantly, relative delta power increased except between the time periods wakefulness and light sleep, and pre-seizure and seizure. Our results demonstrate that both epileptic seizures and deepening sleep are characterized by dramatic fragmentation of larger-scale functional networks, and further support the similarities between sleep and seizures.

Comparative effectiveness of long term drug treatment strategies to prevent asthma exacerbations: network meta-analysis

Objective To determine the comparative effectiveness and safety of current maintenance strategies in preventing exacerbations of asthma. Design Systematic review and network meta-analysis using Bayesian statistics. Data sources Cochrane systematic reviews on chronic asthma, complemented by an updated search when appropriate. Eligibility criteria Trials of adults with asthma randomised to maintenance treatments of at least 24 weeks duration and that reported on asthma exacerbations in full text. Low dose inhaled corticosteroid treatment was the comparator strategy. The primary effectiveness outcome was the rate of severe exacerbations. The secondary outcome was the composite of moderate or severe exacerbations. The rate of withdrawal was analysed as a safety outcome. Results 64 trials with 59 622 patient years of follow-up comparing 15 strategies and placebo were included. For prevention of severe exacerbations, combined inhaled corticosteroids and long acting β agonists as maintenance and reliever treatment and combined inhaled corticosteroids and long acting β agonists in a fixed daily dose performed equally well and were ranked first for effectiveness. The rate ratios compared with low dose inhaled corticosteroids were 0.44 (95% credible interval 0.29 to 0.66) and 0.51 (0.35 to 0.77), respectively. Other combined strategies were not superior to inhaled corticosteroids and all single drug treatments were inferior to single low dose inhaled corticosteroids. Safety was best for conventional best (guideline based) practice and combined maintenance and reliever therapy. Conclusions Strategies with combined inhaled corticosteroids and long acting β agonists are most effective and safe in preventing severe exacerbations of asthma, although some heterogeneity was observed in this network meta-analysis of full text reports.

Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis

OBJECTIVE To investigate whether revascularisation improves prognosis compared with medical treatment among patients with stable coronary artery disease. DESIGN Bayesian network meta-analyses to combine direct within trial comparisons between treatments with indirect evidence from other trials while maintaining randomisation. ELIGIBILITY CRITERIA FOR SELECTING STUDIES A strategy of initial medical treatment compared with revascularisation by coronary artery bypass grafting or Food and Drug Administration approved techniques for percutaneous revascularization: balloon angioplasty, bare metal stent, early generation paclitaxel eluting stent, sirolimus eluting stent, and zotarolimus eluting (Endeavor) stent, and new generation everolimus eluting stent, and zotarolimus eluting (Resolute) stent among patients with stable coronary artery disease. DATA SOURCES Medline and Embase from 1980 to 2013 for randomised trials comparing medical treatment with revascularisation. MAIN OUTCOME MEASURE All cause mortality. RESULTS 100 trials in 93 553 patients with 262 090 patient years of follow-up were included. Coronary artery bypass grafting was associated with a survival benefit (rate ratio 0.80, 95% credibility interval 0.70 to 0.91) compared with medical treatment. New generation drug eluting stents (everolimus: 0.75, 0.59 to 0.96; zotarolimus (Resolute): 0.65, 0.42 to 1.00) but not balloon angioplasty (0.85, 0.68 to 1.04), bare metal stents (0.92, 0.79 to 1.05), or early generation drug eluting stents (paclitaxel: 0.92, 0.75 to 1.12; sirolimus: 0.91, 0.75 to 1.10; zotarolimus (Endeavor): 0.88, 0.69 to 1.10) were associated with improved survival compared with medical treatment. Coronary artery bypass grafting reduced the risk of myocardial infarction compared with medical treatment (0.79, 0.63 to 0.99), and everolimus eluting stents showed a trend towards a reduced risk of myocardial infarction (0.75, 0.55 to 1.01). The risk of subsequent revascularisation was noticeably reduced by coronary artery bypass grafting (0.16, 0.13 to 0.20) followed by new generation drug eluting stents (zotarolimus (Resolute): 0.26, 0.17 to 0.40; everolimus: 0.27, 0.21 to 0.35), early generation drug eluting stents (zotarolimus (Endeavor): 0.37, 0.28 to 0.50; sirolimus: 0.29, 0.24 to 0.36; paclitaxel: 0.44, 0.35 to 0.54), and bare metal stents (0.69, 0.59 to 0.81) compared with medical treatment. CONCLUSION Among patients with stable coronary artery disease, coronary artery bypass grafting reduces the risk of death, myocardial infarction, and subsequent revascularisation compared with medical treatment. All stent based coronary revascularisation technologies reduce the need for revascularisation to a variable degree. Our results provide evidence for improved survival with new generation drug eluting stents but no other percutaneous revascularisation technology compared with medical treatment.

Integrating fragmented evidence by network meta-analysis: relative effectiveness of psychological interventions for adults with post-traumatic stress disorder

BACKGROUND To summarize the available evidence on the effectiveness of psychological interventions for patients with post-traumatic stress disorder (PTSD). METHOD We searched bibliographic databases and reference lists of relevant systematic reviews and meta-analyses for randomized controlled trials that compared specific psychological interventions for adults with PTSD symptoms either head-to-head or against control interventions using non-specific intervention components, or against wait-list control. Two investigators independently extracted the data and assessed trial characteristics. RESULTS The analyses included 4190 patients in 66 trials. An initial network meta-analysis showed large effect sizes (ESs) for all specific psychological interventions (ESs between -1.10 and -1.37) and moderate effects of psychological interventions that were used to control for non-specific intervention effects (ESs -0.58 and -0.62). ES differences between various types of specific psychological interventions were absent to small (ES differences between 0.00 and 0.27). Considerable between-trial heterogeneity occurred (τ 2 = 0.30). Stratified analyses revealed that trials that adhered to DSM-III/IV criteria for PTSD were associated with larger ESs. However, considerable heterogeneity remained. Heterogeneity was reduced in trials with adequate concealment of allocation and in large-sized trials. We found evidence for small-study bias. CONCLUSIONS Our findings show that patients with a formal diagnosis of PTSD and those with subclinical PTSD symptoms benefit from different psychological interventions. We did not identify any intervention that was consistently superior to other specific psychological interventions. However, the robustness of evidence varies considerably between different psychological interventions for PTSD, with most robust evidence for cognitive behavioral and exposure therapies.

Percutaneous closure of patent foramen ovale in patients with cryptogenic embolism: a network meta-analysis

BACKGROUND Up to 40% of ischaemic strokes are cryptogenic. A strong association between cryptogenic stroke and the prevalence of patent foramen ovale (PFO) suggests paradoxical embolism via PFO as a potential cause. Randomized trials failed to demonstrate superiority of PFO closure over medical therapy. METHODS AND RESULTS Randomized trials comparing percutaneous PFO closure against medical therapy or devices head-to-head published or presented by March 2013 were identified through a systematic search. We performed a network meta-analysis to determine the effectiveness and safety of PFO closure with different devices when compared with medical therapy. We included four randomized trials (2963 patients with 9309 patient-years). Investigated devices were Amplatzer (AMP), STARFlex (STF), and HELEX (HLX). Patients allocated to PFO closure with AMP were less likely to experience a stroke than patients allocated to medical therapy [rate ratio (RR) 0.39; 95% CI: 0.17-0.84]. No significant differences were found for STF (RR 1.01; 95% CI: 0.44-2.41), and HLX (RR, 0.71; 95% CI: 0.17-2.78) when compared with medical therapy. The probability to be best in preventing strokes was 77.1% for AMP, 20.9% for HLX, 1.7% for STF, and 0.4% for medical therapy. No significant differences were found for transient ischaemic attack and death. The risk of new-onset atrial fibrillation was more pronounced for STF (RR 7.67; 95% CI: 3.25-19.63), than AMP (RR 2.14; 95% CI: 1.00-4.62) and HLX (RR 1.33; 95%-CI 0.33-4.50), when compared with medical therapy. CONCLUSIONS The effectiveness of PFO closure depends on the device used. PFO closure with AMP appears superior to medical therapy in preventing strokes in patients with cryptogenic embolism.

Initial orthodontic alignment effectiveness with self-ligating and conventional appliances: a network meta-analysis in practice.

Systematic reviews of well-designed trials constitute a high level of scientific evidence and are important for medical decision making. Meta-analysis facilitates integration of the evidence using a transparent and systematic approach, leading to a broader interpretation of treatment effectiveness and safety than can be attained from individual studies. Traditional meta-analyses are limited to comparing just 2 interventions concurrently and cannot combine evidence concerning multiple treatments. A relatively recent extension of the traditional meta-analytical approach is network meta-analysis, which allows, under certain assumptions, the quantitative synthesis of all evidence under a unified framework and across a network of all eligible trials. Network meta-analysis combines evidence from direct and indirect information via common comparators; interventions can therefore be ranked in terms of the analyzed outcome. In this article, the network meta-analysis approach is introduced in a nontechnical manner using a worked example on the treatment effectiveness of conventional and self-ligating appliances.

Percutaneous coronary interventional strategies for treatment of in-stent restenosis: a network meta-analysis.

BACKGROUND Percutaneous coronary intervention (PCI) with drug-eluting stents is the standard of care for treatment of native coronary artery stenoses, but optimum treatment strategies for bare metal stent and drug-eluting stent in-stent restenosis (ISR) have not been established. We aimed to compare and rank percutaneous treatment strategies for ISR. METHODS We did a network meta-analysis to synthesise both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library Central Register of Controlled Trials, and Embase for randomised controlled trials published up to Oct 31, 2014, of different PCI strategies for treatment of any type of coronary ISR. The primary outcome was percent diameter stenosis at angiographic follow-up. This study is registered with PROSPERO, number CRD42014014191. FINDINGS We deemed 27 trials eligible, including 5923 patients, with follow-up ranging from 6 months to 60 months after the index intervention. Angiographic follow-up was available for 4975 (84%) of 5923 patients 6-12 months after the intervention. PCI with everolimus-eluting stents was the most effective treatment for percent diameter stenosis, with a difference of -9·0% (95% CI -15·8 to -2·2) versus drug-coated balloons (DCB), -9·4% (-17·4 to -1·4) versus sirolimus-eluting stents, -10·2% (-18·4 to -2·0) versus paclitaxel-eluting stents, -19·2% (-28·2 to -10·4) versus vascular brachytherapy, -23·4% (-36·2 to -10·8) versus bare metal stents, -24·2% (-32·2 to -16·4) versus balloon angioplasty, and -31·8% (-44·8 to -18·6) versus rotablation. DCB were ranked as the second most effective treatment, but without significant differences from sirolimus-eluting (-0·2% [95% CI -6·2 to 5·6]) or paclitaxel-eluting (-1·2% [-6·4 to 4·2]) stents. INTERPRETATION These findings suggest that two strategies should be considered for treatment of any type of coronary ISR: PCI with everolimus-eluting stents because of the best angiographic and clinical outcomes, and DCB because of its ability to provide favourable results without adding a new stent layer. FUNDING None.

GetReal in network meta-analysis: a review of the methodology.

Pairwise meta-analysis is an established statistical tool for synthesizing evidence from multiple trials, but it is informative only about the relative efficacy of two specific interventions. The usefulness of pairwise meta-analysis is thus limited in real-life medical practice, where many competing interventions may be available for a certain condition and studies informing some of the pairwise comparisons may be lacking. This commonly encountered scenario has led to the development of network meta-analysis (NMA). In the last decade, several applications, methodological developments, and empirical studies in NMA have been published, and the area is thriving as its relevance to public health is increasingly recognized. This article presents a review of the relevant literature on NMA methodology aiming to pinpoint the developments that have appeared in the field. Copyright © 2016 John Wiley & Sons, Ltd.

Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia: A Network Meta-analysis.

Importance In treatment-resistant schizophrenia, clozapine is considered the standard treatment. However, clozapine use has restrictions owing to its many adverse effects. Moreover, an increasing number of randomized clinical trials (RCTs) of other antipsychotics have been published. Objective To integrate all the randomized evidence from the available antipsychotics used for treatment-resistant schizophrenia by performing a network meta-analysis. Data Sources MEDLINE, EMBASE, Biosis, PsycINFO, PubMed, Cochrane Central Register of Controlled Trials, World Health Organization International Trial Registry, and clinicaltrials.gov were searched up to June 30, 2014. Study Selection At least 2 independent reviewers selected published and unpublished single- and double-blind RCTs in treatment-resistant schizophrenia (any study-defined criterion) that compared any antipsychotic (at any dose and in any form of administration) with another antipsychotic or placebo. Data Extraction and Synthesis At least 2 independent reviewers extracted all data into standard forms and assessed the quality of all included trials with the Cochrane Collaboration's risk-of-bias tool. Data were pooled using a random-effects model in a Bayesian setting. Main Outcomes and Measures The primary outcome was efficacy as measured by overall change in symptoms of schizophrenia. Secondary outcomes included change in positive and negative symptoms of schizophrenia, categorical response to treatment, dropouts for any reason and for inefficacy of treatment, and important adverse events. Results Forty blinded RCTs with 5172 unique participants (71.5% men; mean [SD] age, 38.8 [3.7] years) were included in the analysis. Few significant differences were found in all outcomes. In the primary outcome (reported as standardized mean difference; 95% credible interval), olanzapine was more effective than quetiapine (-0.29; -0.56 to -0.02), haloperidol (-0. 29; -0.44 to -0.13), and sertindole (-0.46; -0.80 to -0.06); clozapine was more effective than haloperidol (-0.22; -0.38 to -0.07) and sertindole (-0.40; -0.74 to -0.04); and risperidone was more effective than sertindole (-0.32; -0.63 to -0.01). A pattern of superiority for olanzapine, clozapine, and risperidone was seen in other efficacy outcomes, but results were not consistent and effect sizes were usually small. In addition, relatively few RCTs were available for antipsychotics other than clozapine, haloperidol, olanzapine, and risperidone. The most surprising finding was that clozapine was not significantly better than most other drugs. Conclusions and Relevance Insufficient evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia, and blinded RCTs-in contrast to unblinded, randomized effectiveness studies-provide little evidence of the superiority of clozapine compared with other second-generation antipsychotics. Future clozapine studies with high doses and patients with extremely treatment-refractory schizophrenia might be most promising to change the current evidence.