Interventions for treating pain and disability in adults with complex regional pain syndrome - An overview of systematic reviews

This article is available open access through the publisher’s website at the link below. Copyright © 2013 The Cochrane Collaboration.Background - There is currently no strong consensus regarding the optimal management of complex regional pain syndrome although a multitude of interventions have been described and are commonly used. Objectives - To summarise the evidence from Cochrane and non-Cochrane systematic reviews of the effectiveness of any therapeutic intervention used to reduce pain, disability or both in adults with complex regional pain syndrome (CRPS). Methods - We identified Cochrane reviews and non-Cochrane reviews through a systematic search of the following databases: Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Ovid MEDLINE, Ovid EMBASE, CINAHL, LILACS and PEDro. We included non-Cochrane systematic reviews where they contained evidence not covered by identified Cochrane reviews. The methodological quality of reviews was assessed using the AMSTAR tool. We extracted data for the primary outcomes pain, disability and adverse events, and the secondary outcomes of quality of life, emotional well being and participants' ratings of satisfaction or improvement. Only evidence arising from randomised controlled trials was considered. We used the GRADE system to assess the quality of evidence. Main results - We included six Cochrane reviews and 13 non-Cochrane systematic reviews. Cochrane reviews demonstrated better methodological quality than non-Cochrane reviews. Trials were typically small and the quality variable. There is moderate quality evidence that intravenous regional blockade with guanethidine is not effective in CRPS and that the procedure appears to be associated with the risk of significant adverse events. There is low quality evidence that bisphosphonates, calcitonin or a daily course of intravenous ketamine may be effective for pain when compared with placebo; graded motor imagery may be effective for pain and function when compared with usual care; and that mirror therapy may be effective for pain in post-stroke CRPS compared with a 'covered mirror' control. This evidence should be interpreted with caution. There is low quality evidence that local anaesthetic sympathetic blockade is not effective. Low quality evidence suggests that physiotherapy or occupational therapy are associated with small positive effects that are unlikely to be clinically important at one year follow up when compared with a social work passive attention control. For a wide range of other interventions, there is either no evidence or very low quality evidence available from which no conclusions should be drawn. Authors' conclusions - There is a critical lack of high quality evidence for the effectiveness of most therapies for CRPS. Until further larger trials are undertaken, formulating an evidence-based approach to managing CRPS will remain difficult

Non-invasive brain stimulation techniques for chronic pain

Copyright © 2014 The Cochrane Collaboration.Various devices are available that can electrically stimulate the brain without the need for surgery or any invasive treatment in order to manage chronic pain. There are four main treatment types: repetitive transcranial magnetic stimulation (rTMS) in which the brain is stimulated by a coil applied to the scalp, cranial electrotherapy stimulation (CES) in which electrodes are clipped to the ears or applied to the scalp, transcranial direct current stimulation (tDCS) and reduced impedance non-invasive cortical electrostimulation (RINCE) in which electrodes are applied to the scalp. These have been used to try to reduce pain by aiming to alter the activity of the brain, but the efficacy of these treatments is uncertain. This review update included 56 studies: 30 of rTMS, 11 of CES, 14 of tDCS and one of RINCE. We judged only three studies as having a low risk of bias. Low or very low-quality evidence suggests that low-frequency rTMS and rTMS applied to pre-frontal areas of the brain are not effective but that a single dose of high-frequency stimulation of the motor cortex area of the brain provides short-term pain relief. This effect appears to be small and may be exaggerated by a number of sources of bias. Studies that gave a course of multiple treatments of rTMS produced conflicting results with no overall effect seen when we pooled the results of these studies. Most studies of rTMS are small and there is substantial variation between studies in terms of the treatment methods used. Low-quality evidence does not suggest that CES or tDCS are effective treatments for chronic pain. A single small study of RINCE provided very low-quality evidence of a short-term effect on pain. For all forms of stimulation the evidence is not conclusive and uncertainty remains. The reporting of side effects varied across the studies. Of the studies that clearly reported side effects, short-lived and minor side effects such as headache, nausea and skin irritation were usually reported both after real and sham stimulation. There were two reports of seizure following real rTMS. While the broad conclusions for rTMS and CES have not changed substantially, the addition of this new evidence and the application of the GRADE system has modified some of our interpretation. Previous readers should re-read this update. More studies of rigorous design and adequate size are required to evaluate accurately all forms of non-invasive brain stimulation for the treatment of chronic pain

Effects of cranial electrotherapy stimulation on resting state brain activity

Cranial electrotherapy stimulation (CES) is a U.S. Food and Drug Administration (FDA)-approved treatment for insomnia, depression, and anxiety consisting of pulsed, low-intensity current applied to the earlobes or scalp. Despite empirical evidence of clinical efficacy, its mechanism of action is largely unknown. The goal was to characterize the acute effects of CES on resting state brain activity. Our primary hypothesis was that CES would result in deactivation in cortical and subcortical regions. Eleven healthy controls were administered CES applied to the earlobes at subsensory thresholds while being scanned with functional magnetic resonance imaging in the resting state. We tested 0.5- and 100-Hz stimulation, using blocks of 22 sec “on” alternating with 22 sec of baseline (device was “off”). The primary outcome measure was differences in blood oxygen level dependent data associated with the device being on versus baseline. The secondary outcome measures were the effects of stimulation on connectivity within the default mode, sensorimotor, and fronto-parietal networks. Both 0.5- and 100-Hz stimulation resulted in significant deactivation in midline frontal and parietal regions. 100-Hz stimulation was associated with both increases and decreases in connectivity within the default mode network (DMN). Results suggest that CES causes cortical brain deactivation, with a similar pattern for high- and low-frequency stimulation, and alters connectivity in the DMN. These effects may result from interference from high- or low-frequency noise. Small perturbations of brain oscillations may therefore have significant effects on normal resting state brain activity. These results provide insight into the mechanism of action of CES, and may assist in the future development of optimal parameters for effective treatment

Prescribing hand strengthening exercise for patients with rheumatoid arthritis; clinical cues influencing occupational therapists' and physiotherapists' judgements

Acknowledgements: The authors acknowledge the therapists who took part in both phases of this study. This work was supported by Brunel University London and the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care Oxford at Oxford Health NHS Foundation Trust, and supported by the NIHR Biomedical Research Centre, Oxford.Data Availability Statement: The data that support the findings for phase 2 of this study are openly available in figshare at https://doi.org/10.6084/m9.figshare.24681309 .Supporting Information is available online at: https://onlinelibrary.wiley.com/doi/full/10.1002/msc.1849#support-information-section .Copyright © 2023 The Authors. Objective: To explore the clinical judgements of therapists in prescribing the intensity of hand strengthening exercise in rheumatoid arthritis (RA). Methods: Phase I: Eleven therapists knowledgeable in treating patients with RA subjectively identified seven clinical cues. These were incorporated into 54 hypothetical patient case scenarios. Phase II: Therapists with ≥2 years post-registration experience and current or recent experience in treating patients with RA were asked to assess 69 case scenarios in total (54 + 15 repeats) and judge what intensity of hand strengthening exercise they would prescribe using the OMNI-Resistance Exercise Scale of perceived exertion. Using responses to the repeated cases, the Cochran-Weiss-Shanteau index of expertise was used to identify therapists who prescribed more consistently. Multiple regression was used to determine which clinical cues were most strongly associated with the intensity of exercise prescribed. A sub-group analysis explored differences between consistent and inconsistent prescribers. Results: Fifty-three therapists took part. Thirty completed all 69 case scenarios. Across all therapists, the three most important clinical cues associated with lower intensity of exercise prescribed were (1) Patient's reported pain intensity whilst practising the exercise (β = −1.150, p < 0.001), (2) Disease activity (β = −0.425, p < 0.001) and (3) average hand pain over the last week (β = −0.353 p < 0.001). Twelve therapists were categorised as consistent prescribers. This group relied on fewer clinical cues (three vs. seven) when judging what intensity of exercise to prescribe. Conclusion: This study provides insights into how therapists prescribe hand exercises. Intensity of hand strengthening exercise was influenced by three key clinical cues, including pain intensity and disease activity.Brunel University London; National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care Oxford at Oxford Health NHS Foundation Trust; NIHR Biomedical Research Centre, Oxford

Disfluency in dialogue:an intentional signal from the speaker?

Disfluency is a characteristic feature of spontaneous human speech, commonly seen as a consequence of problems with production. However, the question remains open as to why speakers are disfluent: Is it a mechanical by-product of planning difficulty, or do speakers use disfluency in dialogue to manage listeners' expectations? To address this question, we present two experiments investigating the production of disfluency in monologue and dialogue situations. Dialogue affected the linguistic choices made by participants, who aligned on referring expressions by choosing less frequent names for ambiguous images where those names had previously been mentioned. However, participants were no more disfluent in dialogue than in monologue situations, and the distribution of types of disfluency used remained constant. Our evidence rules out at least a straightforward interpretation of the view that disfluencies are an intentional signal in dialogue. © 2012 Psychonomic Society, Inc

Ferritins: furnishing proteins with iron

Ferritins are a superfamily of iron oxidation, storage and mineralization proteins found throughout the animal, plant, and microbial kingdoms. The majority of ferritins consist of 24 subunits that individually fold into 4-α-helix bundles and assemble in a highly symmetric manner to form an approximately spherical protein coat around a central cavity into which an iron-containing mineral can be formed. Channels through the coat at inter-subunit contact points facilitate passage of iron ions to and from the central cavity, and intrasubunit catalytic sites, called ferroxidase centers, drive Fe2+ oxidation and O2 reduction. Though the different members of the superfamily share a common structure, there is often little amino acid sequence identity between them. Even where there is a high degree of sequence identity between two ferritins there can be major differences in how the proteins handle iron. In this review we describe some of the important structural features of ferritins and their mineralized iron cores and examine in detail how three selected ferritins oxidise Fe2+ in order to explore the mechanistic variations that exist amongst ferritins. We suggest that the mechanistic differences reflect differing evolutionary pressures on amino acid sequences, and that these differing pressures are a consequence of different primary functions for different ferritins

Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk

Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit interindividual differences in effect, termed 'variable penetrance'. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.Peer reviewe

Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank

Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council HR03006. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z. YZ acknowledges support from China Scholarship Council. IJD is supported by the Centre for Cognitive Ageing and Cognitive Epidemiology which is funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (MR/K026992/1). AMMcI and T-KC acknowledges support from the Dr Mortimer and Theresa Sackler Foundation. We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Ethics approval for the study was given by the NHS Tayside committee on research ethics (reference 05/S1401/8)Peer reviewedPublisher PD

Genome-wide meta-analyses of stratified depression in Generation Scotland and UK Biobank

Abstract Few replicable genetic associations for Major Depressive Disorder (MDD) have been identified. Recent studies of MDD have identified common risk variants by using a broader phenotype definition in very large samples, or by reducing phenotypic and ancestral heterogeneity. We sought to ascertain whether it is more informative to maximize the sample size using data from all available cases and controls, or to use a sex or recurrent stratified subset of affected individuals. To test this, we compared heritability estimates, genetic correlation with other traits, variance explained by MDD polygenic score, and variants identified by genome-wide meta-analysis for broad and narrow MDD classifications in two large British cohorts - Generation Scotland and UK Biobank. Genome-wide meta-analysis of MDD in males yielded one genome-wide significant locus on 3p22.3, with three genes in this region (CRTAP, GLB1, and TMPPE) demonstrating a significant association in gene-based tests. Meta-analyzed MDD, recurrent MDD and female MDD yielded equivalent heritability estimates, showed no detectable difference in association with polygenic scores, and were each genetically correlated with six health-correlated traits (neuroticism, depressive symptoms, subjective well-being, MDD, a cross-disorder phenotype and Bipolar Disorder). Whilst stratified GWAS analysis revealed a genome-wide significant locus for male MDD, the lack of independent replication, and the consistent pattern of results in other MDD classifications suggests that phenotypic stratification using recurrence or sex in currently available sample sizes is currently weakly justified. Based upon existing studies and our findings, the strategy of maximizing sample sizes is likely to provide the greater gain

Btk regulates macrophage polarization in response to lipopolysaccharide

Bacterial Lipopolysaccharide (LPS) is a strong inducer of inflammation and does so by inducing polarization of macrophages to the classic inflammatory M1 population. Given the role of Btk as a critical signal transducer downstream of TLR4, we investigated its role in M1/M2 induction. In Btk deficient (Btk (−\−)) mice we observed markedly reduced recruitment of M1 macrophages following intraperitoneal administration of LPS. Ex vivo analysis demonstrated an impaired ability of Btk(−/−) macrophages to polarize into M1 macrophages, instead showing enhanced induction of immunosuppressive M2-associated markers in response to M1 polarizing stimuli, a finding accompanied by reduced phosphorylation of STAT1 and enhanced STAT6 phosphorylation. In addition to STAT activation, M1 and M2 polarizing signals modulate the expression of inflammatory genes via differential activation of transcription factors and regulatory proteins, including NF-κB and SHIP1. In keeping with a critical role for Btk in macrophage polarization, we observed reduced levels of NF-κB p65 and Akt phosphorylation, as well as reduced induction of the M1 associated marker iNOS in Btk(−/−) macrophages in response to M1 polarizing stimuli. Additionally enhanced expression of SHIP1, a key negative regulator of macrophage polarisation, was observed in Btk(−/−) macrophages in response to M2 polarizing stimuli. Employing classic models of allergic M2 inflammation, treatment of Btk (−/−) mice with either Schistosoma mansoni eggs or chitin resulted in increased recruitment of M2 macrophages and induction of M2-associated genes. This demonstrates an enhanced M2 skew in the absence of Btk, thus promoting the development of allergic inflammation