Using Physical Chemistry To Differentiate Nicotinic from Cholinergic Agonists at the Nicotinic Acetylcholine Receptor

The binding of three distinct agonists - acetylcholine (ACh), nicotine, and epibatidine - to the nicotinic acetylcholine receptor has been probed using unnatural amino acid mutagenesis. ACh makes a cation−π interaction with Trp α149, while nicotine employs a hydrogen bond to a backbone carbonyl in the same region of the agonist binding site. The nicotine analogue epibatidine achieves its high potency by taking advantage of both the cation−π interaction and the backbone hydrogen bond. A simple structural model that considers only possible interactions with Trp α149 suggests that a novel aromatic C - H···O=C hydrogen bond further augments the binding of epibatidine. These studies illustrate the subtleties and complexities of the interactions between drugs and membrane receptors and establish a paradigm for obtaining detailed structural information

Is there a causal relationship between acute stage sensorimotor cortex activity and the development of chronic low back pain? : a protocol and statistical analysis plan

Introduction: Why some people develop chronic pain following an acute episode of low back pain is unknown. Recent cross-sectional studies have suggested a relationship between aberrant sensorimotor cortex activity and pain persistence. The UPWaRD (Understanding persistent Pain Where it ResiDes) cohort study is the first prospective, longitudinal investigation of sensorimotor cortex activity in low back pain. This paper describes the development of a causal model and statistical analysis plan for investigating the causal effect of sensorimotor cortex activity on the development of chronic low back pain. Methods and analysis: Sensorimotor cortex activity was assessed within 6 weeks of low back pain onset using somatosensory evoked potentials and transcranial magnetic stimulation mapping techniques. Chronic low back pain is defined as ongoing pain (Numerical Rating score ≥1) or disability (Roland Morris Disability Questionnaire score ≥3) at 6 months follow-up. Variables that could confound the relationship between sensorimotor cortex activity and chronic low back pain were identified using a directed acyclic graph and content expertise was used to specify known causal paths. The statistical model was developed ‘a priori’ to control for confounding variables identified in the directed acyclic graph, allowing an unbiased estimate of the causal effect of sensorimotor activity in acute low back pain on the development of chronic pain. The statistical analysis plan was finalised prior to follow-up of all participants and initiation of analysis. Ethics and dissemination: Ethical approval has been obtained from Western Sydney University Human Research Ethics Committee (H10465) and from Neuroscience Research Australia (SSA: 16/002). Dissemination will occur through presentations at national and international conferences and publications in international peer-reviewed journals. Trial registration number: ACTRN12619000002189 (retrospectively registered)

It\u27s safe to move! A protocol for a randomised controlled trial investigating the effect of a video designed to increase people\u27s confidence becoming more active despite back pain

Introduction Social media provide promising contemporary platforms for sharing public health information with a broad audience. Before implementation, testing social media campaigns that are intended to engage audiences and initiate behaviour change is necessary. This trial aims to investigate the effectiveness of a public health campaign to increase people\u27s confidence in becoming more active despite low back pain in comparison with no intervention. Methods and analysis This is an online randomised controlled trial with two intervention groups and one control group in a 1:1:1 allocation. People over 18 years of age and fluent in English will be recruited via social media advertising. We developed a social media-based public health campaign to support recommendations for managing low back pain. The interventions are two videos. Participants in the control group will be asked questions about low back pain but will not view either video intervention. The primary outcome will be item 10 of the Pain Self-Efficacy Questionnaire, which asks participants to rate how confident they would feel to gradually become more active despite pain ranging from 0 (not at all confident) to 6 (completely confident). This outcome will be measured immediately in all participant groups. We will compare group mean of the three arms of the trial using univariate analyses of variance. Ethics and dissemination This trial has been prospectively registered with the Australian New Zealand Clinical Trials Registry. We obtained ethical approval from our institutions Human Research Ethics Committee before data collection. We will publish the results in a peer-reviewed medical journal and on institution websites

Efficacy and Safety of Medicines Targeting Neurotrophic Factors in the Management of Low Back Pain: Protocol for a Systematic Review and Meta-Analysis (Preprint)

BACKGROUND Low back pain (LBP) is the leading cause of years lived with disability worldwide. Most people with LBP receive the diagnosis of nonspecific LBP or sciatica. Medications are commonly prescribed but have limited analgesic effects and are associated with adverse events. A novel treatment approach is to target neurotrophins such as nerve growth factor (NGF) to reduce pain intensity. NGF inhibitors have been tested in some randomized controlled trials (RCTs) in recent years, showing promise for the treatment of chronic LBP; however, their efficacy and safety need to be evaluated to guide regulatory actions. OBJECTIVE The aim of this study is to evaluate the efficacy and safety of medicines targeting neurotrophins in patients with LBP and sciatica. METHODS In this systematic review, we will include published and unpublished records of parallel RCTs and the first phase of crossover RCTs that compare the effects of medicines targeting neurotrophins with any control group. We will search the CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, EU Clinical Trials Register, and WHO International Clinical Registry Platform databases from inception. Pairs of authors will independently screen the records for eligibility, and we will independently extract data in duplicate. We will conduct a quantitative synthesis (meta-analysis) with the studies that report sufficient data and compare the medicines of interest versus placebo. We will use random-effects models and calculate estimates of effects and heterogeneity for each outcome. We will assess the risk of bias for each study using the Cochrane Collaboration tool, and form judgments of confidence in the evidence according to GRADE recommendations. We will use the PRISMA statement to report the findings. We plan to conduct subgroup analyses by condition, type of medication, and time point. We will also assess the impact of a potential new trial on an existing meta-analysis. Data from studies that meet inclusion criteria but cannot be included in the meta-analysis will be reported narratively. RESULTS The protocol was registered on the Open Science Framework on May 19, 2020. As of December 2020, we have identified 1932 records. CONCLUSIONS This systematic review and meta-analysis will assess the evidence for the efficacy and safety of NGF inhibitors for pain in patients with nonspecific LBP and sciatica. The inclusion of new studies and unpublished data may improve the precision of the effect estimates and guide regulatory actions of the medications for LBP and sciatica. CLINICALTRIAL Open Science Framework; https://osf.io/b8adn/ INTERNATIONAL REGISTERED REPORT DERR1-10.2196/22905 </sec

Development and measurement properties of the AxEL (attitude toward education and advice for low-back-pain) questionnaire

Introduction: Clinician time and resources may be underutilised if the treatment they offer does not match patient expectations and attitudes. We developed a questionnaire (AxEL-Q) to guide clinicians toward elements of first-line care that are pertinent to their patients with low back pain. Methods: We used guidance from the COSMIN consortium to develop the questionnaire and evaluated it in a sample of people with low back pain of any duration. Participants were recruited from the community, were over 18 years and fluent in English. Statements that represented first-line care were identified. Semantic scales were used to measure attitude towards these statements. These items were combined to develop the questionnaire draft. Construct validity was evaluated with exploratory factor analysis and hypotheses testing, comparing to the Back Beliefs Questionnaire and modified Pain Self-Efficacy Questionnaire. Reliability was evaluated and floor and ceiling effects calculated. Results: We recruited 345 participants, and had complete data for analysis for 313 participants. The questionnaire draft was reduced to a 3-Factor questionnaire through exploratory factor analysis. Factor 1 comprised 9 items and evaluated Attitude toward staying active, Factor 2 comprised 4 items and evaluated Attitude toward low back pain being rarely caused by a serious health problem, Factor 3 comprised 4 items and evaluated Attitude toward not needing to know the cause of back pain to manage it effectively. There was a strong inverse association between each factor and the Back Beliefs Questionnaire and a moderate positive association with the modified Pain Self-Efficacy Questionnaire. Each independent factor demonstrated acceptable internal consistency; Cronbach α Factor 1 = 0.92, Factor 2 = 0.91, Factor 3 = 0.90 and adequate interclass correlation coefficients; Factor 1 = 0.71, Factor 2 = 0.73, Factor 3 = 0.79. Conclusion: This study demonstrates acceptable construct validity and reliability of the AxEL-Q, providing clinicians with an insight into the likelihood of patients following first-line care at the outset

Efficacy, acceptability, and safety of muscle relaxants for adults with non-specific low back pain : systematic review and meta-analysis

Abstract: Objective To investigate the efficacy, acceptability, and safety of muscle relaxants for low back pain. Design: Systematic review and meta-analysis of randomised controlled trials. Data sources: Medline, Embase, CINAHL, CENTRAL, ClinicalTrials.gov, clinicialtrialsregister.eu, and WHO ICTRP from inception to 23 February 2021. Eligibility criteria for study selection: Randomised controlled trials of muscle relaxants compared with placebo, usual care, waiting list, or no treatment in adults (≥18 years) reporting non-specific low back pain. Data extraction and synthesis: Two reviewers independently identified studies, extracted data, and assessed the risk of bias and certainty of the evidence using the Cochrane risk-of-bias tool and Grading of Recommendations, Assessment, Development and Evaluations, respectively. Random effects meta-analytical models through restricted maximum likelihood estimation were used to estimate pooled effects and corresponding 95% confidence intervals. Outcomes included pain intensity (measured on a 0-100 point scale), disability (0-100 point scale), acceptability (discontinuation of the drug for any reason during treatment), and safety (adverse events, serious adverse events, and number of participants who withdrew from the trial because of an adverse event). Results: 49 trials were included in the review, of which 31, sampling 6505 participants, were quantitatively analysed. For acute low back pain, very low certainty evidence showed that at two weeks or less non-benzodiazepine antispasmodics were associated with a reduction in pain intensity compared with control (mean difference -7.7, 95% confidence interval-12.1 to-3.3) but not a reduction in disability (-3.3, -7.3 to 0.7). Low and very low certainty evidence showed that non-benzodiazepine antispasmodics might increase the risk of an adverse event (relative risk 1.6, 1.2 to 2.0) and might have little to no effect on acceptability (0.8, 0.6 to 1.1) compared with control for acute low back pain, respectively. The number of trials investigating other muscle relaxants and different durations of low back pain were small and the certainty of evidence was reduced because most trials were at high risk of bias. Conclusions: Considerable uncertainty exists about the clinical efficacy and safety of muscle relaxants. Very low and low certainty evidence shows that non-benzodiazepine antispasmodics might provide small but not clinically important reductions in pain intensity at or before two weeks and might increase the risk of an adverse event in acute low back pain, respectively. Large, high quality, placebo controlled trials are urgently needed to resolve uncertainty. Systematic review registration PROSPERO CRD42019126820 and Open Science Framework https://osf.io/mu2f5/

Complex regional pain syndrome: advances in epidemiology, pathophysiology, diagnosis, and treatment.

Complex regional pain syndrome (CRPS) is a rare pain disorder that usually occurs in a limb after trauma. The features of this disorder include severe pain and sensory, autonomic, motor, and trophic abnormalities. Research from the past decade has offered new insights into CRPS epidemiology, pathophysiology, diagnosis, and treatment. Early identification of individuals at high risk of CRPS is improving, with several risk factors established and some others identified in prospective studies during the past 5 years. Better understanding of the pathophysiological mechanisms of CRPS has led to its classification as a chronic primary pain disorder, and subtypes of CRPS have been updated. Procedures for diagnosis have also been clarified. Although effective treatment of CRPS remains a challenge, evidence-based integrated management approaches provide new opportunities to improve patient care. Further advances in diagnosis and treatment of CRPS will require coordinated, international multicentre initiatives

The RESOLVE Trial for people with chronic low back pain: Statistical analysis plan

Background: Statistical analysis plans describe the planned data management and analysis for clinical trials. This supports transparent reporting and interpretation of clinical trial results. This paper reports the statistical analysis plan for the RESOLVE clinical trial. The RESOLVE trial assigned participants with chronic low back pain to graded sensory-motor precision training or sham-control. Results: We report the planned data management and analysis for the primary and secondary outcomes. The primary outcome is pain intensity at 18-weeks post randomization. We will use mixed-effects models to analyze the primary and secondary outcomes by intention-to-treat. We will report adverse effects in full. We also describe analyses if there is non-adherence to the interventions, data management procedures, and our planned reporting of results. Conclusion: This statistical analysis plan will minimize the potential for bias in the analysis and reporting of results from the RESOLVE trial. Trial registration: ACTRN12615000610538 (https://www.anzctr.org.au/Trial/Registration/ TrialReview.aspx?id=368619). © 2020 Associac¸ao˜ Brasileira de Pesquisa e Pos-Graduac ´ ¸ao˜ em Fisioterapia. Published by Elsevier Editora Ltda. All rights reserved

Development of the TrAnsparent ReportinG of observational studies Emulating a Target trial (TARGET) guideline [protocol].

BACKGROUND Observational studies are increasingly used to inform health decision-making when randomised trials are not feasible, ethical or timely. The target trial approach provides a framework to help minimise common biases in observational studies that aim to estimate the causal effect of interventions. Incomplete reporting of studies using the target trial framework limits the ability for clinicians, researchers, patients and other decision-makers to appraise, synthesise and interpret findings to inform clinical and public health practice and policy. This paper describes the methods that we will use to develop the TrAnsparent ReportinG of observational studies Emulating a Target trial (TARGET) reporting guideline. METHODS/DESIGN The TARGET reporting guideline will be developed in five stages following recommended guidance. The first stage will identify target trial reporting practices by systematically reviewing published studies that explicitly emulated a target trial. The second stage will identify and refine items to be considered for inclusion in the TARGET guideline by consulting content experts using sequential online surveys. The third stage will prioritise and consolidate key items to be included in the TARGET guideline at an in-person consensus meeting of TARGET investigators. The fourth stage will produce and pilot-test both the TARGET guideline and explanation and elaboration document with relevant stakeholders. The fifth stage will disseminate the TARGET guideline and resources via journals, conferences and courses. ETHICS AND DISSEMINATION Ethical approval for the survey has been attained (HC220536). The TARGET guideline will be disseminated widely in partnership with stakeholders to maximise adoption and improve reporting of these studies