Randomized Clinical-Trial of Manipulative Therapy and Physiotherapy for Persistent Back and Neck Complaints - Results of One Year Follow-Up

Objective - To compare the effectiveness of manipulative therapy, physiotherapy, treatment by the general practitioner, and placebo therapy in patients with persistent non-specific back and neck complaints. Design - Randomised clinical trial. Setting-Primary health care in the Netherlands. Patients-256 patients with non-specific back and neck complaints of at least six weeks' duration who had not received physiotherapy or manipulative therapy in the past two years. Interventions - At the discretion of the manipulative therapists, physiotherapists, and general practitioners. Physiotherapy consisted of exercises, massage, and physical therapy (heat, electrotherapy, ultrasound, shortwave diathermy). Manipulative therapy consisted of manipulation and mobilisation of the spine. Treatment by general practitioners consisted of drugs (for example, analgesics), advice about posture, home exercises, and (bed)rest. Placebo treatment consisted of detuned shortwave diathermy (10 minutes) and detuned ultrasound (10 minutes). Main outcome measures - Changes in severity of the main complaint and limitation of physical functioning measured on 10 point scales by a blinded research assistant and global perceived effect measured on a 6 point scale by the patients. Results - Many patients in the general practitioner and placebo groups received other treatment during follow up. Improvement in the main complaint was larger with manipulative therapy (4·5) than with physiotherapy (3·8) after 12 months' follow up (difference 0·9; 95% confidence interval 0·1 to 1·7). Manipulative therapy also gave larger improvements in physical functioning (difference 0·6; -0·1 to 1·3). The global perceived effect after six and 12 months' follow up was similar for both treatments. Conclusions - Manipulative therapy and physiotherapy are better than general practitioner and placebo treatment. Furthermore, manipulative therapy is slightly better than physiotherapy after 12 months

Efficacy of paracetamol, diclofenac and advice for acute low back pain in general practice: design of a randomized controlled trial (PACE Plus)

Background: Low back pain is common and associated with a considerable burden to patients and society. There is uncertainty regarding the relative benefit of paracetamol and diclofenac and regarding the additional effect of pain medication compared with advice only in patients with acute low back pain. This trial will assess the effectiveness of paracetamol, diclofenac and placebo for acute low back pain over a period of 4 weeks. Furthermore, this trial will assess the additional effectiveness of paracetamol, diclofenac and placebo compared with advice only for acute low back pain over a period of 4 weeks. Methods: The PACE Plus trial is a multi-center, placebo-blinded, superiority randomized controlled trial in primary care, with a follow-up of 12 weeks. Patients with acute low back pain aged 18-60 years presenting in general practice will be included. Patients are randomized into four groups: 1) Advice only (usual care conforming with the clinical guideline of the Dutch College of General Practitioners); 2) Advice and paracetamol; 3) Advice and diclofenac; 4) Advice and placebo. The primary outcome is low back pain intensity measured with a numerical rating scale (0-10). Secondary outcomes include compliance to treatment, disability, perceived recovery, costs, adverse reactions, satisfaction, sleep quality, co-interventions and adequacy of blinding. Between group differences for low back pain intensity will be evaluated using a repeated measurements analysis with linear effects models. An economic evaluation will be performed using a cost-effectiveness analysis with low back pain intensity and a cost-utility analysis with quality of life. Explorative analyses will be performed to assess effect modification by predefined variables. Ethical approval has been granted. Trial results will be released to an appropriate peer-viewed journal. Discussion: This paper presents the design of the PACE Plus trial: a multi-center, placebo-blinded, superiority randomized controlled trial in primary care that will assess the effectiveness of advice only, paracetamol, diclofenac and placebo for acute low back pain. Trial registration: Dutch Trial Registration NTR6089 , registered September 14th, 2016. Protocol: Version 4, June 2016

NADPH oxidase 2 inhibitors CPP11G and CPP11H attenuate endothelial cell inflammation & vessel dysfunction and restore mouse hind-limb flow.

First described as essential to the phagocytic activity of leukocytes, Nox2-derived ROS have emerged as mediators of a range of cellular and tissue responses across species from salubrious to deleterious consequences. Knowledge of their role in inflammation is limited, however. We postulated that TNFα-induced endothelial reactive oxygen species (ROS) generation and pro-inflammatory signaling would be ameliorated by targeting Nox2. Herein, we in silico-modelled two first-in-class Nox2 inhibitors developed in our laboratory, explored their cellular mechanism of action and tested their efficacy in in vitro and mouse in vivo models of inflammation. Our data show that these inhibitors (CPP11G and CPP11H) disrupted canonical Nox2 organizing factor, p47phox, translocation to Nox2 in the plasma membrane; and abolished ROS production, markedly attenuated stress-responsive MAPK signaling and downstream AP-1 and NFκB nuclear translocation in human cells. Consequently, cell adhesion molecule expression and monocyte adherence were significantly inhibited by both inhibitors. In vivo, TNFα-induced ROS and inflammation were ameliorated by targeted Nox2 inhibition, which, in turn, improved hind-limb blood flow. These studies identify a proximal role for Nox2 in propagated inflammatory signaling and support therapeutic value of Nox2 inhibitors in inflammatory disease

Reducing progression of knee OA features assessed by MRI in overweight and obese women: Secondary outcomes of a preventive RCT

Objective: To evaluate the preventive effects of a randomized controlled trial on progression of Magnetic Resonance Imaging (MRI) features of knee osteoarthritis (OA) in overweight and obese women. Design: In a 2 × 2 factorial design, 2.5 years effects of a diet and exercise program and of glucosamine sulphate (double-blind, placebo-controlled) were evaluated in 407 middle-aged women with body mass index (BMI) ≥ 27 kg/m2 without clinical signs of knee OA at baseline (ISRCTN 42823086). MRIs were scored with the MRI Osteoarthritis Knee Score (MOAKS). Progression was defined for bone marrow lesions (BMLs), cartilage defects, osteophytes, meniscal abnormalities and meniscal extrusion. Analyses on knee level were performed over the four intervention groups using adjusted Generalized Estimating Equations (GEE). Results: 687 knees of 347 women with mean age 55.7 years (±3.2 SD) and mean BMI 32.3 kg/m2 (±4.2 SD) were analyzed. Baseline prevalence was 64% for BMLs, 70% for cartilage defects, 24% for osteophytes, 66% for meniscal abnormalities and 52% for meniscal extrusions. The diet and exercise program + placebo intervention showed significantly less progression of meniscal extrusion compared to placebo only (12% vs 22%, OR 0.50, 95% CI [0.27-0.92]). The interventions did not result in significant differences on other OA MRI features. Conclusions: In subjects at high risk for future knee OA development, a diet and exercise program, glucosamine sulphate and their combination showed small and mainly non-significant effects on the progression of OA MRI features. Only progression of meniscal extrusion was significantly diminished by the diet and exercise program

Chronic non-specific low back pain - sub-groups or a single mechanism?

Copyright 2008 Wand and O'Connell; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Low back pain is a substantial health problem and has subsequently attracted a considerable amount of research. Clinical trials evaluating the efficacy of a variety of interventions for chronic non-specific low back pain indicate limited effectiveness for most commonly applied interventions and approaches. Discussion: Many clinicians challenge the results of clinical trials as they feel that this lack of effectiveness is at odds with their clinical experience of managing patients with back pain. A common explanation for this discrepancy is the perceived heterogeneity of patients with chronic non-specific low back pain. It is felt that the effects of treatment may be diluted by the application of a single intervention to a complex, heterogeneous group with diverse treatment needs. This argument presupposes that current treatment is effective when applied to the correct patient. An alternative perspective is that the clinical trials are correct and current treatments have limited efficacy. Preoccupation with sub-grouping may stifle engagement with this view and it is important that the sub-grouping paradigm is closely examined. This paper argues that there are numerous problems with the sub-grouping approach and that it may not be an important reason for the disappointing results of clinical trials. We propose instead that current treatment may be ineffective because it has been misdirected. Recent evidence that demonstrates changes within the brain in chronic low back pain sufferers raises the possibility that persistent back pain may be a problem of cortical reorganisation and degeneration. This perspective offers interesting insights into the chronic low back pain experience and suggests alternative models of intervention. Summary: The disappointing results of clinical research are commonly explained by the failure of researchers to adequately attend to sub-grouping of the chronic non-specific low back pain population. Alternatively, current approaches may be ineffective and clinicians and researchers may need to radically rethink the nature of the problem and how it should best be managed

Do self-management supportive interventions reduce healthcare utilization for people with musculoskeletal pain conditions? – A systematic review

Objective: The aim of this systematic review was to investigate the effect of self-management supportive interventions on healthcare utilization in adult cares seekers with musculoskeletal pain conditions. Study design: Systematic review. Methods: We included studies comparing the effect of a self-management supportive intervention against a control intervention and included measures of healthcare utilization. Studies were searched in MEDLINE, Embase, PsycINFO, CINAHL, Pedro, and the Cochrane Library. Results were extracted for the follow-up point closest to 12 months. Risk of bias was assessed using the Cochrane Risk of Bias tool 2, and quality of evidence by The Grading of Recommendations Assessment, Development and Evaluation. Results were synthesized on study level as mean differences or odds ratios with 95 % CI. Results: We included 28 studies. Eighteen studies reported on the use of primary care at follow-up, and ten, four, and 13 on specialty care, diagnostics imaging, and oral pain medication, respectively. Overall, there was very low-quality evidence for no effect of self-management interventions on healthcare utilization in all groups. All studies were classified as either having a “high risk of bias” or “some concerns”. Conclusion: Due to substantial heterogeneity in the types and measurement of healthcare utilization outcomes, it was not feasible to conduct a meta-analysis to estimate an overall effect size. A standardized way of reporting and measuring these outcomes could aid future research in this area. The current evidence suggests that self-management supportive interventions do not affect healthcare utilization in people with musculoskeletal pain conditions, but future high-quality studies may substantially change this conclusion.</p

Risk models for lower extremity injuries among short- and long distance runners: A prospective cohort study

© 2018 Background: Running injuries are very common. Risk factors for running injuries are not consistently described across studies and do not differentiate between runners of long- and short distances within one cohort. Objectives: The aim of this study is to determine risk factors for running injuries in recreational long- and short distance runners separately. Design: A prospective cohort study. Methods: Recreational runners from four different running events are invited to participate. They filled in a baseline questionnaire assessing possible risk factors about 4 weeks before the run and one a week after the run assessing running injuries. Using logistic regression we developed an overall risk model and separate risk models based on the running distance. Results: In total 3768 runners participated in this study. The overall risk model contained 4 risk factors: previous injuries (OR 3.7) and running distance during the event (OR 1.3) increased the risk of a running injury whereas older age (OR 0.99) and more training kilometers per week (OR 0.99) showed a decrease. Models between short- and long distance runners did not differ significantly. Previous injuries increased the risk of a running injury in all models, while more training kilometers per week decreased this risk. Conclusions: We found that risk factors for running injuries were not related to running distances. Previous injury is a generic risk factor for running injuries, as is weekly training distance. Prevention of running injuries is important and a higher weekly training volume seems to prevent injuries to a certain extent

Evaluation of a Theory-Informed Implementation Intervention for the Management of Acute Low Back Pain in General Medical Practice: The IMPLEMENT Cluster Randomised Trial

Introduction: This cluster randomised trial evaluated an intervention to decrease x-ray referrals and increase giving advice to stay active for people with acute low back pain (LBP) in general practice. Methods: General practices were randomised to either access to a guideline for acute LBP (control) or facilitated interactive workshops (intervention). We measured behavioural predictors (e.g. knowledge, attitudes and intentions) and fear avoidance beliefs. We were unable to recruit sufficient patients to measure our original primary outcomes so we introduced other outcomes measured at the general practitioner (GP) level: behavioural simulation (clinical decision about vignettes) and rates of x-ray and CT-scan (medical administrative data). All those not involved in the delivery of the intervention were blinded to allocation. Results: 47 practices (53 GPs) were randomised to the control and 45 practices (59 GPs) to the intervention. The number of GPs available for analysis at 12 months varied by outcome due to missing confounder information; a minimum of 38 GPs were available from the intervention group, and a minimum of 40 GPs from the control group. For the behavioural constructs, although effect estimates were small, the intervention group GPs had greater intention of practising consistent with the guideline for the clinical behaviour of x-ray referral. For behavioural simulation, intervention group GPs were more likely to adhere to guideline recommendations about x-ray (OR 1.76, 95%CI 1.01, 3.05) and more likely to give advice to stay active (OR 4.49, 95%CI 1.90 to 10.60). Imaging referral was not statistically significantly different between groups and the potential importance of effects was unclear; rate ratio 0.87 (95%CI 0.68, 1.10) for x-ray or CT-scan. Conclusions: The intervention led to small changes in GP intention to practice in a manner that is consistent with an evidence-based guideline, but it did not result in statistically significant changes in actual behaviour. Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN01260600009853

Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists

Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure. © 2012 Koes et al