How does individualised physiotherapy work for people with low back pain? A Bayesian Network analysis using randomised controlled trial data.

Purpose Individualised physiotherapy is an effective treatment for low back pain. We sought to determine how this treatment works by using randomised controlled trial data to develop a Bayesian Network model. Methods 300 randomised controlled trial participants (153 male, 147 female, mean age 44.1) with low back pain (of duration 6–26 weeks) received either individualised physiotherapy or advice. Variables with potential to explain how individualised physiotherapy works were included in a multivariate Bayesian Network model. Modelling incorporated the intervention period (0–10 weeks after study commencement–“early” changes) and the follow-up period (10–52 weeks after study commencement–“late” changes). Sequences of variables in the Bayesian Network showed the most common direct and indirect recovery pathways followed by participants with low back pain receiving individualised physiotherapy versus advice. Results Individualised physiotherapy directly reduced early disability in people with low back pain. Individualised physiotherapy exerted indirect effects on pain intensity, recovery expectations, sleep, fear, anxiety, and depression via its ability to facilitate early improvement in disability. Early improvement in disability, led to an early reduction in depression both directly and via more complex pathways involving fear, recovery expectations, anxiety, and pain intensity. Individualised physiotherapy had its greatest influence on early change variables (during the intervention period). Conclusion Individualised physiotherapy for low back pain appears to work predominately by facilitating an early reduction in disability, which in turn leads to improvements in other biopsychosocial outcomes. The current study cannot rule out that unmeasured mechanisms (such as tissue healing or reduced inflammation) may mediate the relationship between individualised physiotherapy treatment and improvement in disability. Further data-driven analyses involving a broad range of plausible biopsychosocial variables are recommended to fully understand how treatments work for people with low back pain

Understanding how individualised physiotherapy or advice altered different elements of disability for people with low back pain using network analysis.

Purpose The Oswestry Disability Index (ODI) is a common aggregate measure of disability for people with Low Back Pain (LBP). Scores on individual items and the relationship between items of the ODI may help understand the complexity of low back disorders and their response to treatment. In this study, we present a network analysis to explore how individualised physiotherapy or advice might influence individual items of the ODI, and the relationship between those items, at different time points for people with LBP. Methods Data from a randomised controlled trial (n = 300) comparing individualised physiotherapy versus advice for low back pain were used. A network analysis was performed at baseline, 5, 10, 26 and 52 weeks, with the 10 items of the Oswestry Disability Index modelled as continuous variables and treatment group (Individualised Physiotherapy or Advice) modelled as a dichotomous variable. A Mixed Graphical Model was used to estimate associations between variables in the network, while centrality indices (Strength, Closeness and Betweenness) were calculated to determine the importance of each variable. Results Individualised Physiotherapy was directly related to lower Sleep and Pain scores at all follow-up time points relative to advice, as well as a lower Standing score at 10-weeks, and higher Lifting and Travelling scores at 5-weeks. The strongest associations in the network were between Sitting and Travelling at weeks 5 and 26, between Walking and Standing at week 10, and between Sitting and Standing scores at week 52. ODI items with the highest centrality measures were consistently found to be Pain, Work and Social Life. Conclusion This study represents the first to understand how individualised physiotherapy or advice differentially altered disability in people with LBP. Individualised Physiotherapy directly reduced Pain and Sleep more effectively than advice, which in turn may have facilitated improvements in other disability items. Through their high centrality measures, Pain may be considered as a candidate therapeutic target for optimising LBP management, while Work and Socialising may need to be addressed via intermediary improvements in lifting, standing, walking, travelling or sleep. Slower (5-week follow-up) improvements in Lifting and Travelling as an intended element of the Individualised Physiotherapy approach did not negatively impact any longer-term outcomes. Trials registration ACTRN12609000834257

Evasion of cytotoxic T lymphocyte (CTL) responses by nef-dependent induction of Fas ligand (CD95L) expression on simian immunodeficiency virus-infected cells.

Published versio

Optimising conservative management of chronic low back pain: study protocol for a randomised controlled trial

BackgroundLower back pain is a global health issue affecting approximately 80% of people at some stage in their life. The current literature suggests that any exercise is beneficial for reducing back pain. However, as pain is a subjective evaluation and physical deficits are evident in low back pain, using it as the sole outcome measure to evaluate superiority of an exercise protocol for low back pain treatment is insufficient. The overarching goal of the current clinical trial is to implement two common, conservative intervention approaches and examine their impact on deficits in chronic low back pain.Methods/designForty participants, 25&ndash;45 years old with chronic (&gt;3 months), non-specific low back pain will be recruited. Participants will be randomised to receive either motor control and manual therapy (n&thinsp;=&thinsp;20) or general strength and conditioning (n&thinsp;=&thinsp;20) exercise treatments for 6 months. The motor control/manual therapy group will receive twelve 30-min sessions, ten in the first 3 months (one or two per week) and two in the last 3 months. The general exercise group will attend two 1-hour sessions weekly for 3 months, and one or two a week for the following 3 months. Primary outcome measures are average lumbar spine intervertebral disc T2 relaxation time and changes in thickness of the transversus abdominis muscle on a leg lift using magnetic resonance imaging (MRI). Secondary outcomes include muscle size and fat content, vertebral body fat content, intervertebral disc morphology and water diffusion measured by MRI, body composition using dual energy X-ray absorptiometry, physical function through functional tests, changes in corticospinal excitability and cortical motor representation of the spinal muscles using transcranial magnetic stimulation and self-reported measure of pain symptoms, health and disability. Outcome measures will be conducted at baseline, at the 3-month follow-up and at 6 months at the end of intervention. Pain, depressive symptomology and emotions will be captured fortnightly by questionnaires.DiscussionChronic low back pain is ranked the highest disabling disorder in Australia. The findings of this study will inform clinical practice guidelines to assist with decision-making approaches where outcomes beyond pain are sought for adults with chronic low back pain.<br /

Specific treatment of problems of the spine (STOPS): design of a randomised controlled trial comparing specific physiotherapy versus advice for people with subacute low back disorders

<p>Abstract</p> <p>Background</p> <p>Low back disorders are a common and costly cause of pain and activity limitation in adults. Few treatment options have demonstrated clinically meaningful benefits apart from advice which is recommended in all international guidelines. Clinical heterogeneity of participants in clinical trials is hypothesised as reducing the likelihood of demonstrating treatment effects, and sampling of more homogenous subgroups is recommended. We propose five subgroups that allow the delivery of specific physiotherapy treatment targeting the pathoanatomical, neurophysiological and psychosocial components of low back disorders. The aim of this article is to describe the methodology of a randomised controlled trial comparing specific physiotherapy treatment to advice for people classified into five subacute low back disorder subgroups.</p> <p>Methods/Design</p> <p>A multi-centre parallel group randomised controlled trial is proposed. A minimum of 250 participants with subacute (6 weeks to 6 months) low back pain and/or referred leg pain will be classified into one of five subgroups and then randomly allocated to receive either physiotherapy advice (2 sessions over 10 weeks) or specific physiotherapy treatment (10 sessions over 10 weeks) tailored according to the subgroup of the participant. Outcomes will be assessed at 5 weeks, 10 weeks, 6 months and 12 months following randomisation. Primary outcomes will be activity limitation measured with a modified Oswestry Disability Index as well as leg and back pain intensity measured on separate 0-10 Numerical Rating Scales. Secondary outcomes will include a 7-point global rating of change scale, satisfaction with physiotherapy treatment, satisfaction with treatment results, the Sciatica Frequency and Bothersomeness Scale, quality of life (EuroQol-5D), interference with work, and psychosocial risk factors (Orebro Musculoskeletal Pain Questionnaire). Adverse events and co-interventions will also be measured. Data will be analysed according to intention to treat principles, using linear mixed models for continuous outcomes, Mann Whitney U tests for ordinal outcomes, and Chi-square, risk ratios and risk differences for dichotomous outcomes.</p> <p>Discussion</p> <p>This trial will determine the difference in outcomes between specific physiotherapy treatment tailored to each of the five subgroups versus advice which is recommended in guidelines as a suitable treatment for most people with a low back disorder.</p> <p>Trial registration</p> <p>Australia and New Zealand Clinical Trials Register (ANZCTR): <a href="http://www.anzctr.org.au/ACTRN12609000834257.aspx">ACTRN12609000834257</a>.</p

A mutant O-GlcNAcase enriches Drosophila developmental regulators

YesProtein O-GlcNAcylation is a reversible post-translational modification of serines/threonines on nucleocytoplasmic proteins. It is cycled by the enzymes O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (O-GlcNAcase or OGA). Genetic approaches in model organisms have revealed that protein O-GlcNAcylation is essential for early embryogenesis. Drosophila melanogaster OGT/supersex combs (sxc) is a polycomb gene, null mutants of which display homeotic transformations and die at the pharate adult stage. However, the identities of the O-GlcNAcylated proteins involved, and the underlying mechanisms linking these phenotypes to embryonic development, are poorly understood. Identification of O-GlcNAcylated proteins from biological samples is hampered by the low stoichiometry of this modification and limited enrichment tools. Using a catalytically inactive bacterial O-GlcNAcase mutant as a substrate trap, we have enriched the O-GlcNAc proteome of the developing Drosophila embryo, identifying, amongst others, known regulators of Hox genes as candidate conveyors of OGT function during embryonic development.Wellcome Trust Investigator Award (110061); MRC grant (MC_UU_12016/5); and Royal Society Research Grant

What controls gain in gain control? Mismatch negativity (MMN), priors and system biases

Repetitious patterns enable the auditory system to form prediction models specifying the most likely characteristics of subsequent sounds. Pattern deviations elicit mismatch negativity (MMN), the amplitude of which is modulated by the size of the deviation and confidence in the model. Todd et al. (2001; 2013) demonstrated that a multi-timescale sequence reveals a bias that profoundly distorts the impact of local sound statistics on the MMN amplitude. Two sounds alternate roles as repetitious “standard” and rare “deviant” rapidly (every 0.8 minutes) or slowly (every 2.4 minutes). The bias manifests as larger MMN to the sound first encountered as deviant in slow compared to fast changing sequences, but no difference for the sound first encountered as a standard. We propose that the bias is due to how Bayesian priors shape filters of sound relevance. By examining the time-course of change in MMN amplitude we show that the bias manifests immediately after roles change but rapidly disappears thereafter. The bias was reflected in the response to deviant sounds only (not in response to standards), consistent with precision estimates extracted from second order patterns modulating gain differentially for the two sounds.. Evoked responses to deviants suggest that pattern extraction and reactivation of priors can operate over tens of minutes or longer. Both MMN and deviant responses establish that: (1) priors are defined by the most proximally encountered probability distribution when one exists but; (2) when no prior exists, one is instantiated by sequence onset characteristics; and (3) priors require context interruption to be updated

Protein structure and evolution: are they constrained globally by a principle derived from information theory?

That the physicochemical properties of amino acids constrain the structure, function and evolution of proteins is not in doubt. However, principles derived from information theory may also set bounds on the structure (and thus also the evolution) of proteins. Here we analyze the global properties of the full set of proteins in release 13-11 of the SwissProt database, showing by experimental test of predictions from information theory that their collective structure exhibits properties that are consistent with their being guided by a conservation principle. This principle (Conservation of Information) defines the global properties of systems composed of discrete components each of which is in turn assembled from discrete smaller pieces. In the system of proteins, each protein is a component, and each protein is assembled from amino acids. Central to this principle is the inter-relationship of the unique amino acid count and total length of a protein and its implications for both average protein length and occurrence of proteins with specific unique amino acid counts. The unique amino acid count is simply the number of distinct amino acids (including those that are post-translationally modified) that occur in a protein, and is independent of the number of times that the particular amino acid occurs in the sequence. Conservation of Information does not operate at the local level (it is independent of the physicochemical properties of the amino acids) where the influences of natural selection are manifest in the variety of protein structure and function that is well understood. Rather, this analysis implies that Conservation of Information would define the global bounds within which the whole system of proteins is constrained; thus it appears to be acting to constrain evolution at a level different from natural selection, a conclusion that appears counter-intuitive but is supported by the studies described herein