Bayesian analysis for mixtures of discrete distributions with a non-parametric component

Bayesian finite mixture modelling is a flexible parametric modelling approach for classification and density fitting. Many areas of application require distinguishing a signal from a noise component. In practice, it is often difficult to justify a specific distribution for the signal component; therefore, the signal distribution is usually further modelled via a mixture of distributions. However, modelling the signal as a mixture of distributions is computationally non-trivial due to the difficulties in justifying the exact number of components to be used and due to the label switching problem. This paper proposes the use of a non-parametric distribution to model the signal component. We consider the case of discrete data and show how this new methodology leads to more accurate parameter estimation and smaller false non-discovery rate. Moreover, it does not incur the label switching problem. We show an application of the method to data generated by ChIP-sequencing experiments

Manipulative therapy and/or NSAIDs for acute low back pain: design of a randomized controlled trial [ACTRN012605000036617]

BACKGROUND: Acute low back pain is a common condition resulting in pain and disability. Current national and international guidelines advocate general practitioner care including advice and paracetamol (4 g daily in otherwise well adults) as the first line of care for people with acute low back pain. Non-steroidal anti-inflammatory drugs (NSAIDs) and spinal manipulative therapy (SMT) are advocated in many guidelines as second line management options for patients with acute low back pain who are not recovering. No studies have explored the role of NSAIDs and/or SMT in addition to first line management for acute low back pain. The primary aim of this study is to investigate if NSAIDs and/or SMT in addition to general practitioner advice and paracetamol results in shorter recovery times for patients with acute low back pain. The secondary aims of the study are to evaluate whether the addition of SMT and/or NSAIDs influences pain, disability and global perceived effect at 1, 2, 4 and 12 weeks after onset of therapy for patients with significant acute low back pain. METHODS/DESIGN: This paper presents the rationale and design of a randomised controlled trial examining the addition of NSAIDs and/or SMT in 240 people who present to their general practitioner with significant acute low back pain

Drugs for relief of pain in patients with sciatica: systematic review and meta-analysis

Objective To investigate the efficacy and tolerability of analgesic and adjuvant pain drugs typically administered in primary care for the management of patients with sciatica

Assessment and improvement of biotransfer models to cow’s milk and beef used in exposure assessment tools for organic pollutants

The aim of this study was to assess and improve the accuracy of biotransfer models for the organic pollutants (PCBs, PCDD/Fs, PBDEs, PFCAs, and pesticides) into cow’s milk and beef used in human exposure assessment. Metabolic rate in cattle is known as a key parameter for this biotransfer, however few experimental data and no simulation methods are currently available. In this research, metabolic rate was estimated using existing QSAR biodegradation models of microorganisms (BioWIN) and fish (EPI-HL and IFS-HL). This simulated metabolic rate was then incorporated into the mechanistic cattle biotransfer models (RAIDAR, ACC-HUMAN, OMEGA, and CKow). The goodness of fit tests showed that RAIDAR, ACC-HUMAN, OMEGA model performances were significantly improved using either of the QSARs when comparing the new model outputs to observed data. The CKow model is the only one that separates the processes in the gut and liver. This model showed the lowest residual error of all the models tested when the BioWIN model was used to represent the ruminant metabolic process in the gut and the two fish QSARs were used to represent the metabolic process in the liver. Our testing included EUSES and CalTOX which are KOW-regression models that are widely used in regulatory assessment. New regressions based on the simulated rate of the two metabolic processes are also proposed as an alternative to KOW-regression models for a screening risk assessment. The modified CKow model is more physiologically realistic, but has equivalent usability to existing KOW-regression models for estimating cattle biotransfer of organic pollutants

An Electronic Clinical Decision Support System for the Management of Low Back Pain in Community Pharmacy: Development and Mixed Methods Feasibility Study

Background People with low back pain (LBP) in the community often do not receive evidence-based advice and management. Community pharmacists can play an important role in supporting people with LBP as pharmacists are easily accessible to provide first-line care. However, previous research suggests that pharmacists may not consistently deliver advice that is concordant with guideline recommendations and may demonstrate difficulty determining which patients require prompt medical review. A clinical decision support system (CDSS) may enhance first-line care of LBP, but none exists to support the community pharmacist–client consultation. Objective This study aimed to develop a CDSS to guide first-line care of LBP in the community pharmacy setting and to evaluate the pharmacist-reported usability and acceptance of the prototype system. Methods A cross-platform Web app for the Apple iPad was developed in conjunction with academic and clinical experts using an iterative user-centered design process during interface design, clinical reasoning, program development, and evaluation. The CDSS was evaluated via one-to-one user-testing with 5 community pharmacists (5 case vignettes each). Data were collected via video recording, screen capture, survey instrument (system usability scale), and direct observation. Results Pharmacists’ agreement with CDSS-generated self-care recommendations was 90% (18/20), with medicines recommendations was 100% (25/25), and with referral advice was 88% (22/25; total 70 recommendations). Pharmacists expressed uncertainty when screening for serious pathology in 40% (10/25) of cases. Pharmacists requested more direction from the CDSS in relation to automated prompts for user input and page navigation. Overall system usability was rated as excellent (mean score 92/100, SD 6.5; 90th percentile compared with similar systems), with acceptance rated as good to excellent. Conclusions A novel CDSS (high-fidelity prototype) to enhance pharmacist care of LBP was developed, underpinned by clinical practice guidelines and informed by a multidisciplinary team of experts. User-testing revealed a high level of usability and acceptance of the prototype system, with suggestions to improve interface prompts and information delivery. The small study sample limits the generalizability of the findings but offers important insights to inform the next stage of system development. </jats:sec

Too Much Medicine in older people? Deprescribing through Shared Decision Making

Too much medicine is an increasingly recognised problem,1 2 and one manifestation is inappropriate polypharmacy in older people. Polypharmacy is usually defined as taking more than five regular prescribed medicines.3 It can be appropriate (when potential benefits outweigh potential harms)4 but increases the risk of older people experiencing adverse drug reactions, impaired physical and cognitive function, and hospital admission.5 6 7 There is limited evidence to inform polypharmacy in older people, especially those with multimorbidity, cognitive impairment, or frailty.8 Systematic reviews of medication withdrawal trials (deprescribing) show that reducing specific classes of medicines may decrease adverse events and improve quality of life.9 10 11 Two recent reviews of the literature on deprescribing stressed the importance of patient involvement and shared decision making.12 13 Patients and clinicians typically overestimate the benefits of treatments and underestimate their harms.14 When they engage in shared decision making they become better informed about potential outcomes and as a result patients tend to choose more conservative options (eg, fewer medicines), facilitating deprescribing.15 However, shared decision making in this context is not easy, and there is little guidance on how to do it.16 We draw together evidence from the psychology, communication, and decision making literature (see appendix on thebmj.com). For each step of the shared decision making process we describe the unique tasks required for deprescribing decisions; identify challenges for older adults, their companions, and clinicians (figure); give practical advice on how challenges may be overcome; highlight where more work is needed; and identify priorities for future research (table). Key messages Deprescribing is a process of planned and supervised tapering or ceasing of inappropriate medicines Shared decision making should be an integral part of the deprescribing process Many factors affect this process, including trust in clinicians’ advice, contradictory patient attitudes about medication, cognitive biases that lead to a preference for the status quo and positive information, and information processing difficulties There is uncertainty about the effect of risk communication and preference elicitation tools in older people Older people’s preferences for discussing life expectancy and quality of life vary widely, but even those who wish to delegate their decisions still appreciate discussion of optionsJJ is supported by a National Health and Medical Research Council (NHMRC) early career fellowship (1037028) and KM is supported by an NHMRC career development fellowship (1029241

PRECISE - pregabalin in addition to usual care: Statistical analysis plan

Background: Sciatica is a severe, disabling condition that lacks high quality evidence for effective treatment strategies. This a priori statistical analysis plan describes the methodology of analysis for the PRECISE study. Methods/design: PRECISE is a prospectively registered, double blind, randomised placebo controlled trial of pregabalin compared to placebo, in addition to usual care in patients with sciatica. The aim of this study is to determine the efficacy and cost-effectiveness of pregabalin in reducing leg pain intensity (primary outcome). Secondary outcomes include disability (key secondary), back pain intensity, quality of life, participants' perceived global effect, work absenteeism and health utilisation. Information about medication usage and tolerability are also collected. Outcomes are collected over one year (weeks 2, 4, 8, 12, 26 and 52). Double data entry will be conducted for primary and key secondary outcomes. Other outcomes will be checked using a risk-based approach. Analyses will be consistent with the intention-to-treat principle. Statistical tests will be two-tailed with a p value <0.05 considered significant. Group allocation will remain masked until analyses and interpretation are finalised. Repeated-measure linear mixed models will assess the effect of treatment (pregabalin versus placebo) on primary and secondary outcomes at all time points. Fixed effects will include group allocation, visit as a categorical variable and the interaction between group and visit. Covariates will include baseline leg pain and symptom duration, with an interaction term between baseline leg pain and visit. Pairwise differences between groups will be tested at weeks 8 and 52. The number of serious adverse events and adverse events will be reported, and the proportion of patients per group who have at least one event will be compared using Fisher's exact test. An economic evaluation will be conducted if there is a treatment effect on the primary outcome at week 8. A subgroup analysis will assess whether presenting features of neuropathic pain at baseline modify the treatment effect of leg pain at week 8. Discussion: This statistical analysis plan provides detailed methodology for the analysis of the PRECISE study, which aims to deliver much needed evidence about effective and affordable management of sciatica. Trial registration: Australian and New Zealand Clinical Trials Registry ( ACTRN12613000530729. Registered 13 May 2013

PRECISE - pregabalin in addition to usual care for sciatica: Study protocol for a randomised controlled trial

Background: Sciatica is a type of neuropathic pain that is characterised by pain radiating into the leg. It is often accompanied by low back pain and neurological deficits in the lower limb. While this condition may cause significant suffering for the individual, the lack of evidence supporting effective treatments for sciatica makes clinical management difficult. Our objectives are to determine the efficacy of pregabalin on reducing leg pain intensity and its cost-effectiveness in patients with sciatica.Methods/Design: PRECISE is a prospectively registered, double-blind, randomised placebo-controlled trial of pregabalin compared to placebo, in addition to usual care. Inclusion criteria include moderate to severe leg pain below the knee with evidence of nerve root/spinal nerve involvement. Participants will be randomised to receive either pregabalin with usual care (n = 102) or placebo with usual care (n = 102) for 8 weeks. The medicine dosage will be titrated up to the participant's optimal dose, to a maximum 600 mg per day. Follow up consultations will monitor individual progress, tolerability and adverse events. Usual care, if deemed appropriate by the study doctor, may include a referral for physical or manual therapy and/or prescription of analgesic medication. Participants, doctors and researchers collecting participant data will be blinded to treatment allocation. Participants will be assessed at baseline and at weeks 2, 4, 8, 12, 26 and 52. The primary outcome will determine the efficacy of pregabalin in reducing leg pain intensity. Secondary outcomes will include back pain intensity, disability and quality of life. Data analysis will be blinded and by intention-to-treat. A parallel economic evaluation will be conducted from health sector and societal perspectives.Discussion: This study will establish the efficacy of pregabalin in reducing leg pain intensity in patients with sciatica and provide important information regarding the effect of pregabalin treatment on disability and quality of life. The impact of this research may allow the future development of a cost-effective conservative treatment strategy for patients with sciatica.Trial registration: ClinicalTrial.gov, ACTRN 12613000530729

S-Brane Thermodynamics

The description of string-theoretic s-branes at g_s=0 as exact worldsheet CFTs with a (lambda cosh X^0) or (lambda e^(X^0)) boundary interaction is considered. Due to the imaginary-time periodicity of the interaction under X^0 -> X^0 + 2 pi i, these configurations have intriguing similarities to black hole or de Sitter geometries. For example, the open string pair production as seen by an Unruh detector is thermal at temperature T = 1/4 pi. It is shown that, despite the rapid time dependence of the s-brane, there exists an exactly thermal mixed state of open strings. The corresponding boundary state is constructed for both the bosonic and superstring cases. This state defines a long-distance Euclidean effective field theory whose light modes are confined to the s-brane. At the critical value of the coupling lambda=1/2, the boundary interaction simply generates an SU(2) rotation by pi from Neumman to Dirichlet boundary conditions. The lambda=1/2 s-brane reduces to an array of sD-branes (D-branes with a transverse time dimension) on the imaginary time axis. The long range force between a (bosonic) sD-brane and an ordinary D-brane is shown from the annulus diagram to be 11/12 times the force between two D-branes. The linearized time-dependent RR field F=dC produced by an sD-brane in superstring theory is explicitly computed and found to carry a half unit of s-charge Q_s=\int_S *F=1/2, where S is any transverse spacelike slice.Comment: 42 page