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Concept: Experimental design


BACKGROUND: Prolonged physical impairments in range of movement, postural stability and walking speed are commonly reported following total hip replacement (THR). It is unclear from the current body of evidence what kind of exercises should be performed to maximize patient function and quality of life.Methods/designThis will be a single blind multi centre randomized control trial with two arms. Seventy subjects post primary total hip arthroplasty will be randomized into either an experimental group (n=35), or to a control group (n=35).. The experimental group will attend a functional exercise class twice weekly for a six week period from week 12 to week 18 post surgery. The functional exercise group will follow a circuit based functional exercise class supervised by a chartered Physiotherapist. The control group will receive usual care. The principal investigator (BM) will perform blinded outcome assessments on all patients using validated measures for pain, stiffness, and function using the Western Ontario and Mc Master Universities Osteoarthritis index (WOMAC). This is the primary outcome measurement tool. Secondary outcome measurements include Quality of life (SF-36), 6 min walk test, Visual Analogue Scale, and the Berg Balance score. The WOMAC score will be collated on day five post surgery and repeated at week twelve and week eighteen. All other measurements will be taken at week 12 and repeated at week eighteen. In addition a blinded radiologist will measure gluteus medius cross sectional area using real time ultrasound for all subjects at week 12 and at week 18 to determine if the functional exercise programme has any effect on muscle size. DISCUSSION: This randomised controlled trial will add to the body of evidence on the relationship between muscle size, functional ability, balance, quality of life and time post surgery in patients following total hip arthroplasty. The CONSORT guidelines will be followed to throughout. Ethical approval has been gained from the Ethics committee Health Services Executive Dublin North East.Trial registrationThis trial is registered with (a service of the United States National Institutes of Health) identifier NCT01683201.

Concepts: Experimental design, Randomized controlled trial, Hip replacement, Hip, Pelvis, Orthopedic surgery, Joint replacement


MOTIVATION: Biochemical reaction networks in the form of coupled ordinary differential equations (ODEs) provide a powerful modeling tool for understanding the dynamics of biochemical processes. During the early phase of modeling, scientists have to deal with a large pool of competing nonlinear models. At this point, discrimination experiments can be designed and conducted to obtain optimal data for selecting the most plausible model. Since biological ODE models have widely distributed parameters due to, e.g., biologic variability or experimental variations, model responses become distributed. Therefore, a robust optimal experimental design (OED) for model discrimination can be used to discriminate models based on their response probability distribution functions (PDFs). RESULTS: In this work we present an optimal control based methodology for designing optimal stimulus experiments aimed at robust model discrimination. For estimating the time-varying model response PDF, which results from the nonlinear propagation of the parameter PDF under the ODE dynamics, we suggest using the Sigma-Point approach. Using the model overlap (expected likelihood) as a robust discrimination criterion to measure dissimilarities between expected model response PDFs, we benchmark the proposed nonlinear design approach against linearization with respect to prediction accuracy and design quality for two nonlinear biological reaction networks. As we show, the Sigma-Point outperforms the linearization approach in the case of widely distributed parameter sets and/or existing multiple steady states. Since the Sigma-Point approach scales linearly with the number of model parameter, it can be applied to large systems for robust experimental planing. AVAILABILITY: An implementation of the method in MATLAB/AMPL is available at CONTACT: flassig@mpi-magdeburg.mpg SUPPLEMENTARY INFORMATION: Supplementary details and discussions are available at Bioinformatics online.

Concepts: Experimental design, Experiment, Model, Design of experiments, Differential equation, Design, Charles Sanders Peirce, Optimal design


Prescription opioid use is highly associated with risk of opioid-related death, with 1 of every 550 chronic opioid users dying within approximately 2.5 years of their first opioid prescription. Although gabapentin is widely perceived as safe, drug-induced respiratory depression has been described when gabapentin is used alone or in combination with other medications. Because gabapentin and opioids are both commonly prescribed for pain, the likelihood of co-prescription is high. However, no published studies have examined whether concomitant gabapentin therapy is associated with an increased risk of accidental opioid-related death in patients receiving opioids. The objective of this study was to investigate whether co-prescription of opioids and gabapentin is associated with an increased risk of accidental opioid-related mortality.

Concepts: Experimental design, Epidemiology, Death, Drug, Opioid, Morphine, Psychoactive drug, Recreational drug use


BACKGROUND: Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true disease-modifying effects. A systematic review was undertaken to determine what biomarkers for disease progression in Parkinson’s disease (PD) exist. METHODS: MEDLINE and EMBASE (1950–2010) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with idiopathic PD diagnosed by formal criteria or clearly described clinical means were included. We made no restriction on age, disease duration, drug treatment, or study design. We included studies which attempted to draw associations between any tests used to investigate disease progression and any clinical measures of disease progression. The electronic search was validated by hand-searching the two journals from which most included articles came. RESULTS: 183 studies were included: 163 (89%) cross-sectional, 20 (11%) longitudinal. The electronic search strategy had a sensitivity of 71.4% (95% CI 51.1-86.0) and a specificity of 97.1% (95% CI 96.5-97.7). In longitudinal studies median follow-up was 2.0 years (IQR 1.1-3.5). Included studies were generally poor quality - cross-sectional with small numbers of participants, applying excessive inclusion/exclusion criteria, with flawed methodologies and simplistic statistical analyses. CONCLUSION: We found insufficient evidence to recommend the use of any biomarker for disease progression in PD clinical trials, which may simply reflect the poor quality of research in this area. We therefore present a provisional ‘roadmap’ for conducting future disease progression biomarker studies, and recommend new quality criteria by which future studies may be judged.

Concepts: Alzheimer's disease, Cohort study, Medicine, Experimental design, Epidemiology, Cross-sectional study, Effectiveness, Parkinson's disease


This exploratory clinical trial evaluated the safety and clinical activity of a novel, sustained-exposure formulation of ciprofloxacin microparticulates in poloxamer (OTO-201) administered during tympanostomy tube placement in children.

Concepts: Pharmacology, Experimental design, Epidemiology, Clinical trial, Randomized controlled trial,, Pharmaceutical industry, Clinical research



A single-centre, prospective randomised clinical trial investigating the analgesic efficacy of the transversus abdominis plane (TAP) block for adult patients undergoing laparoscopic appendicectomy was conducted.

Concepts: Experimental design, Clinical trial, Randomized controlled trial, Effectiveness,, Transversus abdominis muscle, Pharmaceutical industry, Clinical research


Bronchiolitis obliterans syndrome (BOS) remains the major problem which precludes long-term survival after lung transplantation. Previously, an open label pilot study from our group demonstrated a possible beneficial effect of montelukast in progressive BOS patients with low airway neutrophilia (<15%), and already on azithromycin treatment, in whom the further decline in pulmonary function was attenuated. This was, however, a non-randomized and non-placebo controlled trial. The study design is a single center, prospective, interventional, randomized, double blind, placebo-controlled trial, with a two arm parallel group design and an allocation ratio of 1:1. Randomization to additional montelukast (10 mg/day, n = 15) or placebo (n = 15) was performed from 2010 to 2014 at the University Hospitals Leuven (Leuven, Belgium) in all consecutive patients with late-onset (>2years posttransplant) BOS ≥1. Primary end-point was freedom from graft loss 1 year after randomization; secondary end-points were acute rejection, lymphocytic bronchiolitis, respiratory infection rate; and change in FEV1, airway and systemic inflammation during the study period. Graft loss at 1 y and 2y was similar in both groups (respectively p = 0. 981 and p = 0.230). Montelukast had no effect on lung function decline in the overall cohort. However, in a post-hoc subanalysis of BOS stage 1 patients, montelukast attenuated further decline of FEV1 during the study period, both in absolute (L) (p = 0.008) and % predicted value (p = 0.0180). A linear mixed model confirmed this association. Acute rejection, lymphocytic bronchiolitis, respiratory infections, systemic and airway inflammation were comparable between groups over the study period. This randomized controlled trial showed no additional survival benefit with montelukast compared to placebo, although the study was underpowered. The administration of montelukast was associated with an attenuation of the rate of FEV1 decline, however, only in recipients with late-onset BOS stage 1.

Concepts: Immune system, Inflammation, Experimental design, Pulmonology, Asthma, Lung, Randomized controlled trial, Bronchiolitis obliterans


Many randomized controlled trials (RCTs) employ mortality at a given time as a primary outcome. There are at least three common ways to measure 90-day mortality: first, all-location mortality, that is, all-cause mortality within 90 days of randomization at any location. Second, ARDSnet mortality is death in a healthcare facility of greater intensity than the patient was in prior to the hospitalization during which they were randomized. Finally, in-hospital mortality is death prior to discharge from the primary hospitalization of randomization. Data comparing the impact of these different measurements on sample size are lacking. We evaluated the extent to which event rates vary by mortality definition.

Concepts: Cohort study, Experimental design, Epidemiology, Clinical trial, Sampling, Patient, Randomized controlled trial, Measurement


Current guidelines for the provision of protein for critically ill patients are based on incomplete evidence, due to limited data from randomised controlled trials. The present pilot randomised controlled trial is part of a program of work to expand knowledge about the clinical effects of protein delivery to critically ill patients. The primary aim of this pilot study is to determine whether an enteral feeding protocol using a volume target, with additional protein supplementation, delivers a greater amount of protein and energy to mechanically ventilated critically ill patients than a standard nutrition protocol. The secondary aims are to evaluate the potential effects of this feeding strategy on muscle mass and other patient-centred outcomes.

Concepts: Experimental design, Epidemiology, Metabolism, Energy, Randomized controlled trial, Pharmaceutical industry, Clinical research, Dieting