Does parallel item content on WOMAC's Pain and Function Subscales limit its ability to detect change in functional status?

BACKGROUND: Although the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) is considered the leading outcome measure for patients with osteoarthritis of the lower extremity, recent work has challenged its factorial validity and the physical function subscale's ability to detect valid change when pain and function display different profiles of change. This study examined the etiology of the WOMAC's physical function subscale's limited ability to detect change in the presence of discordant changes for pain and function. We hypothesized that the duplication of some items on the WOMAC's pain and function subscales contributed to this shortcoming. METHODS: Two eight-item physical function scales were abstracted from the WOMAC's 17-item physical function subscale: one contained activities and themes that were duplicated on the pain subscale (SIMILAR-8); the other version avoided overlapping activities (DISSIMILAR-8). Factorial validity of the shortened measures was assessed on 310 patients awaiting hip or knee arthroplasty. The shortened measures' abilities to detect change were examined on a sample of 104 patients following primary hip or knee arthroplasty. The WOMAC and three performance measures that included activity specific pain assessments – 40 m walk test, stair test, and timed-up-and-go test – were administered preoperatively, within 16 days of hip or knee arthroplasty, and at an interval of greater than 20 days following the first post-surgical assessment. Standardized response means were used to quantify change. RESULTS: The SIMILAR-8 did not demonstrate factorial validity; however, the factorial structure of the DISSIMILAR-8 was supported. The time to complete the performance measures more than doubled between the preoperative and first postoperative assessments supporting the theory that lower extremity functional status diminished over this interval. The DISSIMILAR-8 detected this deterioration in functional status; however, no significant change was noted for the SIMILAR-8. The WOMAC pain scale demonstrated a slight reduction in pain and the performance specific pain measures did not reflect a change in pain. All measures showed substantial improvement over the second assessment interval. CONCLUSIONS: These findings support the hypothesis that activity overlap on the pain and function subscales plays a causal role in limiting the WOMAC physical function subscale's ability to detect change

Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

Background: The development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method: 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results: Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n=4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8+/-5.9 vs 59+/-2.0 mmHg), increased cardiac output (7.26+/-1.86 vs 3.30+/-0.40 l/min) and decreased systemic vascular resistance (8.48+/-2.75 vs 16.2+/-1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636+/-95 vs 301+/-26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23+/-0.05 vs 7.45+/-0.02) and prothrombin time (36+/-2 vs 8.9+/-0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5+/-210 vs 42+/-8.14) coincided with a marked reduction in serum albumin (11.5+/-1.71 vs 25+/-1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2+/-36.5 vs 131.6+/-9.33 mumol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06. Conclusion: We have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems

Classification of patients with knee osteoarthritis in clinical phenotypes: data from the osteoarthritis initiative

<div><p>Objectives</p><p>The existence of phenotypes has been hypothesized to explain the large heterogeneity characterizing the knee osteoarthritis. In a previous systematic review of the literature, six main phenotypes were identified: Minimal Joint Disease (MJD), Malaligned Biomechanical (MB), Chronic Pain (CP), Inflammatory (I), Metabolic Syndrome (MS) and Bone and Cartilage Metabolism (BCM). The purpose of this study was to classify a sample of individuals with knee osteoarthritis (KOA) into pre-defined groups characterized by specific variables that can be linked to different disease mechanisms, and compare these phenotypes for demographic and health outcomes.</p><p>Methods</p><p>599 patients were selected from the OAI database FNIH at 24 months’ time to conduct the study. For each phenotype, cut offs of key variables were identified matching the results from previous studies in the field and the data available for the sample. The selection process consisted of 3 steps. At the end of each step, the subjects classified were excluded from the further classification stages. Patients meeting the criteria for more than one phenotype were classified separately into a ‘complex KOA’ group.</p><p>Results</p><p>Phenotype allocation (including complex KOA) was successful for 84% of cases with an overlap of 20%. Disease duration was shorter in the MJD while the CP phenotype included a larger number of Women (81%). A significant effect of phenotypes on WOMAC pain (F = 16.736 p <0.001) and WOMAC physical function (F = 14.676, p < 0.001) was identified after controlling for disease duration.</p><p>Conclusion</p><p>This study signifies the feasibility of a classification of KOA subjects in distinct phenotypes based on subgroup-specific characteristics.</p></div

A preliminary study of genetic factors that influence susceptibility to bovine tuberculosis in the British cattle herd

Associations between specific host genes and susceptibility to Mycobacterial infections such as tuberculosis have been reported in several species. Bovine tuberculosis (bTB) impacts greatly the UK cattle industry, yet genetic predispositions have yet to be identified. We therefore used a candidate gene approach to study 384 cattle of which 160 had reacted positively to an antigenic skin test (‘reactors’). Our approach was unusual in that it used microsatellite markers, embraced high breed diversity and focused particularly on detecting genes showing heterozygote advantage, a mode of action often overlooked in SNP-based studies. A panel of neutral markers was used to control for population substructure and using a general linear model-based approach we were also able to control for age. We found that substructure was surprisingly weak and identified two genomic regions that were strongly associated with reactor status, identified by markers INRA111 and BMS2753. In general the strength of association detected tended to vary depending on whether age was included in the model. At INRA111 a single genotype appears strongly protective with an overall odds ratio of 2.2, the effect being consistent across nine diverse breeds. Our results suggest that breeding strategies could be devised that would appreciably increase genetic resistance of cattle to bTB (strictly, reduce the frequency of incidence of reactors) with implications for the current debate concerning badger-culling

Novel human genetic variants associated with extrapulmonary tuberculosis: a pilot genome wide association study

<p>Abstract</p> <p>Background</p> <p>Approximately 5-10% of persons infected with <it>M. tuberculosis </it>develop tuberculosis, but the factors associated with disease progression are incompletely understood. Both linkage and association studies have identified human genetic variants associated with susceptibility to pulmonary tuberculosis, but few genetic studies have evaluated extrapulmonary disease. Because extrapulmonary and pulmonary tuberculosis likely have different underlying pathophysiology, identification of genetic mutations associated with extrapulmonary disease is important.</p> <p>Findings</p> <p>We performed a pilot genome-wide association study among 24 persons with previous extrapulmonary tuberculosis and well-characterized immune defects; 24 pulmonary tuberculosis patients and 57 patients with <it>M. tuberculosis </it>infection served as controls. The Affymetrix GeneChip Human Mapping Xba Array was used for genotyping; after careful quality control, genotypes at 44,175 single nucleotide polymorphisms (SNPs) were available for analysis. Eigenstrat quantified population stratification within our sample; logistic regression, using results of the Eigenstrat analysis as a covariate, identified significant associations between groups. Permutation testing controlled the family-wise error rate for each comparison between groups. Four SNPs were significantly associated with extrapulmonary tuberculosis compared to controls with <it>M. tuberculosis </it>infection; one (rs4893980) in the gene PDE11A, one (rs10488286) in KCND2, and one (rs2026414) in PCDH15; one was in chromosome 7 but not associated with a known gene. Two additional variants were significantly associated with extrapulmonary tuberculosis compared with pulmonary tuberculosis; one (rs340708) in the gene FAM135B and one in chromosome 13 but not associated with a known gene. The function of all four genes affects cell signaling and activity, including in the brain.</p> <p>Conclusions</p> <p>In this pilot study, we identified 6 novel variants not previously known to be associated with extrapulmonary tuberculosis, including two SNPs more common in persons with extrapulmonary than pulmonary tuberculosis. This provides some support for the hypothesis that the pathogenesis and genetic predisposition to extrapulmonary tuberculosis differs from pulmonary tuberculosis. Further study of these novel SNPs, and more well-powered genome-wide studies of extrapulmonary tuberculosis, is warranted.</p

Analysis of Group Randomized Trials with Multiple Binary Endpoints and Small Number of Groups

The group randomized trial (GRT) is a common study design to assess the effect of an intervention program aimed at health promotion or disease prevention. In GRTs, groups rather than individuals are randomized into intervention or control arms. Then, responses are measured on individuals within those groups. A number of analytical problems beset GRT designs. The major problem emerges from the likely positive intraclass correlation among observations of individuals within a group. This paper provides an overview of the analytical method for GRT data and applies this method to a randomized cancer prevention trial, where multiple binary primary endpoints were obtained. We develop an index of extra variability to investigate group-specific effects on response. The purpose of the index is to understand the influence of individual groups on evaluating the intervention effect, especially, when a GRT study involves a small number of groups. The multiple endpoints from the GRT design are analyzed using a generalized linear mixed model and the stepdown Bonferroni method of Holm

Planning a cluster randomized trial with unequal cluster sizes: practical issues involving continuous outcomes

BACKGROUND: Cluster randomization design is increasingly used for the evaluation of health-care, screeening or educational interventions. At the planning stage, sample size calculations usually consider an average cluster size without taking into account any potential imbalance in cluster size. However, there may exist high discrepancies in cluster sizes. METHODS: We performed simulations to study the impact of an imbalance in cluster size on power. We determined by simulations to which extent four methods proposed to adapt the sample size calculations to a pre-specified imbalance in cluster size could lead to adequately powered trials. RESULTS: We showed that an imbalance in cluster size can be of high influence on the power in the case of severe imbalance, particularly if the number of clusters is low and/or the intraclass correlation coefficient is high. In the case of a severe imbalance, our simulations confirmed that the minimum variance weights correction of the variation inflaction factor (VIF) used in the sample size calculations has the best properties. CONCLUSION: Publication of cluster sizes is important to assess the real power of the trial which was conducted and to help designing future trials. We derived an adaptation of the VIF from the minimum variance weights correction to be used in case the imbalance can be a priori formulated such as "a proportion (γ) of clusters actually recruit a proportion (τ) of subjects to be included (γ ≤ τ)"

Activity pacing for osteoarthritis symptom management: study design and methodology of a randomized trial testing a tailored clinical approach using accelerometers for veterans and non-veterans

<p>Abstract</p> <p>Background</p> <p>Osteoarthritis (OA) is a prevalent chronic disease and a leading cause of disability in adults. For people with knee and hip OA, symptoms (e.g., pain and fatigue) can interfere with mobility and physical activity. Whereas symptom management is a cornerstone of treatment for knee and hip OA, limited evidence exists for behavioral interventions delivered by rehabilitation professionals within the context of clinical care that address how symptoms affect participation in daily activities. Activity pacing, a strategy in which people learn to preplan rest breaks to avoid symptom exacerbations, has been effective as part of multi-component interventions, but hasn't been tested as a stand-alone intervention in OA or as a tailored treatment using accelerometers. In a pilot study, we found that participants who underwent a tailored activity pacing intervention had reduced fatigue interference with daily activities. We are now conducting a full-scale trial.</p> <p>Methods/Design</p> <p>This paper provides a description of our methods and rationale for a trial that evaluates a tailored activity pacing intervention led by occupational therapists for adults with knee and hip OA. The intervention uses a wrist accelerometer worn during the baseline home monitoring period to glean recent symptom and physical activity patterns and to tailor activity pacing instruction based on how symptoms relate to physical activity. At 10 weeks and 6 months post baseline, we will examine the effectiveness of a tailored activity pacing intervention on fatigue, pain, and physical function compared to general activity pacing and usual care groups. We will also evaluate the effect of tailored activity pacing on physical activity (PA).</p> <p>Discussion</p> <p>Managing OA symptoms during daily life activity performance can be challenging to people with knee and hip OA, yet few clinical interventions address this issue. The activity pacing intervention tested in this trial is designed to help people modulate their activity levels and reduce symptom flares caused by too much or too little activity. As a result of this trial, we will be able to determine if activity pacing is more effective than usual care, and among the intervention groups, if an individually tailored approach improves fatigue and pain more than a general activity pacing approach.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01192516">NCT01192516</a></p

Defining the effect and mediators of two knowledge translation strategies designed to alter knowledge, intent and clinical utilization of rehabilitation outcome measures: a study protocol [NCT00298727]

BACKGROUND: A substantial number of valid outcome measures have been developed to measure health in adult musculoskeletal and childhood disability. Regrettably, national initiatives have merely resulted in changes in attitude, while utilization remains unacceptably low. This study will compare the effectiveness and mediators of two different knowledge transfer (KT) interventions in terms of their impact on changing knowledge and behavior (utilization and clinical reasoning) related to health outcome measures. METHOD/DESIGN: Physical and occupational therapists (n = 144) will be recruited in partnership with the national professional associations to evaluate two different KT interventions with the same curriculum: 1) Stakeholder-Hosted Interactive Problem-Based Seminar (SHIPS), and 2) Online Problem-Based course (e-PBL). SHIPS will consist of face-to-face problem-based learning (PBL) for 2 1/2 days with outcome measure developers as facilitators, using six problems generated in consultation with participants. The e-PBL will consist of a 6-week web-based course with six generic problems developed by content experts. SHIPS will be conducted in three urban centers in Canada. Participants will be block-allocated by a minimization procedure to either of the two interventions to minimize any prognostic differences. Trained evaluators at each site will conduct chart audits and chart-stimulated recall. Trained interviewers will conduct semi-structured interviews focused on identifying critical elements in KT and implementing practice changes. Interviews will be transcribed verbatim. Baseline predictors including demographics, knowledge, attitudes/barriers regarding outcome measures, and Readiness to Change will be assessed by self-report. Immediately post-intervention and 6 months later, these will be re-administered. Primary qualitative and quantitative evaluations will be conducted 6-months post-intervention to assess the relative effectiveness of KT interventions and to identify elements that contribute to changing clinical behavior. Chart audits will determine the utilization of outcome measures (counts). Incorporation of outcome measures into clinical reasoning will be assessed using an innovative technique: chart-stimulated recall. DISCUSSION: A strategy for optimal transfer of health outcome measures into practice will be developed and shared with multiple disciplines involved in primary and specialty management of musculoskeletal and childhood disability