Septic arthritis

No Abstract

Potential implications of practice effects in Alzheimer's disease prevention trials.

IntroductionPractice effects (PEs) present a potential confound in clinical trials with cognitive outcomes. A single-blind placebo run-in design, with repeated cognitive outcome assessments before randomization to treatment, can minimize effects of practice on trial outcome.MethodsWe investigated the potential implications of PEs in Alzheimer's disease prevention trials using placebo arm data from the Alzheimer's Disease Cooperative Study donepezil/vitamin E trial in mild cognitive impairment. Frequent ADAS-Cog measurements early in the trial allowed us to compare two competing trial designs: a 19-month trial with randomization after initial assessment, versus a 15-month trial with a 4-month single-blind placebo run-in and randomization after the second administration of the ADAS-Cog. Standard power calculations assuming a mixed-model repeated-measure analysis plan were used to calculate sample size requirements for a hypothetical future trial designed to detect a 50% slowing of cognitive decline.ResultsOn average, ADAS-Cog 13 scores improved at first follow-up, consistent with a PE and progressively worsened thereafter. The observed change for a 19-month trial (1.18 points) was substantively smaller than that for a 15-month trial with 4-month run-in (1.79 points). To detect a 50% slowing in progression under the standard design (i.e., a 0.59 point slowing), a future trial would require 3.4 times more subjects than would be required to detect the comparable percent slowing (i.e., 0.90 points) with the run-in design.DiscussionAssuming the improvement at first follow-up observed in this trial represents PEs, the rate of change from the second assessment forward is a more accurate representation of symptom progression in this population and is the appropriate reference point for describing treatment effects characterized as percent slowing of symptom progression; failure to accommodate this leads to an oversized clinical trial. We conclude that PEs are an important potential consideration when planning future trials

Multimodal Partial-Volume Correction: Application to 18F-Fluoride PET/CT Bone Metastases Studies

18F-fluoride PET/CT offers the opportunity for accurate skeletal metastasis staging, compared with conventional imaging methods. 18F-fluoride is a bone-specific tracer whose uptake depends on osteoblastic activity. Because of the resulting increase in bone mineralization and sclerosis, the osteoblastic process can also be detected morphologically in CT images. Although CT is characterized by high resolution, the potential of PET is limited by its lower spatial resolution and the resulting partial-volume effect. In this context, the synergy between PET and CT presents an opportunity to resolve this limitation using a novel multimodal approach called synergistic functional–structural resolution recovery (SFS-RR). Its performance is benchmarked against current resolution recovery technology using the point-spread function (PSF) of the scanner in the reconstruction procedure. Methods: The SFS-RR technique takes advantage of the multiresolution property of the wavelet transform applied to both functional and structural images to create a high-resolution PET image that exploits the structural information of CT. Although the method was originally conceived for PET/MR imaging of brain data, an ad hoc version for whole-body PET/CT is proposed here. Three phantom experiments and 2 datasets of metastatic bone 18F-fluoride PET/CT images from primary prostate and breast cancer were used to test the algorithm performances. The SFS-RR images were compared with the manufacturer’s PSF-based reconstruction using the standardized uptake value (SUV) and the metabolic volume as metrics for quantification. Results: When compared with standard PET images, the phantom experiments showed a bias reduction of 14% in activity and 1.3 cm3 in volume estimates for PSF images and up to 20% and 2.5 cm3 for the SFS-RR images. The SFS-RR images were characterized by a higher recovery coefficient (up to 60%) whereas noise levels remained comparable to those of standard PET. The clinical data showed an increase in the SUV estimates for SFS-RR images up to 34% for peak SUV and 50% for maximum SUV and mean SUV. Images were also characterized by sharper lesion contours and better lesion detectability. Conclusion: The proposed methodology generates PET images with improved quantitative and qualitative properties. Compared with standard methods, SFS-RR provides superior lesion segmentation and quantification, which may result in more accurate tumor characterization

Predicting Progression in Parkinson's Disease Using Baseline and 1-Year Change Measures.

BackgroundImproved prediction of Parkinson's disease (PD) progression is needed to support clinical decision-making and to accelerate research trials.ObjectivesTo examine whether baseline measures and their 1-year change predict longer-term progression in early PD.MethodsParkinson's Progression Markers Initiative study data were used. Participants had disease duration ≤2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score and DAT specific binding ratios (SBR) using linear mixed-effects models.ResultsAmong 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (β= 0.351; 95% CI = 0.146, 0.555), male gender (β= 3.090; 95% CI = 0.310, 5.869), and baseline (β= -0.199; 95% CI = -0.315, -0.082) and 1-year change (β= 0.540; 95% CI = 0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (β= -0.6229; 95% CI = -1.2910, 0.0452), baseline (β= 7.232; 95% CI = 2.268, 12.195) and 1-year change (β= 45.918; 95% CI = 35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (β= -0.325;95% CI = -0.695, 0.045); predictors in the model accounted for 44.1% of the variance.ConclusionsBaseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding

Predictors of quality of life ratings from persons with dementia: the role of insight

Objective: Evidence suggests that people with dementia are able to respond accurately and consistently to questions about quality of life (QoL), although large discrepancies exist between patient and proxy ratings. This may be due, in part, to the reduced insight of the person with dementia. The aim of this study was to explore the predictors of QoL ratings in a sample of people with mild dementia, with a particular focus on the role of insight. Methods: Sixty-nine participants and their caregivers were recruited from a memory clinic setting. The Bath Assessment of Subjective Quality of Life in Dementia (BASQID), Alzheimer’s Disease-Related Quality of Life Scale, Memory Functioning Scale, Alzheimer's Disease Cooperative Study Activities of Daily Living (ADL) Inventory and Mini Mental Status Examination were administered. Results: Regression analyses indicated that the strongest predictor of QoL ratings from persons with dementia was their awareness of memory function, such that lower awareness was associated with higher QoL ratings. Proxy ratings of activity performance and enjoyment of activity were also significant predictors of BASQID scores. Conclusions: Awareness of memory function impacts directly on patient QoL ratings and can also mask the effects of changes in other outcomes such as ADL function. Measures of awareness should therefore be employed alongside patient QoL ratings in order to ensure they are interpreted accurately. Discrepancies between patient and proxy QoL ratings do not necessarily occur because of patient unreliability, but may instead reflect the application of distinct modes of QoL assessment that emphasise very different outcomes

Clinical and Economic Characteristics of Milestones Along the Continuum of Alzheimer's Disease: Transforming Functional Scores into Levels of Dependence

BACKGROUND: Because Alzheimer’s disease (AD) is characterized by a gradual decline, it can be difficult to identify distinct clinical milestones that signal disease advancement. Adapting a functional scale may be a useful way of staging disease progression that is more informative for healthcare systems. Objectives: To adapt functional scale scores into discrete levels of dependence as a way of staging disease progression that is more informative to care providers and stakeholders who rely on the functional impact of diseases to determine access to supportive services and interventions. Design: Analysis of data from the GERAS study. Setting: GERAS is an 18-month prospective, multicenter, naturalistic, observational cohort study reflecting the routine care of patients with AD in France, Germany, and the United Kingdom. Participants: Data were from baseline results of 1497 community-living patients, aged ≥55 years, diagnosed with probable AD and their caregivers. Measurements: We used data from the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) and mapped items onto established categories of functional dependence, validated using clinical and economic measures. Cognitive function, behavioral symptoms, caregiver burden, and cost were assessed. Based on stages of functional dependence described by the Dependence Scale, individual ADCS-ADL items were used to approximate 6 dependence levels. Results: There was a significant relationship between assigned level of dependence derived from the ADCS-ADL score and cognitive severity category. As the assigned level of dependence increased, the associated clinical and economic indicators demonstrated a pattern of greater disease severity. Conclusions: This mapping provides initial support for dependence levels as appropriate interim clinical milestones that characterize the functional deficits associated with AD