Evaluating more naturalistic outcome measures:A 1-year smartphone study in multiple sclerosis

Objective: In this cohort of individuals with and without multiple sclerosis (MS), we illustrate some of the novel approaches that smartphones provide to monitor patients with chronic neurologic disorders in their natural setting. Methods: Thirty-eight participant pairs (MS and cohabitant) aged 18–55 years participated in the study. Each participant received an Android HTC Sensation 4G smartphone containing a custom application suite of 19 tests capturing participant performance and patient-reported outcomes (PROs). Over 1 year, participants were prompted daily to complete one assigned test. Results: A total of 22 patients with MS and 17 cohabitants completed the entire study. Among patients with MS, low scores on PROs relating to mental and visual function were associated with dropout (p < 0.05). We illustrate several novel features of a smartphone platform. First, fluctuations in MS outcomes (e.g., fatigue) were assessed against an individual's ambient environment by linking responses to meteorological data. Second, both response accuracy and speed for the Ishihara color vision test were captured, highlighting the benefits of both active and passive data collection. Third, a new trait, a person-specific learning curve in neuropsychological testing, was identified using spline analysis. Finally, averaging repeated measures over the study yielded the most robust correlation matrix of the different outcome measures. Conclusions: We report the feasibility of, and barriers to, deploying a smartphone platform to gather useful passive and active performance data at high frequency in an unstructured manner in the field. A smartphone platform may therefore enable large-scale naturalistic studies of patients with MS or other neurologic diseases

A signature for immune response correlates with HCV treatment outcome in Caucasian subjects

This data article contains Supplementary material for a published research article describing a whole-blood proteomic signature that predicts treatment outcome for subjects infected with hepatitis C virus (HCV) [1]. The proteomic signature is derived from whole-blood samples from subjects infected with HCV. The article includes detailed experimental and computational methods used in the analysis. The article also includes tables of demographic and other information about the subjects. Finally, the article includes several figures and tables showing detailed results of the analyses (e.g. lists of identified proteins and coefficients/ROC curves for the regression models)

Dynamic changes in HCV RNA levels and viral quasispecies in a patient with chronic hepatitis C after telaprevir-based treatment

Background: Telaprevir is a selective inhibitor of the hepatitis C virus NS3 center dot 4A serine protease. Treatment with telaprevir resulted in a rapid HCV-RNA decline in chronic hepatitis C genotype 1 patients. Objectives: To report the clinical and viral course of a patient treated with telaprevir in combination with pegylated interferon-alpha-2a and ribavirin in a Phase 2 clinical trial (PROVE3). Study design: This previous non-responder to interferon based therapy was treated for 40 weeks with a telaprevir, pegylated interferon alpha-2a, and ribavirin regimen. Viral sequencing and phylogenetic analysis were performed before, during and after therapy. Results: The patient, a 54 years old male patient, experienced a viral relapse 4 weeks post-treatment and HCV-RNA levels continued to increase 14 weeks post-treatment (150,000 IU/mL). The viral population, which was wild type at baseline, consisted of only V36A variants at both of these post-treatment time-points. Subsequently, this patient had a transient disappearance of HCV-RNA for more than 1 year in the absence of antiviral therapy. Thereafter, HCV-RNA reappeared again with a viral population consisting of only wild type virus. Phylogenetic analysis of NS3 center dot 4A corresponded with a viral population bottleneck resulting in changes in viral quasispecies. Conclusion: In this case report, significant viral load reductions resulted in a genetic bottleneck leading to a reduction of variability in the hepatitis C viral population. We hypothesize that the reduction in viral heterogeneity potentially led to a reduced viral capacity to adapt to a host immune response leading to a transient loss of detectable HCV-RNA. (C) 2011 Elsevier B.V. All rights reserve

Objective Measurement of Gait Abnormalities in Huntington Disease using a Shoe-Worn Inertial Sensor (P5.291)

OBJECTIVE: To evaluate the feasibility and utility of a shoe-worn inertial sensor to measure gait abnormalities in Huntington disease (HD) in the home setting. BACKGROUND: Clinical rating scales provide only point assessments of disease-related impairments in HD, lack sensitivity, and require that a clinician experienced in the scale’s use evaluate the patient. A tool that would allow longitudinal, objective, quantitative measurement of impairments may offer advantages over standard clinical rating scales. DESIGN/METHODS: This was a pilot, single-blind, controlled observational study. Five ambulatory HD subjects and 5 age/gender-matched healthy controls wore inertial sensors manufactured by APDM, Inc. attached to each shoe during waking hours for 7 days. Gait parameters calculated from the sensors included stride length([percnt]height); stride velocity([percnt]height/sec); step duration(sec); double support time([percnt]); pitch at toe off (degrees) and heel strike (degrees); cadence(steps/min); and variability in each of these measures. Following blinded descriptive data analysis by APDM, independent samples t-tests were used to compare means for selected gait metrics between HD and control subjects, and Pearson correlation coefficients were used to interrogate the relationships between gait metrics, chorea score, and Total Functional Capacity (TFC, a measure of disease severity). RESULTS: Subjects were able to successfully apply, wear and charge the sensors. Blinded gait analysis correctly identified the HD and control subjects for 4/5 pairs. Significant differences were found between HD/control groups in mean(SD) stride length [53.96(9.25), 67.68(7.25), p=0.03]; mean(SD) variability per week (as measured by coefficient of variation) in stride length [28.57(5.54), 20.27(3.78), p=0.02] and pitch at toe off [25.57(4.00), 17.56(4.07), p=0.01]. Lower TFC scores correlated with greater variability in stride length[R=-0.82]; pitch at toe off[R=-0.80]; and increased double support time[R=-0.75]. Higher chorea scores correlated with shorter stride length[R=-0.76]. CONCLUSIONS: Inertial sensors may offer a feasible mechanism to objectively measure clinically-relevant gait abnormalities in HD

Assessment of repeatability of hyperpolarized gas MR ventilation functional imaging in cystic fibrosis

RATIONALE AND OBJECTIVES: Hyperpolarized (HP) gas magnetic resonance imaging (MRI) is an advanced imaging technique that provides high-resolution regional information on lung function without using ionizing radiation. Before this modality can be considered for assessing clinical or investigational interventions, baseline repeatability needs to be established. We assessed repeatability of lung function measurement using HP helium-3 MRI (HP (3)He MRI) in a small cohort of patients with cystic fibrosis (CF). MATERIALS AND METHODS: We examined repeatability of HP (3)He MR images of five patients with CF in four scanning sessions over a 4-week period. We acquired images on a Philips 3.0 Tesla Achieva MRI scanner using a quadrature, flexible, wrap-around, (3)He radiofrequency coil with a fast gradient-echo pulse sequence. We determined ventilation volume and ventilation defect volume using an advanced semiautomatic segmentation algorithm and also quantified ventilation heterogeneity. RESULTS: There were no significant differences in total ventilation volume, ventilation defect volume, ventilation defect percentage, or mean ventilation heterogeneity (repeated-measures analysis of variance, P = .2116, P = .2825, P = .2871, and P = .7265, respectively) in the patients across the four scanning sessions. CONCLUSIONS: Our results indicate that total ventilation volume, ventilation defect volume, ventilation defect percentage, and mean ventilation heterogeneity as assessed by HP gas MRI in CF patients with stable health are reproducible over time. This repeatability and the technique\u27s capability to provide noninvasive high-resolution data on regional lung function without ionizing radiation make (3)He MRI a potentially useful outcome measure for CF-related clinical trials

Active-Site Residues of Escherichia coli DNA Gyrase Required in Coupling ATP Hydrolysis to DNA Supercoiling and Amino Acid Substitutions Leading to Novobiocin Resistance

DNA gyrase is a bacterial type II topoisomerase which couples the free energy of ATP hydrolysis to the introduction of negative supercoils into DNA. Amino acids in proximity to bound nonhydrolyzable ATP analog (AMP · PNP) or novobiocin in the gyrase B (GyrB) subunit crystal structures were examined for their roles in enzyme function and novobiocin resistance by site-directed mutagenesis. Purified Escherichia coli GyrB mutant proteins were complexed with the gyrase A subunit to form the functional A(2)B(2) gyrase enzyme. Mutant proteins with alanine substitutions at residues E42, N46, E50, D73, R76, G77, and I78 had reduced or no detectable ATPase activity, indicating a role for these residues in ATP hydrolysis. Interestingly, GyrB proteins with P79A and K103A substitutions retained significant levels of ATPase activity yet demonstrated no DNA supercoiling activity, even with 40-fold more enzyme than the wild-type enzyme, suggesting that these amino acid side chains have a role in the coupling of the two activities. All enzymes relaxed supercoiled DNA to the same extent as the wild-type enzyme did, implying that only ATP-dependent reactions were affected. Mutant genes were examined in vivo for their abilities to complement a temperature-sensitive E. coli gyrB mutant, and the activities correlated well with the in vitro activities. We show that the known R136 novobiocin resistance mutations bestow a significant loss of inhibitor potency in the ATPase assay. Four new residues (D73, G77, I78, and T165) that, when changed to the appropriate amino acid, result in both significant levels of novobiocin resistance and maintain in vivo function were identified in E. coli