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Background: No evidence of disease activity (NEDA) is a composite endpoint being increasingly applied as an outcome measure in clinical trials as well as proposed for individual therapeutic decisions in multiple sclerosis (MS). Objective: Assess the proportion of patients with relapsing-remitting MS achieving NEDA in the DECIDE study of daclizumab 150 mg subcutaneous versus intramuscular interferon beta-1a 30 µg for 96-144 weeks. Methods: NEDA was defined as no relapses, no onset of 12-week confirmed disability progression (CDP), no new/newly enlarging T2 hyperintense lesions (NET2), and no gadolinium-enhancing (Gd+) lesions. Logistic regression models adjusted for baseline covariates compared treatment groups for baseline to week 96, weeks 0-24, and weeks 24-96. Results: From baseline to week 96, more daclizumab versus intramuscular interferon beta-1a patients achieved NEDA (24.6% vs 14.2%; odds ratio (OR; 95% confidence interval): 2.059 (1.592-2.661); p < 0.0001). ORs for clinical NEDA (no relapses, no CDP) and magnetic resonance imaging (MRI) NEDA (no NET2, no Gd+ lesions) were 1.651 (1.357-2.007; p < 0.0001) and 2.051 (1.628-2.582; p < 0.0001), respectively. ORs in favor of daclizumab for weeks 24-96 were consistently higher than for weeks 0-24. Conclusion: More daclizumab versus intramuscular interferon beta-1a patients achieved NEDA early in DECIDE, with effects increasing over time. [ABSTRACT FROM AUTHOR]

Background: Subcutaneous peginterferon beta-1a has previously been shown to reduce the number of T2-hyperintense and gadolinium-enhancing (Gd+) lesions over 2 years in patients with relapsing-remitting multiple sclerosis (RRMS), and to reduce T1-hypointense lesion formation and the proportion of patients showing evidence of disease activity, based on both clinical and radiological measures, compared with placebo over 1 year of treatment. The objectives of the current analyses were to evaluate T1 lesions and other magnetic resonance imaging (MRI) measures, including whole brain volume and magnetization transfer ratio (MTR) of normal appearing brain tissue (NABT), and the proportions of patients with no evidence of disease activity (NEDA), over 2 years.Methods: Patients enrolled in the ADVANCE study received continuous peginterferon beta-1a every 2 or 4 weeks for 2 years, or delayed treatment (placebo in Year 1; peginterferon beta-1a every 2 or 4 weeks in Year 2). MRI scans were performed at baseline and Weeks 24, 48, and 96. Proportions of patients with NEDA were calculated based on radiological criteria (absence of Gd + and new/newly-enlarging T2 lesions) and clinical criteria (no relapse or confirmed disability progression) separately and overall.Results: Peginterferon beta-1a every 2 weeks significantly reduced the number and volume of T1-hypointense lesions compared with delayed treatment over 2 years. Changes in whole brain volume and MTR of NABT were suggestive of pseudoatrophy during the first 6 months of peginterferon beta-1a treatment, which subsequently began to resolve. Significantly more patients in the peginterferon beta-1a every 2 weeks group compared with the delayed treatment group met MRI-NEDA criteria (41% vs 21%; odds ratio [OR] 2.56; p < 0.0001), clinical-NEDA criteria (71% vs 57%; OR 1.90; p < 0.0001) and achieved overall-NEDA (37% vs 16%; OR 3.09; p < 0.0001).Conclusion: Peginterferon beta-1a provides significant improvements in MRI measures and offers patients a good chance of remaining free from evidence of MRI, clinical and overall disease activity over a sustained 2-year period.Trial Registration: ClinicalTrials.gov: NCT00906399 ; Registered on: May 20, 2009. [ABSTRACT FROM AUTHOR]

Background: In the pivotal phase III 2-year ADVANCE study, subcutaneous peginterferon beta-1a 125 mcg every 2 weeks demonstrated significant improvements in clinical outcomes, including disability endpoints, in patients with relapsing-remitting multiple sclerosis (RRMS). Here, we aim to further evaluate disability data from ADVANCE, and explore associations between confirmed disability progression (CDP), functional status, and health-related quality of life (HRQoL). Methods: In total, 1512 patients were randomized to placebo or peginterferon beta-1a 125 mcg every 2 or 4 weeks. After 1 year, patients on placebo were re-randomized to peginterferon beta-1a every 2 or 4 weeks. CDP was defined as ≥1.0 point increase from a baseline Expanded Disability Status Scale (EDSS) score ≥ 1.0, or ≥1.5-point increase from baseline 0, confirmed 12 or 24 weeks after onset. Results: Peginterferon beta-1a every 2 weeks significantly reduced risk of 12- and 24-week CDP at 1 year compared with placebo (12-week CDP: 6.8% versus 10.5%, p = 0.038; 24- week CDP: 4% versus 8.4%, p = 0.0069, peginterferon beta-1a every 2 weeks versus placebo, respectively). Benefits were maintained over 2 years (11.2% and 7.7%, peginterferon beta-1a every 2 weeks in 12- and 24-week CDP, respectively). Approximately 90% of patients with 24- week CDP had simultaneous worsening by ≥1 point in at least one functional system score, most commonly pyramidal. Displaying a 24-week CDP was associated with worse scores on the Multiple Sclerosis Functional Composite (MSFC) scale and several HRQoL instruments; the impact of CDP was attenuated by treatment with peginterferon beta-1a every 2 weeks. Conclusions: Peginterferon beta-1a has the potential to prevent/delay worsening of disability in patients with relapsing-remitting multiple sclerosis. Furthermore, improved benefits in disability status with peginterferon beta-1a were also associated with improved functional status and HRQoL [ClinicalTrials.gov identifier: NCT00906399]. [ABSTRACT FROM AUTHOR]

Background: Flu-like symptoms (FLSs) and injection-site reactions (ISRs) have been reported with inter-feron beta treatments for multiple sclerosis (MS). We sought to obtain consensus on the characteristics/ management of FLSs/ISRs in patients with relapsing-remitting MS based on experiences from the randomized, placebo-controlled ADVANCE study of peginterferon beta-1a. Methods: ADVANCE investigators with a predefined number of enrolled patients were eligible to participate in a consensus-generating exercise using a modified Delphi method. An independent steering committee oversaw the development of two sequential Delphi questionnaires. An average rating (AR) of 2.7 or more was defined as consensus a priori. Results: Thirty and 29 investigators (ie, responders) completed questionnaires 1 and 2, respectively, representing 374 patients from ADVANCE. Responders reported that the incidence/duration of FLSs/ISRs in their typical patient generally declined after 3 months of treatment. Responders reached consensus that FLSs typically last up to 24 hours (AR = 3.17) and have mild/moderate effects on activities of daily living (AR = 3.34). Patients should initiate acetaminophen/nonsteroidal anti-inflammatory drug treatment on a scheduled basis (AR = 3.31) and change the timing of injection (AR = 3.28) to manage FLSs. Injection-site rotation/cooling and drug administration at room temperature (allAR ≥ 3.10) were recommended for managing ISRs. Patient education on FLSs/ISRs was advocated before treatment initiation. Conclusions: Delphi responders agreed on the management strategies for FLSs/ISRs and agreed that patient education is critical to set treatment expectations and promote adherence. [ABSTRACT FROM AUTHOR]

Background: The main clinical determinants of quality of life (QOL) 5 years after clinically isolated syndrome (CIS) are Expanded Disability Status Scale (EDSS) score and conversion to clinically definite multiple sclerosis (CDMS). The aim of this study was to determine the demographic, clinical, and magnetic resonance imaging (MRI) factors associated with QOL 10 years after CIS. Methods: Controlled High Risk Avonex® Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance (CHAMPIONS) 10-year patients were assessed for CDMS, EDSS score, MRI T2 activity, brain parenchymal fraction, and patient-reported QOL. Associations were evaluated using analysis of variance models. Results: A second clinical event consistent with CDMS and higher EDSS scores at years 5 and 10 were associated with lower 36-item Short Form Health Status Survey (SF-36) Physical Component Summary scores at year 10 (P < .01). Patients with earlier onset of CDMS had worse patient-reported Physical Component Summary, SF-36 Mental Component Summary, fatigue, and pain scores at year 10 than patients with later or no onset of CDMS. Neither initial randomization group nor any MRI metrics assessed at baseline or during follow-up were associated with QOL at 10 years. Conclusions: These results support the development of therapies for patients with CIS that significantly reduce the risk of conversion to CDMS and the progression of physical disability to milestones as low as EDSS scores of 2.0. [ABSTRACT FROM AUTHOR]

Background Subcutaneous peginterferon beta-1a provided clinical benefits versus placebo at Year 1 of the 2-Year Phase 3 ADVANCE study in relapsing-remitting multiple sclerosis (RRMS). Here we report its effect on brain magnetic resonance imaging (MRI) lesions, and no evidence of disease activity (NEDA; absence of clinical [relapses and 12-week confirmed disability progression] and MRI [gadolinium-enhancing, and new or newly-enlarging T2 hyperintense lesions] disease activity). Methods RRMS patients (18?65 years; Expanded Disability Status Scale score ≤5) were randomized to double-blind placebo or peginterferon beta-1a 125 μg every 2 or 4 weeks. Sensitivity analyses of last observation carried forward and composite disease activity (using minimal MRI allowance definitions) were conducted. Results 1512 patients were randomized and dosed (placebo n = 500; peginterferon beta-1a every 2 [n = 512] or 4 [n = 500] weeks). Every 2 week dosing significantly reduced, versus placebo and every 4 week dosing, the number of new or newly-enlarging T2 hyperintense lesions at Weeks 24 (61% and 51%, respectively) and 48 (secondary endpoint; 67% and 54%, respectively); all p < 0.0001. Every 2 week dosing also significantly reduced the number of new T1 hypointense, gadolinium-enhancing, and new active (gadolinium-enhancing plus non-enhancing new T2) lesions (all p < 0.0001), as well as the volume of T2 and T1 lesions (p < 0.05) at Weeks 24 and 48 versus placebo and every 4 week dosing. Significantly more patients dosed every 2 weeks had NEDA versus placebo and every 4 weeks (all p < 0.01) from baseline to Week 48 (33.9% versus 15.1% and 21.5%, respectively [odds ratios, ORs: 2.89 and 1.87]), from baseline to Week 24 (41.0% versus 21.9% and 30.7%, [ORs: 2.47 and 1.57]) and from Week 24 to Week 48 (60.2% versus 28.9% and 36.6%, [ORs: 3.71 and 2.62]). Consistent results were seen allowing for minimal MRI activity. Conclusion During Year 1 of ADVANCE, significantly more RRMS patients receiving peginterferon beta-1a every 2 weeks had NEDA, and early and sustained improvements in MRI endpoints, versus placebo and every 4 week dosing. Sensitivity analyses align with switch strategies in clinical practice settings and provide insight into future responders/non-responders. Trial registration ClinicalTrials.gov: NCT00906399 [ABSTRACT FROM AUTHOR]

Background: Bladder dysfunction is a common symptom of multiple sclerosis (MS). This study was designed to evaluate effects of natalizumab on bladder function in patients with relapsing-remitting MS. Methods: The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) study was an open-label, single-arm, two-center study. Natalizumabnaive MS patients with disabling bladder dysfunction and initiating natalizumab were enrolled and followed for 6 months. The primary endpoint was change in the Urogenital Distress Inventory short form (UDI-6) score from baseline. Change in Incontinence Impact Questionnaire short form (IIQ-7) score from baseline was a secondary endpoint. Results: Thirty patients were enrolled. Mean baseline characteristics were age 49.9 years, Expanded Disability Status Scale score 4.6, number of relapses in previous year 2.4, UDI-6 score 10.4, and IIQ-7 score 12.3. Mean changes in UDI-6 and IIQ-7 scores were significantly improved from baseline beginning at week 4 and up to week 24; mean improvements at 24 weeks were 4.4 (P < .0001) and 4.9 (P = .0005) points, respectively. At week 24, 85.7% and 78.6% of patients demonstrated improvements from baseline in UDI-6 and IIQ-7 scores, respectively. Conclusions: Incontinence-related quality of life as measured by UDI-6 and IIQ-7 scores improved significantly during natalizumab treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate the value of Expanded Disability Status Scale (EDSS) worsening sustained for at least 6 months and other parameters as predictors for disability status. Design: Retrospective analysis of the Multiple Sclerosis Collaborative Research Group study data. Setting: The intramuscular interferon beta-1a pivotal trial was a double-blind, placebo-controlled phase 3 study. Participants: Patients with relapsing-remitting multiple sclerosis who received at least 2 years of treatment and completed an EDSS evaluation 8 years postrandomization. Intervention: Thirty micrograms of intramuscular interferon beta-1a or placebo once weekly during the 2-year clinical trial. Main Outcome Measures: Positive predictive values for 6-month sustained progression during 2 years were calculated to determine the ability to predict disability status at 8 years. A multivariate logistic regression model was used to assess the relationship between predictors and EDSS milestones at follow-up. Results: Forty-five patients had sustained 6-month EDSS progression during the clinical trial and 115 did not. Progression during the trial was the strongest predictor of reaching EDSS milestones at the follow-up visit, 8 years after randomization. Other independent predictors were treatment arm assignment and baseline EDSS score. Conclusion: In this phase 3 clinical trial of intramuscular interferon beta-1a, compared with effects of treatment, baseline EDSS score, and number of relapses during the study, worsening of 1 point or more on EDSS from baseline lasting 6 months was the strongest predictor of clinically significant disability 8 years after randomization into the clinical trial. [ABSTRACT FROM AUTHOR]

The objective of this article is to develop a hypothesis-testing procedure to determine whether a common source outbreak has ended. We consider the case when neither the calendar date of exposure to the pathogen nor the exact incubation period distribution is known. The hypothesis-testing procedure is based on the spacings between ordered calendar dates of disease onset of the cases. A simulation study was performed to evaluate the robustness of the methods to various models for the incubation period of infectious diseases. We investigated the impact of multiple testing on the overall outbreak-wise type I error probability. We derive expressions for the outbreak-wise type I error probability and show that multiple testing has minimal effect on inflating that error probability. The results are discussed in the context of the 2001 U.S. anthrax outbreak. [ABSTRACT FROM AUTHOR]

Since the discovery of catalase, it has been postulated that aerobic organisms generate enough oxidants to threaten their own fitness and, in particular, their genetic stability. An alternative is that these enzymes exist to defend the cell against more-abundant oxidants imposed by external sources. These hypotheses were tested directly through study of Hpr (katG katE ahpCf) mutants of Escherichia coli, which lack enzymes to scavenge hydrogen peroxide (H2O2). These strains grew well in anaerobic medium but poorly when they were aerated. The Hpr bacteria formed filaments and exhibited high rates of mutagenesis, both indicators of DNA damage. An additional recA mutation caused Hpr cells to die rapidly upon aeration, even though the intracellular H2O2 was <1 μM. Spin-trap experiments detected substantial hydroxyl radicals, and cell-permeable iron chelators eliminated both the phenotypic defects and hydroxyl-radical formation, confirming that the Fenton reaction was responsible. An Hproxy R strain exhibited even more DNA lesions than did the Hpx mutant indicating that the OxyR stress response induced protein(s) that suppressed DNA damage. One critical protein was Dps, an iron-sequestration protein, because Hpr dps mutants exhibited sensitivity similar to that of the Hproxy R mutant. These results reveal that aerobic E. coli generates sufficient H2O2 to create toxic levels of DNA damage. Scavenging enzymes and controls on free iron are required to avoid that fate. The rate constant of the Fenton reaction measured at physiological pH was much higher than under the acidic conditions that were used to determine the commonly cited value. [ABSTRACT FROM AUTHOR]

This paper presents a novel capacitive pressure sensor that is capable of making highly accurate measurements at low pressure. Different from the method that many researchers have successfully used to improve the sensitivity of capacitive sensors by using a micro-structured dielectric layer (such as the micro-structured PDMS film), this paper creatively used an elastic metallized sponge (nickel-plated polyurethane sponge) as the elastic porous electrode of the capacitive sensor, so that it can detect very low pressure (such as a 0.2 g soybean). Compared with the traditional capacitive sensor using an insulative polyurethane sponge as the dielectric, the baseline capacitance of the sensor of the same size can increase by 10 times, and it has a better signal-to-noise ratio. In addition, the sensor has good robustness due to the good mechanical properties of the nickel-plated polyurethane sponge. The fabrication process of the sensor is extremely simple, the cost is low, and it can be made into any planar shape. In this paper, we describe the structure, principle and manufacture of the sensor, and present the application on robotic grasping. [ABSTRACT FROM AUTHOR]