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Purpose This paper aims to report a flexible position-sensitive sensor that can be applied as large-area electronic skin over the stiff media. Design/methodology/approach The sensor uses a whole piezoresistive film as a touch sensing area. By alternately constructing two uniform electric fields with orthogonal directions in the piezoresistive film, the local changes in conductivity caused by touch can be projected to the boundary along the equipotential line under the constraint of electric field. Based on the change of boundary potential in the two uniform electric fields, it can be easy to determine the position of the contact area in the piezoresistive film. Findings Experiment results show the proposed tactile sensor is capable of detecting the contact position and classifying the contact force in real-time based on the changes of the potential differences on the boundary of the sensor. Practical implications The application example of using the sensor sample as a controller in shooting game is presented in this paper. It shows that the sensor has excellent touch sensing performance. Originality/value In this paper, a position-sensitive electronic skin is proposed. The experiment results show that the sensor has great application prospects in the field of interactive tactile sensing.

Zheng Qin,1 Dawei Liu,2 Xiaojun You,3 Qin Duan,3 Yu Zhao1 1Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Department of Cardiovascular Medicine, The Bishan Hospital of Chongqing Medical University, Chongqing, 402760, People’s Republic of China; 3Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Qin Duan, Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China, Email duanqin11@126.com Yu Zhao, Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China, Email zhaoyucqmu@126.comBackground: The impact of pulse pressure (PP) on indexes of myocardial work (MWIs). This study aims to explore the potential association of high PP with myocardial work (MW).Hypothesis: PP had an association with four indexes of MW in a mixed population of normotensive, prehypertensive and newly diagnosed hypertensive individuals.Methods: The study was a single-center, cross-sectional, observational study. A total of 204 participants (66 normotensive, 35 prehypertensive and 103 newly diagnosed hypertensive individuals) were evaluated by speckle-tracking echocardiography (STE) and blood pressure measurement. According to the PP tertiles, the participants were divided into three groups: Group I (< 44 mmHg, n=67), Group II (44– 52 mmHg, n=68) and Group III (≥ 52 mmHg, n=69).Results: In Group II and Group III, the proportion of males was higher than that in Group I (median 46 vs 30 (P=0.002)). With increasing PP, the three indexes of MW, namely, GWI, GCW and GWW, increased, and the differences among the three groups were statistically significant (P< 0.001). PP was positively related to GWI, GCW and GWW and negatively correlated with GWE. After adjusting for E/e’, LVMI, LAVI and GLS, PP was still significantly correlated with the four MW indexes (both P< 0.001).Conclusion: PP had a strong association with four indexes of MW in a mixed population of normotensive, prehypertensive and newly diagnosed hypertensive individuals. The evaluation of PP and MWIs might be valuable for identifying very early diastolic impairment of the heart.Keywords: arterial stiffness, myocardial work, hypertension, speckle-tracking echocardiography, pulse pressure

Collaborative innovation can promote scientific productivity and the development of clean technology and thus has a great potential in constraining the ecological footprint. However, current studies on the impact of collaborative innovation on ecological footprint are insufficient, and results remain controversial. To better understand these impacts, this paper took Guangdong-Hong Kong-Macao Greater Bay Area of China as a case, estimated the ecological footprint at the municipal level from 2008 to 2018, measured collaborative innovation both from four dimensions and from a composite approach, then applied threshold regression models to compare the impact of collaborative innovation on the ecological footprint across different economic intervals. The findings showed that: the ecological footprint of the Greater Bay Area displayed an overall upward trend with prominent spatial heterogeneity. The impact of collaborative innovation on the ecological footprint presented a double-threshold effect when examined with different indicators. Among which, the flow of scientific personnel and capital boosted the ecological footprint, which intensified with economic development, while collaboration in technology exerted significant inhibitory effects on ecological footprint, and the influence of inter-city knowledge collaboration was limited. Overall, collaborative innovation inhibited ecological footprint when measured by a composite index. This might inspire policymakers to adopt sustainable strategies depending on the type of collaborative innovation and the economic status of the city to constrain growth of the ecological footprint, thus minimizing the pressures of human activities on the environment and moving towards a more carbon neutral society.

China is under rapid urbanization and consequently facing increasing carbon emissions (CE). Economic growth (EG) and innovation performance (IP), as two critical indicators of urbanization, are considered the driving forces of CE. Although economy and innovation are entangled and can jointly affect CE in reality, the measured effects of economy and innovation on CE are often treated separately in traditional studies. We adopted a three-part research framework including the total, interaction and mediation effect tests to elucidate how EG and IP affected CE in China from 2005 to 2015 based on insights from 282 Chinese cities. The empirical results showed that both economy and innovation contributed to CE, although the contribution has reduced over the 11 years. In particular, the interaction effect between economy and innovation for North China, Northeast China, and Southwest China was -4.201, -8.442, and - 3.897, respectively, in 2015, meaning that these regions adversely affect CE. In addition, we found that the economy helps reduce CE via innovation. When considering the changes of economy and innovation, their mediation effect on CE changes varied in different regions, attributable to the level of economy and innovation as well as the stocks of energy resources. Therefore, future planning for low-carbon transition should regard the economy and innovation together. Based on this principle, we propose five detailed policies. Overall, this study is valuable not only for further understanding the triangle relationship among economy, innovation, and CE, but also for reaching low-carbon goals.

The impact of lumacaftor/ivacaftor on exercise tolerance in people with cystic fibrosis (CF) has not been thoroughly studied.We conducted a multisite Phase 4 trial comparing the impact of lumacaftor/ivacaftor on exercise tolerance with that of placebo in participants ≥ 12 years of age with CF homozygous for F508del-CFTR. The primary endpoint was relative change from baseline in maximum oxygen consumption (VOSeventy participants were randomized to receive lumacaftor/ivacaftor (n = 34) or placebo (n = 36). The least-squares mean difference for lumacaftor/ivacaftor versus placebo in relative change in VODefinitive conclusions regarding the impact of lumacaftor/ivacaftor on exercise tolerance cannot be drawn from these results; however, multicenter studies using CPETs can be reliably performed with multiple time points and conventional methods, provided that calibration can be achieved. Future studies of exercise tolerance may benefit from lessons learned from this study. NCT02875366.

The presence of chronic black holes, i.e., chronic lesions that are hypointense on T1-weighted images and are indicative of more severe tissue injury, has been increasingly utilized as a surrogate marker of therapeutic outcome in multiple sclerosis. The ADVANCE study was a 2-year, double-blind, pivotal trial evaluating the safety and efficacy of subcutaneous peginterferon beta-1a 125 mcg in 1512 patients with relapsing–remitting multiple sclerosis (RRMS). This report describes the correlation of clinical outcomes with the evolution of acute lesions into chronic black holes in ADVANCE, and the efficacy of peginterferon beta-1a in reducing this evolution. Treatment with peginterferon beta-1a significantly reduced the mean number of new/enlarging T2-weighted (NET2) lesions (0.76 vs. 1.03 from week 24, p = 0.0037; 0.44 vs. 0.99 from week 48, p

Given the rapid development within China, the inequality of available water resources has been increasingly of interest. Current methods for assessing water stress are inadequate for province-scale rapid monitoring. A more responsive indicator at a finer scale is needed to understand the distribution of water stress in China. This paper selected Defense Meteorological Satellite Program Operational Line-scan System night-time stable lights as a proxy for water stress at the province level in China from 2004 to 2012, as night-time lights are closely linked with population density, electricity consumption and other social, economic and environmental indicators associated with water stress. The linear regression results showed the intensity of night-time lights can serve as a predictive tool to assess water stress across provinces with an R2 from 0.797 to 0.854. The model worked especially well in some regions, such as East China, North China and South West China. Nonetheless, confounding factors interfered with the predictive relationship, including population density, level of economic development, natural resource endowment and industrial structures, etc. The model was not greatly improved by building a multi-variable linear regression including agricultural and industrial indicators. A straightforward predictor of water stress using remotely sensed data was developed.

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 + lesions) were 1.651 (1.357−2.007; p Conclusion: More daclizumab versus intramuscular interferon beta-1a patients achieved NEDA early in DECIDE, with effects increasing over time.

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].

There remains a lack of data on the epidemiological characteristics of surgical site infection (SSI) following the open reduction and internal fixation (ORIF) of intra-articular fractures of distal femur, and the aim of this study was to solve this key clinical issue. The electronic medical records (EMRs) of patients who underwent ORIF for distal femoral fracture from January 2013 to December 2017 were reviewed to identify those who developed a SSI. Then, we conducted univariate Chi-square analyses and used a multivariate logistic regression analysis model to determine the adjusted risk factors associated with SSI. A total of 724 patients who underwent ORIF of intra-articular fractures of the distal femur were studied retrospectively, and 29 patients had postoperative SSIs. The overall incidence of SSIs was 4.0% (29/724), with deep SSIs being 1.5% (11/724), and superficial SSIs being 2.5% (18/724). Staphylococcus aureus was the most common causative pathogen (8, 42.1%), followed by mixed bacterial pathogens (5, 26.3%). Open fracture, obesity, smoking, and diabetes mellitus were identified as the adjusted risk factors associated with SSIs. Although modification of these risk factors may be difficult, patients and families should be counselled regarding their increased risk of SSI because these patients potentially benefit from focused perioperative medical optimisation.

Background: Flu-like symptoms (FLSs) and injection-site reactions (ISRs) have been reported with interferon 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 (all AR ≥ 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.

Introduction Cutaneous adverse events (AEs) have been observed in clinical studies of daclizumab high-yield process (HYP) in relapsing-remitting multiple sclerosis (RRMS). Here, we report cutaneous AEs observed in the randomized, double-blind, active-comparator DECIDE study (ClinicalTrials.gov identifier, NCT01064401). Methods DECIDE was a randomized, double-blind, active-controlled phase 3 study of daclizumab HYP 150 mg subcutaneous every 4 weeks versus interferon (IFN) beta-1a 30 mcg intramuscular (IM) once weekly in RRMS. Treatment-emergent AEs were classified and recorded by investigators. Investigators also assessed the severity of each AE, and whether it met the criteria for a serious AE. Cutaneous AEs were defined as AEs coded to the Medical Dictionary for Regulatory Activities System Organ Class of skin and subcutaneous tissue disorders. The incidence, severity, onset, resolution, and management of AEs were analyzed by treatment group. Results Cutaneous AEs were reported in 37% of daclizumab HYP-treated patients and 19% of IFN beta-1a-treated patients. The most common investigator-reported cutaneous AEs with daclizumab HYP were rash (7%) and eczema (4%). Most patients with cutaneous AEs remained on treatment (daclizumab HYP, 81%; IM IFN beta-1a, 90%) and had events that were mild or moderate (94% and 98%) and subsequently resolved (78% and 82%). Most patients with cutaneous AEs did not require treatment with corticosteroids or were treated with topical corticosteroids (daclizumab HYP, 73%; IM IFN beta-1a, 81%). Serious cutaneous AEs were reported in 14 (2%) daclizumab HYP patients and one (

Background and purpose In the SELECT study, treatment with daclizumab high-yield process (DAC HYP) versus placebo reduced the frequency of gadolinium-enhancing (Gd+) lesions in patients with relapsing−remitting multiple sclerosis (RRMS). The objective of this post hoc analysis of SELECT was to evaluate the effect of DAC HYP on the evolution of new Gd+ lesions to T1 hypointense lesions (T1 black holes). Methods SELECT was a randomized double-blind study of subcutaneous DAC HYP 150 or 300 mg or placebo every 4 weeks. Magnetic resonance imaging (MRI) scans were performed at baseline and weeks 24, 36 and 52 in all patients and monthly between weeks 4 and 20 in a subset of patients. MRI scans were evaluated for new Gd+ lesions that evolved to T1 black holes at week 52. Data for the DAC HYP groups were pooled for analysis. Results Daclizumab high-yield process reduced the number of new Gd+ lesions present at week 24 (P = 0.005) or between weeks 4 and 20 (P = 0.014) that evolved into T1 black holes at week 52 versus placebo. DAC HYP treatment also reduced the percentage of patients with Gd+ lesions evolving to T1 black holes versus placebo. Conclusions Treatment with DAC HYP reduced the evolution of Gd+ lesions to T1 black holes versus placebo, suggesting that inflammatory lesions that evolved during DAC HYP treatment are less destructive than those evolving during placebo treatment.

The Phase III ADVANCE study has shown clinical benefits for peginterferon beta-1a 125 µg dosed every 2 weeks versus placebo at 1 year in patients with relapsing-remitting multiple sclerosis (MS). This study assessed the impact of peginterferon beta-1a and disease factors on health-related quality of life (HRQoL) using data from ADVANCE.HRQoL was assessed at baseline and 12, 24, and 48 weeks using the 29-item Multiple Sclerosis Impact Scale (MSIS-29) and other generic HRQoL measures. Changes in scores from baseline within each group and differences in mean change from baseline between groups were evaluated. Post-hoc mixed-effects repeated measures analyses were performed to assess the impact of confirmed disability progression and relapses, and the interactions of treatment and these MS events on HRQoL. Predictors with p≥0.1 were excluded from the final models, unless they were clinically meaningful.Relapses and confirmed disability progression were major drivers of HRQoL. When comparing week 48 to baseline, in placebo-treated patients (n=500), confirmed disability progression was associated with a 6.0-point worsening (p0.0001) of MSIS-29 physical scores, relative to a 1.9-point worsening (p=0.044) with peginterferon beta-1a every 2 weeks (n=512). Such findings were observed consistently with other generic HRQoL measures. Additionally, having a recent relapse (≤29 days before the HRQoL assessment) was associated with a 10.0-point worsening (p0.0001) of MSIS-29 psychological scores in placebo-treated patients, compared with a 3.5-point (p=0.031) worsening with peginterferon beta-1a every 2 weeks.Treatment with peginterferon beta-1a could help to improve or maintain HRQoL in addition to clinical outcomes.ClinicalTrials.gov: NCT00906399.

Regulatory T cells (Tregs) mediate immune tolerance to self and depend on IL-2 for homeostasis. Treg deficiency, dysfunction, and instability are implicated in the pathogenesis of numerous autoimmune diseases. There is considerable interest in therapeutic modulation of the IL-2 pathway to treat autoimmunity, facilitate transplantation tolerance, or potentiate tumor immunotherapy. Daclizumab is a humanized mAb that binds the IL-2 receptor α subunit (IL-2Rα or CD25) and prevents IL-2 binding. In this study, we investigated the effect of daclizumab-mediated CD25 blockade on Treg homeostasis in patients with relapsing-remitting multiple sclerosis. We report that daclizumab therapy caused an ∼50% decrease in Tregs over a 52-wk period. Remaining FOXP3+ cells retained a demethylated Treg-specific demethylated region in the FOXP3 promoter, maintained active cell cycling, and had minimal production of IL-2, IFN-γ, and IL-17. In the presence of daclizumab, IL-2 serum concentrations increased and IL-2Rβγ signaling induced STAT5 phosphorylation and sustained FOXP3 expression. Treg declines were not associated with daclizumab-related clinical benefit or cutaneous adverse events. These results demonstrate that Treg phenotype and lineage stability can be maintained in the face of CD25 blockade.

Innovation has been widely acknowledged as one of the key driving forces for regional economic development. Since nighttime lights based on Defense Meteorological Satellite Program Operational Line-scan System has been used as an effective tool to estimate economic growth, a potential correlation between nighttime stable lights (NTSL) and innovation performance has been strongly indicated. To this end, this study examined the relationship between NTSL and innovation performance of 3105 counties in the United States of America through grey relation analysis. In order to test the validity of NTSL mapping of the innovation performance, all the sample data of NTSL and innovation performance were separately grouped into five categories using k-means clustering method, and the deviation between two classifications was calculated. Overall, NTSL shows a noticeable connection to innovation performance with a grey relation grade of 0.76, indicating that NTSL could properly simulate innovation performance with sligh...

Background: Patients with clinically isolated syndrome (CIS) and characteristic magnetic resonance imaging (MRI) lesions are at high risk for multiple sclerosis (MS). However, patients with a minimal MRI lesion burden (a low T2-hyperintense [low T2] lesion count) may have borderline formal diagnostic criteria, presenting a clinical management challenge. Objective: Compare the 10-year disease progression of patients with low and higher T2 lesion counts treated over most intervals. Methods: CIS patients from the original CHAMPS MS trial were retrospectively assigned to low-T2 (first quartile; 2–8 lesions) or higher-T2 (second through fourth quartiles; ≥ 9 lesions) groups using baseline T2 lesion counts. The 5- and 10-year open-label extension of CHAMPS (CHAMPIONS) evaluated conversion to clinically definite MS (CDMS), MRI activity, relapses, and disability. Results: The vast majority of patients showed new disease activity by MRI and/or clinical criteria at 10 years (low-T2 86%; higher-T2 98%). Fewer low-T2 than higher-T2 patients developed CDMS (40% vs. 63%; p = 0.013); low-T2 patients also had fewer new brain lesions, less brain volume loss, and less disability progression. Conclusion: CIS patients with low T2 lesion counts show continued disease activity. However, all assessments of disease progression over 10 years indicated a significantly less severe disease course for low-T2 patients.

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

MRI acquisition parameters and analysis. (DOCX 27kb)

Summary of MRI endpoints over 2 years by original randomisation group [6]. (DOC 53kb)

Background Subcutaneous peginterferon beta-1a every 2 weeks significantly affects clinical outcomes in patients with relapsing–remitting multiple sclerosis (RRMS). Objectives To explore relationships between relapses and worsening of disability in patients with RRMS, and assess the treatment effect of peginterferon beta-1a on relapse recovery. Methods Post-hoc analysis of the 2-year, randomized, double-blind, parallel-group, Phase 3 ADVANCE study. The severity of relapses, proportion of patients with relapses associated with residual disability (onset of 24-week confirmed disability progression (CDP) within 90 days following a relapse), and persistence of changes in Functional Systems Scores, were compared between treatment groups. Results Subcutaneous peginterferon beta-1a every 2 weeks significantly reduced the proportion of patients experiencing relapse associated with CDP over 2 years (6.6%, compared with 15.1% of patients who received placebo in Year 1; p = 0.02). Reduction in relapses associated with residual disability was greater than the treatment effect on overall relapse rate, and occurred despite similar relapse severity across treatment groups. Conclusions The beneficial effect of peginterferon beta-1a on risk of CDP may be attributable to the combination of an overall reduction in the risk of relapses and improvement in recovery from relapses, thus limiting further disability progression. Trial registration ClinicalTrials.gov identifier: NCT00906399

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.

Injectable first-line disease-modifying therapies (DMTs) for multiple sclerosis (MS) are generally prescribed for continuous use. Accordingly, the various factors that influence patient persistence with treatment and that can lead some patients to switch medications or discontinue treatment may affect clinical outcomes. Using data from the North American Research Committee on Multiple Sclerosis (NARCOMS) database, this study evaluated participants' reasons for discontinuation of injectable DMTs as well as the relationship between staying on therapy and sustained patient-reported disease progression and annualized relapse rates. Participants selected their reason(s) for discontinuation from among 16 possible options covering the categories of efficacy, safety, tolerability, and burden, with multiple responses permitted. Both unadjusted data and data adjusted for baseline age, disease duration, disability, and sex were evaluated. Discontinuation profiles varied among DMTs. Participants on intramuscular interferon beta-1a (IM IFNβ-1a) and glatiramer acetate (GA) reported the fewest discontinuations based on safety concerns, although GA was associated with reports of higher burden and lower efficacy than other therapies. Difficulties with tolerability were more often reported as a reason for discontinuing subcutaneous (SC) IFNβ-1a than as a reason for discontinuing IM IFNβ-1a, GA, or SC IFNβ-1b. In the persistent therapy cohort, less patient-reported disability progression was reported with IM IFNβ-1a treatment than with SC IFNβ-1a, IFNβ-1b, or GA. These findings have relevance to clinical decision making and medication compliance in MS patient care.

Fatigue and cognitive impairment are debilitating features of multiple sclerosis (MS). ENER-G was a 12-month, open-label, multicenter, single-arm observational study designed to evaluate changes in fatigue and cognition in MS patients treated with natalizumab. Adults with relapsing MS and initiating natalizumab were enrolled. The primary endpoint was change in Visual Analog Scale for Fatigue (VAS-F) score over 12 weeks. Changes in Modified Fatigue Impact Scale (MFIS) score, Fatigue Severity Scale (FSS) score, and cognitive performance, using Automated Neuropsychological Assessment Metrics (ANAM), were also assessed. Patients (N = 89) had a mean age of 41 years and a median Expanded Disability Status Scale score of 3.0, and 83% had used at least two prior MS therapies. Significant improvements were observed and maintained at 12 weeks in VAS-F (mean ± SD baseline score, 77.7 ± 10.2; mean ± SD change, −14.9 ± 17.1; P < .0001), MFIS (mean baseline score, 59.1 ± 12.2; mean change, −7.4 ± 11.8; P < .0001), and FSS (median baseline score, 6.3 [range, 3.9–7.0]; median change, −0.4 [range, −2.9–1.4]; P < .0001). Cognitive performance remained stable or improved (depending on the ANAM measure). Thus significant improvements in fatigue were maintained over time, and cognitive performance improved or remained stable up to 48 weeks after initiation of natalizumab in MS patients with some degree of fatigue.

Background: Efficacy and safety data have not previously been compiled for intramuscular interferon beta-1a (IM IFNβ-1a) in patients with multiple sclerosis (MS) ≥ 50 years of age. We investigated the efficacy and safety of IM IFNβ-1a in patients segregated by 50 and 40 years of age in separate meta-analyses. Methods: The MS Clinical Research Group Study, the Controlled High-Risk Subjects AVONEX® (IM IFNβ-1a) MS Prevention Study, the IFNβ-1a European Dose-Comparison Study, and a multicenter, open-label antigenicity and safety study of human serum albumin-free IM IFNβ-1a were analyzed. Results: Overall, 906 patients (68 aged ≥ 50 years and 838 aged

Background: A randomized, placebo-controlled, multicenter study of weekly intramuscular injections of interferon beta-1a (IFNβ-1a) in relapsing–remitting multiple sclerosis included the Sickness Impact Profile (SIP), a validated measure of patient-reported quality of life (QoL). Objective: To demonstrate the impact of moderate to severe SIP disability at baseline and change in QoL as measured by SIP over 2 years in relation to other study parameters. Methods: In 158 patients, SIP scores were determined at baseline and 2 years. Scores were correlated with disease progression and treatment. Results: Patients who experienced disability progression, as defined by Expanded Disability Status Scale (EDSS) and annualized relapse rate, during the study demonstrated significant worsening in Physical SIP scores compared with patients who did not progress ( p = 0.031). In patients with low SIP scores, indicating moderate or severe disability at baseline, treatment with IFNβ-1a significantly improved Physical SIP subscores. Conclusions: Patients with disability progression defined using EDSS, the physician-derived primary outcome measure, had Physical SIP scores indicating worsening disability, validating the physician-derived primary outcome measure using patient self-report. Treatment with IFNβ-1a had beneficial effects on QoL in patients with worse SIP scores at baseline.

Disease-modifying drugs are initiated early and continued for years in patients with multiple sclerosis. Long-term tolerability and impact are not known. The objective of this study was to evaluate long-term tolerability of intramuscular interferon beta-1a and effects on disability and quality of life. Patients were evaluated an average of 15 years after randomization into a placebo-controlled, double-blind trial of intramuscular interferon beta-1a for relapsing multiple sclerosis. Patient-reported Expanded Disability Status Scale, the Short Form-36, a visual analog scale of self-care independence, and a living situation questionnaire were administered. Status was ascertained in 79% (136/172) of eligible patients. Analysis focused on 122 living patients. Despite open-label, non-standardized treatment after the 2-year clinical trial, 46% ( n= 56) of the patients remained on intramuscular interferon beta-1a. Expanded Disability Status Scale scores were correlated highly with Short Form-36 subcategories and visual analog scale scores. Patients currently using intramuscular interferon beta-1a had a significantly lower mean Expanded Disability Status Scale score ( p= 0.011), less progression to Expanded Disability Status Scale milestones, significantly better scores on the physical component of the Short Form-36 ( p< 0.0001), and reported better general health and greater independence. We conclude that patients continuing to use intramuscular interferon beta-1a had less disability and better quality of life compared with patients not currently using intramuscular interferon beta-1a 15 years after randomization into a clinical trial.

Background—In vitro, human isoenzymes encoded by genes homozygous for the ADH1C*1 or ADH1B*2 alleles metabolize ethanol to acetaldehyde at a faster rate than those homozygous for the ADH1C*2 or ADH1B*1 allele. Because alcohol is a known risk factor for breast cancer, we evaluated the joint association of genetic variants in ADH and alcohol consumption in relation to breast cancer. Methods—A nested case-control study of 321 cases and matched controls was conducted. Five single nucleotide polymorphisms (SNPs) of the ADH1C and ADH1B genes were genotyped. Conditional logistic regression was used to assess odds ratios (OR) and 95% confidence intervals (CI) for each SNP. Haplotype analysis of all 5 SNPs was also undertaken. Results—Among drinkers, the median intake of total alcohol was 13 grams per week (10 th to 90 th percentiles; 4.5 – 135.9) in cases and 18 grams per week (10 th to 90 th percentiles; 4.5–104.1) in controls. Women who drank alcohol tended to be at an increased risk of developing breast cancer compared to those who did not drink (O.R. =1.40, 95% CI 0.97, 2.03), particularly those who were pre-menopausal at the time of breast cancer diagnosis (OR = 2.69, 95% CI: 1.00, 7.26). Of the known functional alleles, breast cancer risk was not significantly increased among carriers of at least one ADH1C*1 or ADH1B*2 allele, when compared to those heterozygous or homozygous for either the ADH1C*2 or ADH1B*1 allele. However, breast cancer risk tended to be lower among women who inherited the ADH1B*896G allele (O.R. = 0.62, 95%CI 0.37,_ 1.04). Haplotype frequencies were not significantly different between cases and controls. Conclusion—Low levels of alcohol are associated with a modest increase in breast cancer risk that is not altered by known functional allelic variants of the ADH1B and 1C gene. The protective association conferred by the ADH1B*896G allele needs further evaluation.

Background: Changes in gray matter (GM) volume may be a useful measure of tissue loss in multiple sclerosis (MS). Objectives: To investigate the rate, patterns, and disability correlates of GM volume change in an MS treatment clinical trial. Methods: Patients ( n=140) with relapsing−remitting MS were randomized to intramuscular (IM) interferon (IFN) beta-1a or placebo. Treatment effects on GM fraction (GMF) and white matter (WM) fraction (WMF) changes, differences in rates of GMF and WMF change in year one and two on treatment, and differences in atrophy rates by disease progression status were assessed retrospectively. Results: Significantly less GM atrophy (during year two), but not WM atrophy (at any point), was observed with IM IFN beta-1a compared with placebo. Pseudoatrophy effects were more apparent in WM than in GM; in year one, greater WM volume loss was observed with IM IFN beta-1a than with placebo, whereas GM volume loss was similar between groups. Risk of sustained disability progression was significantly associated with GM, but not WM, atrophy. Conclusions: These results suggest that GMF change is more meaningful than WMF as a marker of tissue loss and may be useful to augment whole brain atrophy measurements in MS clinical trials.

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.

Background Subcutaneous peginterferon beta-1a provided clinical benefits at Year 1 (placebo-controlled period) of the 2-Year Phase 3 ADVANCE study in relapsing-remitting multiple sclerosis (RRMS). Here we report the effect of peginterferon beta-1a 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) during Year 1. 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 (by 61% and 51%, respectively) and 48 (secondary endpoint; by 67% and 54%, respectively); all p

Objectives: The 12-month observational PERSIST study (NCT01405872) evaluated adherence associated with the intramuscular IFN beta-1a (i.m. IFN-beta-1a) autoinjector pen in multiple sclerosis (MS) patients. Methods: MS patients initiating i.m. IFN-beta-1a autoinjector treatment were prospectively assessed for physician-reported persistence (percentage of patients remaining on therapy) and patient-reported outcomes, including adherence (percentage of unmissed injections), compliance (percentage of patients missing no injections), tolerability (injection-site reactions [ISRs] and pain) and satisfaction. Results: The intent-to-treat population included 232 patients; of the 188 physician-reported 12-month completers, 182 patients remained on treatment (96.8% persistence). Monthly compliance rates were 87.5 - 96.2%. Mean monthly pain scores were 1.5 - 1.8 (scale: 0 = 'no pain'; 10 = 'extremely painful'). At 12 months, 73.5% of respondents reported no ISRs, 94.9% were satisfied/very satisfied with the autoinjector and 88.2% found using the device easy/very easy. Injection fear, injection anxiety and need for injection assistance by caregivers decreased from the initial visit to 12 months. No new safety signals were observed. Conclusions: The autoinjector pen is associated with high levels of persistence, compliance, adherence, and satisfaction, little-to-no pain and low need for caregiver assistance. Although these data are limited by reliance on patient questionnaires and the absence of a direct comparator group, this treatment may reduce barriers to injection therapy, while supporting long-term MS management.

Background Study objectives were to evaluate the Multiple Sclerosis Impact Scale (MSIS-29) and explore an optimized scoring structure based on empirical post-hoc analyses of data from the Phase III ADVANCE clinical trial. Methods ADVANCE MSIS-29 data from six time-points were analyzed in a sample of patients with relapsing–remitting multiple sclerosis (RRMS). Rasch Measurement Theory (RMT) analysis was undertaken to examine three broad areas: sample-to-scale targeting, measurement scale properties, and sample measurement validity. Interpretation of results led to an alternative MSIS-29 scoring structure, further evaluated alongside responsiveness of the original and revised scales at Week 48. Results RMT analysis provided mixed evidence for Physical and Psychological Impact scales that were sub-optimally targeted at the lower functioning end of the scales. Their conceptual basis could also stand to improve based on item fit results. The revised MSIS-29 rescored scales improved but did not resolve the measurement scale properties and targeting of the MSIS-29. In two out of three revised scales, responsiveness analysis indicated strengthened ability to detect change. Conclusion The revised MSIS-29 provides an initial evidence-based improved patient-reported outcome (PRO) instrument for evaluating the impact of MS. Revised scoring improves conceptual clarity and interpretation of scores by refining scale structure to include Symptoms, Psychological Impact, and General Limitations. Clinical trial ADVANCE (ClinicalTrials.gov identifier NCT00906399).

Background and purpose Impaired ambulation is a prominent disabling symptom of multiple sclerosis and can lead to reduced quality of life. Whether natalizumab, a monoclonal antibody shown to reduce disease activity in relapsing−remitting multiple sclerosis, could impact ambulation performance was examined. Methods A prospective open-label study, TIMER, was conducted in natalizumab-naive patients (n = 215). The timed 25-foot walk (T25FW) and timed 100-m walk (T100MW) were assessed at baseline and at weeks 24 and 48 of natalizumab therapy, together with Expanded Disability Status Scale scores. The effects of natalizumab on T25FW performance were also examined in a retrospective analysis of natalizumab-treated patients (n = 627) and placebo control patients (n = 315) from the AFFIRM study. Results In TIMER, a significant increase from baseline in T25FW speed was seen at week 24 (P = 0.0074) and in T100MW speed at weeks 24 and 48 (both P

Multiple sclerosis (MS) is a progressive, degenerative disease of the central nervous system (CNS) characterized by a variety of clinical courses.1,2 The majority of MS patients present with episodic neurologic symptoms and will have bouts of disease activity (relapses) separated by periods of total or partial remission.1,2 Patients with MS may experience symptoms such as bladder dysfunction, fatigue, spasticity, pain, and depression.1 Bladder dysfunction is common in MS patients3–5 and may increase with increasing spinal cord involvement.4,6–9 The types of bladder dysfunction that typically occur in MS are failure to store, failure to empty, and a combination of both.10,11 The Urogenital Distress Inventory (UDI) and the Incontinence Impact Questionnaire (IIQ) were both developed to assess the impact of urinary incontinence on quality of life (QOL) in women.12 Shorter versions of the UDI and the IIQ, the UDI-6 and the IIQ-7, have become standard, validated measures for urologic investigations.13,14 The North American Research Committee on Multiple Sclerosis (NARCOMS) validated the bladder/bowel subscale (PSB) of its patient-reported Performance Scale (PS).15,16 In the phase 3 pivotal AFFIRM and SENTINEL studies, natalizumab (Tysabri; Biogen Idec Inc, Cambridge, MA, and Elan Pharmaceuticals, Inc, South San Francisco, CA) reduced MS relapse rates, slowed progression of MS-related disability, and improved QOL in patients with relapsing forms of MS.17–19 This observation, coupled with anecdotal reports, led us to hypothesize that natalizumab may have a demonstrable beneficial effect on bladder function in MS patients. The primary study endpoint in the TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) study was change in bladder function, as measured by the UDI-6 score from baseline through 24 weeks of natalizumab treatment. Secondary study endpoints included change from baseline over 24 weeks in the following parameters: IIQ-7 score, NARCOMS PSB score, the number of urinary incontinence episodes per patient per week, and the number of micturitions per patient per day.

Fatigue and cognitive impairment are debilitating features of multiple sclerosis (MS). ENER-G was a 12-month, open-label, multicenter, single-arm observational study designed to evaluate changes in fatigue and cognition in MS patients treated with natalizumab. Adults with relapsing MS and initiating natalizumab were enrolled. The primary endpoint was change in Visual Analog Scale for Fatigue (VAS-F) score over 12 weeks. Changes in Modified Fatigue Impact Scale (MFIS) score, Fatigue Severity Scale (FSS) score, and cognitive performance, using Automated Neuropsychological Assessment Metrics (ANAM), were also assessed. Patients (N = 89) had a mean age of 41 years and a median Expanded Disability Status Scale score of 3.0, and 83% had used at least two prior MS therapies. Significant improvements were observed and maintained at 12 weeks in VAS-F (mean ± SD baseline score, 77.7 ± 10.2; mean ± SD change, −14.9 ± 17.1; P < .0001), MFIS (mean baseline score, 59.1 ± 12.2; mean change, −7.4 ± 11.8; P < .0001), and FSS (median baseline score, 6.3 [range, 3.9–7.0]; median change, −0.4 [range, −2.9–1.4]; P < .0001). Cognitive performance remained stable or improved (depending on the ANAM measure). Thus significant improvements in fatigue were maintained over time, and cognitive performance improved or remained stable up to 48 weeks after initiation of natalizumab in MS patients with some degree of fatigue.

Background: There is a scarcity of reports comparing efficacy and tolerability of the multiple sclerosis (MS) disease-modifying therapies [DMTs; intramuscular interferon-β1a (IM IFNβ-1a), subcutaneous (SC) IFNβ-1a, SC IFNβ-1b, SC glatiramer acetate (GA)] in a real-world setting. Methods: This multicenter, non-interventional, retrospective cohort study analyzed data from 546 patients with clinically isolated or relapsing-remitting MS constantly treated with one DMT for 2 years. Annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) scores, and DMT tolerability were assessed. Results: Demographic data were comparable across DMTs. There were no significant differences between DMT groups in ARR during study year 1 (p = 0.277) or study year 2 (p = 0.670), or in EDSS change between years 1 and 2 (p = 0.624). Adverse events were frequent (39-56%) in all groups. Flu-like symptoms were less frequent with GA treatment (2.3% vs. IM IFNβ-1a, 46.7%; SC IFNβ-1a, 39.8%; SC IFNβ-1b, 25.8%; p < 0.05). Injection site reactions were less often reported with IM IFNβ-1a (10.5% vs. SC IFNβ-1a, 33.9%; SC IFNβ-1b, 38.3%; GA, 26.1%; p < 0.05). Conclusions: All DMTs showed comparable effects on MS relapse rate and EDSS change, with IM IFNβ-1a and GA being more tolerable with respect to injection site reactions and flu-like symptoms, respectively.

Background: Criteria for identifying relapsing multiple sclerosis (RMS) patients with aggressive disease, which would be useful for clinical decision making, are currently unavailable. Objective: Identify RMS patients with aggressive disease characterized by rapid disability progression. Methods: Data from a 2-year, phase 3, double-blind, placebo-controlled trial with long-term follow-up evaluations of RMS patients taking either intramuscular interferon beta-1a (IM IFNβ1a, 30 μg) or placebo with baseline Expanded Disability Status Scale (EDSS) scores of 1.0–3.5 were retrospectively analyzed. Patients with a ≥2.0-point increase in EDSS score, resulting in a score ≥4.0 by study end, were considered to have aggressive RMS. The risk of a poor long-term outcome, defined as an EDSS score ≥8.0 at 8 years of follow-up, was calculated as an odds ratio from a logistic regression model comparing patients with and without aggressive RMS. Results: Only 25 patients met the criteria for aggressive RMS. Among these patients, mean disease duration was 5.1±3.85 years, mean baseline age was 37.2±6.35 years, and mean baseline EDSS score was 2.8±0.74. Fewer IM IFNβ-1a-treated than placebo-treated patients met the criteria for aggressive RMS at 2 years (7% vs 22% on placebo, p=0.0072). Thirteen patients reached the EDSS milestone of ≥8.0 by the end of the 8-year follow-up. The odds ratio for attaining severe disability was 86.4 (95% CI, 10.3–726.4; po0.0001) for patients with aggressive RMS compared to patients without aggressive RMS. Conclusions: Defining aggressive RMS based on rapid EDSS progression was useful in identifying patients at risk for more severe disease course.

Objective: To identify early predictors of long-term outcomes in patients with relapsing–remitting multiple sclerosis (RRMS) treated with intramuscular (IM) interferon beta-1a (IFNβ-1a). Methods: A multicenter, observational, 15-year follow-up study of patients who completed ≥2 years in the pivotal trial of IM IFNβ-1a for RRMS was conducted. One hundred thirty-six patients participated in the 15-year follow-up (69 originally randomized to IM IFNβ-1a and 67 to placebo). After the 2-year clinical trial, treatment was not regulated by study protocol. Disease activity during the 2-year trial was defined as: ≥2 gadolinium-enhancing lesions (cumulative) on year 1 and/or year 2 magnetic resonance imaging (MRI); ≥3 new T2 lesions on year 2 MRI compared to baseline; and ≥2 relapses over 2 years. Odds ratios were calculated for early disease activity predicting severe Expanded Disability Status Scale (EDSS) worsening (worst quartile of change, ≥4.5 EDSS points) during the 15-year interval. Results: The proportion of patients experiencing early disease activity was lower in patients on IM IFNβ-1a than placebo for all disease activity markers (range, 23.5–29.0% vs 41.0–45.5%). In the IM IFNβ-1a group, persistent disease activity predicted severe EDSS worsening: gadolinium-enhancing lesions (odds ratio [OR], 8.96; p < 0.001); relapses (OR, 4.44; p = 0.010); and new T2 lesions (OR, 2.90; p = 0.080). In placebo patients, early disease activity was not as strongly associated with long-term outcomes (OR range, 1.53–2.62; p = 0.069–0.408). Interpretation: Disease activity despite treatment with IFNβ is associated with unfavorable long-term outcomes. Particular attention should be paid to gadolinium-enhancing lesions on IFNβ therapy, as their presence strongly correlates with severe disability 15 years later. The results provide rationale for monitoring IFNβ-treated patients with MRI, and for changing therapy in patients with active disease. ANN NEUROL 2013.

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-la pivotal trial was a double-blind, placebo-controlled phase 3 study. Partiaipants: 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-la 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-la, 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.

To study the effect of low-dose cyclophosphamide (CY) on apoptosis of lung parenchyma cells in the early severe burn stage in rats.Ninety clean SD male rats were randomly divided into 3 groups: the normal group (n = 10), the experimental group (n = 40) and the burn group (n = 40). The model of degree III with 30% burn area was made in the experimental group and the burn group. CY (2 mg/kg) was injected into the abdominal cavity right after burn in the experimental group. No treatment was done in the normal group and burn group. Lung tissues were obtained at 3, 6, 12 and 24 hours, respectively, after burn, and were observed by HE staining. Apoptosis of lung parenchyma cells was observed by TUNEL.Lung tissues were observed under the optical microscopy in the normal group: the pulmonary structure was clear, and there were no inflammatory cells and exudation in the alveolar space and bronchial lumen. Besides, a few RBCs were seen. Pathological changes of lung tissues were observed under the optical microscopy in the burn group: alveolar septum was obviously widened; alveolar wall was destroyed; interstitial edema and atelectasis occurred; and pathological lesion was gradually aggravated as time passed by. The pathological lesion of lung tissues mentioned above in the experimental group was better than those in the burn group. Compared with the normal group, the apoptosis ratio of lung parenchyma cells continuously increased in the burn group from the 3 hour after burn, and reached the peak at 12 hours. There were significant differences between the two groups (P0.05). However, in the experimental group, the apoptosis ratio of lung parenchyma cells increased at 3 hours after burn, cut down to normal at 6 and 12 hours, respectively, and notably decreased at 24 hours. There were significant differences between the experimental group and the normal group (P0.05). Compared with the burn group, the apoptosis rate of lung parenchyma cells in the experimental group began to decrease strikingly from the 6 hours after burn, and there were significant differences between the two groups (P0.05).Low-dose CY can restrain the apoptosis of lung parenchyma cells in the early severe burn stage in rats and alleviate the injury of the lung.