Diroximel fumarate in patients with relapsing-remitting multiple sclerosis: Final safety and efficacy results from the phase 3 EVOLVE-MS-1 study

BACKGROUND: Diroximel fumarate (DRF) is approved for adults with relapsing-remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF. OBJECTIVE: To report final outcomes from EVOLVE-MS-1. METHODS: EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory. RESULTS: Overall, 75.7% (800/1057) of patients completed the study; median exposure was 1.8 (range: 0.0-2.0) years. AEs occurred in 938 (88.7%) patients, mostly of mild (28.9%) or moderate (50.3%) severity. DRF was discontinued due to AEs in 85 (8.0%) patients, with \u3c 2% discontinuing due to GI or flushing/flushing-related AEs. At Week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (72.7%; CONCLUSION: DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS

Ode to positive constructive daydreaming

Nearly 60 years ago, Jerome L. Singer launched a groundbreaking research program into daydreaming (Singer, 1955, 1975, 2009) that presaged and laid the foundation for virtually every major strand of mind wandering research active today (Antrobus, 1999; Klinger, 1999, 2009). Here we review Singer’s enormous contribution to the field, which includes insights, methodologies, and tools still in use today, and trace his enduring legacy as revealed in the recent proliferation of mind wandering studies. We then turn to the central theme in Singer’s work, the adaptive nature of positive constructive daydreaming, which was a revolutionary idea when Singer began his work in the 1950s and remains underreported today. Last, we propose a new approach to answering the enduring question: Why does mind wandering persist and occupy so much of our time, as much as 50% of our waking time according to some estimates, if it is as costly as most studies suggest

Antigenic variation in <i>Trypanosoma brucei</i>: joining the DOTs

African trypanosomes, such as &lt;i&gt;Trypanosoma brucei&lt;/i&gt;, are protistan parasites that cause sleeping sickness. Though first described more than a century ago, trypanosomes remain a blight on the health of the human population and on the economy of sub-Saharan Africa. &lt;i&gt;T. brucei&lt;/i&gt; replicates in the bloodstream of infected mammals and traverses the blood-brain barrier to enter the central nervous system in the late, frequently fatal, stages of the disease. Because of its extracellular lifestyle, &lt;i&gt;T. brucei&lt;/i&gt; is continuously exposed to antibody challenge. To circumvent this, the parasite uses antigenic variation of a surface protein named the variant surface glycoprotein (VSG). Around 107 VSG molecules are expressed on the parasite's cell surface, creating a dense coat that prevents adaptive immunity from detecting or accessing invariant antigens. However, antibodies against the expressed VSG are generated, and periodic switches to an immunologically distinct VSG coat are necessary for parasite survival. Such switches are pre-emptive of the immune response and contribute to the pattern of trypanosome growth seen in an infected host (Figure 1): parasite numbers increase, but then drop as VSG-specific antibodies are raised by the host. Cells that have switched to another VSG coat survive this killing and seed the outgrowth of a subsequent peak of parasites, which is again decimated by anti-VSG immune killing. As a survival strategy, antigenic variation succeeds by prolonging the time that the parasite

Safety and efficacy with alemtuzumab over 13 years in relapsing-remitting multiple sclerosis: final results from the open-label TOPAZ study

Alemtuzumab; Disease-modifying therapy; Multiple sclerosisAlemtuzumab; Teràpia modificadora de la malaltia; Esclerosi múltipleAlemtuzumab; Terapia modificadora de la enfermedad; Esclerosis múltipleBackground and objectives: Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants (‘alemtuzumab-only’) could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab (‘IFN-alemtuzumab’). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5–7 years (11–13 years after alemtuzumab/IFN initiation). Methods: Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)]. Results: 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3–13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15–0.20] and IFN-alemtuzumab (0.14; 0.11–0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent. Conclusion: Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11–13 years, and most participants did not require more than one additional course.The TOPAZ study as well as writing and editorial support for this article were funded by Sanofi

Aortic Pulse Wave Velocity as a Measure of Cardiovascular Risk in Chronic Obstructive Pulmonary Disease: Two-Year Follow-Up Data from the ARCADE Study

Background and objectives: Cardiovascular (CV) disease is a major cause of morbidity and mortality in chronic obstructive pulmonary disease (COPD). Patients with COPD have increased arterial stiffness, which may predict future CV risk. However, the development of arterial stiffness in COPD has not yet been studied prospectively. The Assessment of Risk in Chronic Airways Disease Evaluation (ARCADE) is a longitudinal study of CV risk and other comorbidities in COPD. The aims of this analysis were to explore factors associated with aortic pulse wave velocity (aPWV) at baseline and to describe the progression of aPWV in patients with COPD and comparators over two years. Materials and methods: At baseline, 520 patients with COPD (confirmed by spirometry) and 150 comparators free from respiratory disease were assessed for body composition, blood pressure, aPWV, noninvasive measures of cardiac output, inflammatory biomarkers, and exercise capacity. This was repeated after two years, and mortality cases and causes were also recorded. Results: At baseline, aPWV was greater in COPD patients 9.8 (95% confidence interval (CI) 9.7–10) versus comparators 8.7 (8.5–9.1) m/s (p < 0.01) after adjustments for age, mean arterial pressure (MAP), and heart rate. Mean blood pressure was 98 ± 11 in COPD patients and 95 ± 10 mmHg in comparators at baseline (p = 0.004). After two years, 301 patients and 105 comparators were fully reassessed. The mean (95% CI) aPWV increased similarly in patients 0.44 (0.25–0.63) and comparators 0.46 (0.23–0.69) m/s, without a change in blood pressure. At the two-year follow-up, there were 29 (6%) deaths in COPD patients, with the majority due to respiratory causes, with an overall dropout of 43% of patients with COPD and 30% of comparators. Conclusions: This was the first large longitudinal study of CV risk in COPD patients, and we confirmed greater aPWV in COPD patients than comparators after adjustments for confounding factors. After two years, patients and comparators had a similar increase of almost 0.5 m/s aPWV

Why equality? On justifying liberal egalitarianism

The debate over the nature of egalitarianism has come to dominate political philosophy. As ever more sophisticated attempts are made to describe the principles of an egalitarian distribution or to specify the good or goods that should be distributed equally, little is said about the fundamental basis of equality. In virtue of what should people be regarded as equal? Egalitarians have tended to dismiss this question of fundamental equality. In the first part of the paper I will examine some of these strategies of marginalisation and assess whether the issue of fundamental equality matters. Jeremy Waldron has criticised this strategy of avoidance in his recent book God, Locke and equality. He argues that Locke's turn to a theistic grounding for fundamental equality provides a better approach to the problem than the approach taken by contemporary liberals such as John Rawls. I will examine Waldron's critique of Rawls and show that it is wanting. I will conclude by suggesting that Rawls's approach to the issue has a bearing on the way in which equality should be understood as a political value. This argument for the primacy of a political conception of egalitarianism has a bearing on the interconnection between core liberal values and the idea of the state that has been emphasised by Rawls, Dworkin and Nagel

Security: Collective good or commodity?

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2008 Sage.The state monopoly on the legitimate use of violence in Europe and North America has been central to the development of security as a collective good. Not only has it institutionalized the state as the prime national and international security provider, it has helped to reduce the threat from other actors by either prohibiting or limiting their use of violence. The recent growth of the private security industry appears to undermine this view. Not only are private security firms proliferating at the national level; private military companies are also taking over an increasing range of military functions in both national defence and international interventions. This article seeks to provide an examination of the theoretical and practical implications of the shift from states to markets in the provision of security. Specifically, it discusses how the conceptualization of security as a commodity rather than a collective good affects the meaning and implementation of security in Western democracies.ESR