Assessing the long-term effectiveness of cladribine vs. placebo in the relapsing-remitting multiple sclerosis CLARITY randomized controlled trial and CLARITY extension using treatment switching adjustment methods

Objectives: Treatment switching adjustment methods are often used to adjust for switching in oncology randomized controlled trials (RCTs). In this exploratory analysis, we apply these methods to adjust for treatment changes in the setting of an RCT followed by an extension study in relapsing-remitting multiple sclerosis. Methods: The CLARITY trial evaluated cladribine tablets versus placebo over 96 weeks. In the 96-week CLARITY Extension, patients who received placebo in CLARITY received cladribine tablets; patients who received cladribine tablets in CLARITY were re-randomized to placebo or cladribine tablets. Endpoints were time to first qualifying relapse (FQR) and time to 3- and 6-month confirmed disability progression (3mCDP, 6mCDP). We aimed to compare the effectiveness of cladribine tablets to placebo over CLARITY and the extension. The rank preserving structural failure time model (RPSFTM) and Iterative Parameter Estimation (IPE) were used to estimate what would have happened if patients had received placebo in CLARITY and the extension, versus patients that received cladribine tablets and switched to placebo. To gauge whether treatment effect waned after the 96 weeks of CLARITY, we compared hazard ratios (HRs) from the adjustment analysis with HRs from CLARITY. Results: The RPSFTM resulted in a HR of 0.48 (95% confidence interval [CI] 0.36-0.62) for FQR, 0.62 (95% CI 0.46-0.84) for 3mCDP, and 0.62 (95% CI 0.44-0.88) for 6mCDP. IPE algorithm results were similar. CLARITY HRs were 0.44 (95% CI 0.34-0.58), 0.60 (95% CI 0.41-0.87) and 0.58 (95% CI 0.40-0.83) for FQR, 3mCDP and 6mCDP respectively. Conclusions: Treatment switching adjustment methods are applicable in non-oncology settings. Adjusted CLARITY plus CLARITY Extension HRs were similar to the CLARITY HRs, demonstrating significant treatment benefits associated with cladribine tablets versus placebo

Heating rate and electrode charging measurements in a scalable, microfabricated, surface-electrode ion trap

We characterise the performance of a surface-electrode ion "chip" trap fabricated using established semiconductor integrated circuit and micro-electro-mechanical-system (MEMS) microfabrication processes which are in principle scalable to much larger ion trap arrays, as proposed for implementing ion trap quantum information processing. We measure rf ion micromotion parallel and perpendicular to the plane of the trap electrodes, and find that on-package capacitors reduce this to <~ 10 nm in amplitude. We also measure ion trapping lifetime, charging effects due to laser light incident on the trap electrodes, and the heating rate for a single trapped ion. The performance of this trap is found to be comparable with others of the same size scale.Comment: 6 pages, 10 figure

Background-free detection of trapped ions

We demonstrate a Doppler cooling and detection scheme for ions with low-lying D levels which almost entirely suppresses scattered laser light background, while retaining a high fluorescence signal and efficient cooling. We cool a single ion with a laser on the 2S1/2 to 2P1/2 transition as usual, but repump via the 2P3/2 level. By filtering out light on the cooling transition and detecting only the fluorescence from the 2P_3/2 to 2S1/2 decays, we suppress the scattered laser light background count rate to 1 per second while maintaining a signal of 29000 per second with moderate saturation of the cooling transition. This scheme will be particularly useful for experiments where ions are trapped in close proximity to surfaces, such as the trap electrodes in microfabricated ion traps, which leads to high background scatter from the cooling beam

Measurements of 12C(&#8594;γ,pp) photon asymmetries for Eγ= 200–450 MeV

The 12C (&#8594;γ ,pp) reaction has been studied in the photon energy range 200-450 MeV at the Mainz microtron MAMI-C, where linearly polarised photons were energy-tagged using the Glasgow-Mainz Tagged Photon Spectrometer and protons were detected in the Crystal Ball detector. The photon asymmetry Σ has been measured over a wider Eγ range than previous measurements. The strongest asymmetries were found at low missing energies where direct emission of nucleon pairs is expected. Cuts on the difference in azimuthal angles of the two ejected protons increased the magnitude of the observed asymmetries. At low missing energies the Σ data exhibit a strong angular dependence, similar to deuteron photodisintegration

Polarization degrees of freedom in photoinduced two-nucleon knockout from finite nuclei

The polarization degrees of freedom in photoinduced two-nucleon knockout from finite nuclei are studied. It is pointed out that they open good perspectives to study the dynamics of dinucleons in the medium in detail. The ($\gamma,pp$) and ($\gamma,pn$) angular cross sections, photon asymmetries and outgoing nucleon polarizations are calculated for the target nuclei $^{16}$O and $^{12}$C and photonenergies ranging from 100 up to 500 MeV. It is investigated to which degree the two-nucleon emission reaction is dominated by photoabsorption on $^3S_1(T=0)$ proton-neutron and $^1S_0(T=1)$ proton-proton pairs in the nuclear medium. The calculations demonstrate that dominance of $S$ wave photoabsorption in the ($\gamma,pn$) channel does not necessarily imply that the reaction mechanism is similar to what is observed in deuteron photodisintegration.Comment: 27 pages, REVTeX 3.0 with epsf.sty, 11 figures in EPS forma

Prefrontal modulation of the sustained attention network in ageing, a tDCS-EEG co-registration approach

The ability to sustain attention is integral to healthy cognition in aging. The right PFC (rPFC) is critical for maintaining high levels of attentional focus. Whether plasticity of this region can be harnessed to support sustained attention in older adults is unknown. We used transcranial direct current stimulation to increase cortical excitability of the rPFC, while monitoring behavioral and electrophysiological markers of sustained attention in older adults with suboptimal sustained attention capacity. During rPFC transcranial direct current stimulation, fewer lapses of attention occurred and electroencephalography signals of frontal engagement and early visual attention were enhanced. To further verify these results, we repeated the experiment in an independent cohort of cognitively typical older adults using a different sustained attention paradigm. Again, prefrontal stimulation was associated with better sustained attention. These experiments suggest the rPFC can be manipulated in later years to increase top–down modulation over early sensory processing and improve sustained attention performance. This holds valuable information for the development of neurorehabilitation protocols to ameliorate age-related deficits in this capacity

Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base

Reduction of heating rate in a microfabricated ion trap by pulsed-laser cleaning

Laser-cleaning of the electrodes in a planar micro-fabricated ion trap has been attempted using ns pulses from a tripled Nd:YAG laser at 355nm. The effect of the laser pulses at several energy density levels has been tested by measuring the heating rate of a single 40Ca+ trapped ion as a function of its secular frequency. A reduction of the electric-field noise spectral density by ~50% has been observed and a change in the frequency dependence also noticed. This is the first reported experiment where the "anomalous heating" phenomenon has been reduced by removing the source as opposed to reducing its thermal driving by cryogenic cooling. This technique may open the way to better control of the electrode surface quality in ion microtraps

Temporal Regulation of Rapamycin on Memory CTL Programming by IL-12

Mammalian target of rapamycin (mTOR) is a master regulator of cell growth. Recent reports have defined its important role in memory cytotoxic T lymphocyte (CTL) differentiation in infections and memory programming. We report that rapamycin regulated memory CTL programming by IL-12 to a similar level in a wide range of concentrations, and the enhanced memory CTLs by rapamycin were functional and provided similar protection against Listeria Monocytogenes challenge compared to the control. In addition, rapamycin-experienced CTLs went through substantially enhanced proliferation after transfer into recipients. Furthermore, the regulatory function of rapamycin on CD62L expression in memory CTLs was mainly contributed by the presence of rapamycin in the first 24-hr of stimulation in vitro, whereas the effective window of rapamycin on the size of memory CTLs was determined between 24 to 72 hrs. In conclusion, rapamycin regulates IL-12-driven programming of CTLs to a similar level in a wide range of concentrations, and regulates the phenotype and the size of memory CTLs in different temporal windows