A 24-week, randomized, controlled trial of rivastigmine patch 13.3 mg/24 h versus 4.6 mg/24 h in severe Alzheimer's dementia

AIMS: The 24-week, prospective, randomized, double-blind ACTION study investigated the efficacy, safety, and tolerability of 13.3 versus 4.6 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease (AD). METHODS: Patients had probable AD and Mini-Mental State Examination scores ≥3-≤12. Primary outcome measures were as follows: Severe Impairment Battery (SIB) and AD Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV). Secondary outcomes were as follows: ADCS-Clinical Global Impression of Change (ADCS-CGIC), 12-item Neuropsychiatric Inventory (NPI-12), and safety/tolerability. RESULTS: Of 1014 patients screened, 716 were randomized to 13.3 mg/24 h (N = 356) or 4.6 mg/24 h (N = 360) patch. Baseline characteristics/demographics were comparable. Completion rates were as follows: 64.3% (N = 229) with 13.3 mg/24 h and 65.0% (N = 234) with 4.6 mg/24 h patch. The 13.3 mg/24 h patch was significantly superior to 4.6 mg/24 h patch on cognition (SIB) and function (ADCS-ADL-SIV) at Week 16 (P < 0.0001 and P = 0.049, respectively) and 24 (primary endpoint; P < 0.0001 and P = 0.025). Significant between-group differences (Week 24) were observed on the ADCS-CGIC (P = 0.0023), not NPI-12 (P = 0.1437). A similar proportion of the 13.3 mg/24 h and 4.6 mg/24 h patch groups reported adverse events (AEs; 74.6% and 73.3%, respectively) and serious AEs (14.9% and 13.6%). CONCLUSIONS: The 13.3 mg/24 h patch demonstrated superior efficacy to 4.6 mg/24 h patch on SIB and ADCS-ADL-SIV, without marked increase in AEs, suggesting higher-dose patch has a favorable benefit-to-risk profile in severe AD

Next-to-leading-order QCD Corrections to Higgs Production in association with a Jet

We compute the next-to-leading-order (NLO) QCD corrections to the Higgs pT distribution in Higgs production in association with a jet via gluon fusion at the LHC, with exact dependence on the mass of the quark circulating in the heavy-quark loops. The NLO corrections are presented including the top-quark mass, and for the first time, the bottom-quark mass as well. Further, besides the on-shell mass scheme, we consider for the first time a running mass renormalisation scheme. The computation is based on amplitudes which are valid for arbitrary heavy-quark masses.Comment: LaTeX, 7 pages, 5 figure

The fully differential hadronic production of a Higgs boson via bottom quark fusion at NNLO

The fully differential computation of the hadronic production cross section of a Higgs boson via bottom quarks is presented at NNLO in QCD. Several differential distributions with their corresponding scale uncertainties are presented for the 8 TeV LHC. This is the first application of the method of non-linear mappings for NNLO differential calculations at hadron colliders.Comment: 27 pages, 13 figures, 1 lego plo

A model for inter-module analysis and optimizing compilation

Recent research into the implementation of logic programming languages has demonstrated that global program analysis can be used to speed up execution by an order of magnitude. However, currently such global program analysis requires the program to be analysed as a whole: sepárate compilation of modules is not supported. We describe and empirically evalúate a simple model for extending global program analysis to support sepárate compilation of modules. Importantly, our model supports context-sensitive program analysis and multi-variant specialization of procedures in the modules

Morphine activates neuroinflammation in a manner parallel to endotoxin

Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.Xiaohui Wang, Lisa C. Loram, Khara Ramos, Armando J. de Jesus, Jacob Thomas, Kui Cheng, Anireddy Reddy, Andrew A. Somogyi, Mark R. Hutchinson, Linda R. Watkins and Hang Yi

Boolean Dynamics with Random Couplings

This paper reviews a class of generic dissipative dynamical systems called N-K models. In these models, the dynamics of N elements, defined as Boolean variables, develop step by step, clocked by a discrete time variable. Each of the N Boolean elements at a given time is given a value which depends upon K elements in the previous time step. We review the work of many authors on the behavior of the models, looking particularly at the structure and lengths of their cycles, the sizes of their basins of attraction, and the flow of information through the systems. In the limit of infinite N, there is a phase transition between a chaotic and an ordered phase, with a critical phase in between. We argue that the behavior of this system depends significantly on the topology of the network connections. If the elements are placed upon a lattice with dimension d, the system shows correlations related to the standard percolation or directed percolation phase transition on such a lattice. On the other hand, a very different behavior is seen in the Kauffman net in which all spins are equally likely to be coupled to a given spin. In this situation, coupling loops are mostly suppressed, and the behavior of the system is much more like that of a mean field theory. We also describe possible applications of the models to, for example, genetic networks, cell differentiation, evolution, democracy in social systems and neural networks.Comment: 69 pages, 16 figures, Submitted to Springer Applied Mathematical Sciences Serie

Functional analysis of the SRV-1 RNA frameshifting pseudoknot

Simian retrovirus type-1 uses programmed ribosomal frameshifting to control expression of the Gag-Pol polyprotein from overlapping gag and pol open-reading frames. The frameshifting signal consists of a heptanucleotide slippery sequence and a downstream-located 12-base pair pseudoknot. The solution structure of this pseudoknot, previously solved by NMR [Michiels,P.J., Versleijen,A.A., Verlaan,P.W., Pleij,C.W., Hilbers,C.W. and Heus,H.A. (2001) Solution structure of the pseudoknot of SRV-1 RNA, involved in ribosomal frameshifting. J. Mol. Biol., 310, 1109–1123] has a classical H-type fold and forms an extended triple helix by interactions between loop 2 and the minor groove of stem 1 involving base–base and base–sugar contacts. A mutational analysis was performed to test the functional importance of the triple helix for −1 frameshifting in vitro. Changing bases in L2 or base pairs in S1 involved in a base triple resulted in a 2- to 5-fold decrease in frameshifting efficiency. Alterations in the length of L2 had adverse effects on frameshifting. The in vitro effects were well reproduced in vivo, although the effect of enlarging L2 was more dramatic in vivo. The putative role of refolding kinetics of frameshifter pseudoknots is discussed. Overall, the data emphasize the role of the triple helix in −1 frameshifting

Assessment of Forest Biomass and Carbon Stocks at Stand Level Using Site-Specific Primary Data to Support Forest Management

To quantify and map woody biomass (WB) and forest carbon (C) stocks, several models were developed. They differ in terms of scale of application, details related to the input data required and outputs provided. Local Authorities, such as Mountain Communities, can be supported in sustainable forest planning and management by providing specific models in which the reference unit is the same as the one reported in the Forest Management Plans (FMP), i.e. the forest stand. In the Lombardy Region (Northern Italy), a few studies were performed to assess WB and forest C stocks, and they were generally based on data coming from regional\u2014or national\u2014forest inventories and remote sensing, without taking into account data collected in the FMPs. For this study, the first version of the stand-level model \u201cWOody biomass and Carbon ASsessment\u201d (WOCAS) for WB and C stocks calculation was improved into a second version (WOCAS v2) and preliminary results about its first application to 2019 forest stands of Valle Camonica District (Lombardy Region) are presented. Since the model WOCAS uses the growing stock as the main driver for the calculation, it can be applied in any other forest area where the same input data are available