Healthcare costs for treating relapsing multiple sclerosis and the risk of progression: a retrospective Italian cohort study from 2001 to 2015

Background Disease modifying treatments (DMTs) are the main responsible for direct medical costs in multiple sclerosis (MS). The current investigation aims at evaluating possible associations between healthcare costs for treating relapsing remitting MS (RRMS) and disease evolution. Methods The present cohort study retrospectively included 544 newly diagnosed RRMS patients, prospectively followed up for 10.1±3.3 years. Costs for DMT administration and management were calculated for each year of observation. Following clinical endpoints were recorded: time to first relapse, 1-point EDSS progression, reaching of EDSS 4.0, reaching of EDSS 6.0, and conversion to secondary progressive MS (SP). Covariates for statistical analyses were age, gender, disease duration and EDSS at diagnosis. Results At time varying Cox regression models, 10% increase in annual healthcare costs was associated with 1.1% reduction in 1-point EDSS progression (HR = 0.897; p = 0.018), with 0.7% reduction in reaching EDSS 6.0 (HR = 0.925; p = 0.030), and with 1.0% reduction in SP conversion (HR = 0.902; p = 0.006). Conclusion Higher healthcare costs for treating MS have been associated with a milder disease evolution after 10 years, with possible reduction of long-term non-medical direct and indirect costs

Pacific Plate slab pull and intraplate deformation in the early Cenozoic

Large tectonic plates are known to be susceptible to internal deformation, leading to a range of phenomena including intraplate volcanism. However, the space and time dependence of intraplate deformation and its relationship with changing plate boundary configurations, subducting slab geometries, and absolute plate motion is poorly understood. We utilise a buoyancy driven Stokes flow solver, BEM-Earth, to investigate the contribution of subducting slabs through time on Pacific Plate motion and plate-scale deformation, and how this is linked to intraplate volcanism. We produce a series of geodynamic models from 62 to 42 Ma in which the plates are driven by the attached subducting slabs and mantle drag/suction forces. We compare our modelled intraplate deformation history with those types of intraplate volcanism that lack a clear age progression. Our models suggest that changes in Cenozoic subduction zone topology caused intraplate deformation to trigger volcanism along several linear seafloor structures, mostly by reactivation of existing seamount chains, but occasionally creating new volcanic chains on crust weakened by fracture zones and extinct ridges. Around 55 Ma subduction of the Pacific-Izanagi ridge reconfigured the major tectonic forces acting on the plate by replacing ridge push with slab pull along its north-western perimeter, causing lithospheric extension along pre-existing weaknesses. Large scale deformation observed in the models coincides with the seamount chains of Hawaii, Louisville, Tokelau, and Gilbert during our modelled time period of 62 to 42 Ma. We suggest that extensional stresses between 72 and 52 Ma are the likely cause of large parts of the formation of the Gilbert chain and that localised extension between 62 and 42 Ma could cause late-stage volcanism along the Musicians Volcanic Ridges. Our models demonstrate that early Cenozoic changes in Pacific plate driving forces only cause relatively minor changes in Pacific absolute plate motions, and cannot be responsible for the Hawaii-Emperor Bend (HEB), confirming previous interpretations that the 47 Ma HEB does not reflect an absolute plate motion event

Dual transcriptional-translational cascade permits cellular level tuneable expression control.

The ability to induce gene expression in a small molecule dependent manner has led to many applications in target discovery, functional elucidation and bio-production. To date these applications have relied on a limited set of protein-based control mechanisms operating at the level of transcription initiation. The discovery, design and reengineering of riboswitches offer an alternative means by which to control gene expression. Here we report the development and characterization of a novel tunable recombinant expression system, termed RiboTite, which operates at both the transcriptional and translational level. Using standard inducible promoters and orthogonal riboswitches, a multi-layered modular genetic control circuit was developed to control the expression of both bacteriophage T7 RNA polymerase and recombinant gene(s) of interest. The system was benchmarked against a number of commonly used E. coli expression systems, and shows tight basal control, precise analogue tunability of gene expression at the cellular level, dose-dependent regulation of protein production rates over extended growth periods and enhanced cell viability. This novel system expands the number of E. coli expression systems for use in recombinant protein production and represents a major performance enhancement over and above the most widely used expression systems

Coexistence of Haldane gap excitations and long range antiferromagnetic order in mixed-spin nickelates R_2 Ba Ni O_5

The spin dynamics of the S=1 Ni-chains in mixed-spin antiferromagnets Pr_2 Ba Ni O_5 and Nd_x Y_2-x Ba Ni O_5 is described in terms of a simple Ginzburg-Landau Lagrangian coupled to the sublattice of rare-earth ions. Within this framework we obtain a theoretical explanation for the experimentally observed coexistence of Haldane gap excitations and long-range magnetic order, as well as for the increase of the Haldane gap energy below the Neel point. We also predict that the degeneracy of the Haldane triplet is lifted in the magnetically ordered phase. The theoretical results are consistent with the available experimental data.Comment: 4 pages, 1 figure, submitted to PRL An alternative derivation of main results and new references adde

Σ−p\Sigma^- p emission rates in K−K^- absorptions at rest on 6^6Li, 7^7Li, 9^{9}Be, 13^{13}C and 16^{16}O

An experimental study of the $K^-_{stop}A\rightarrow \Sigma^- p A'$ reaction on $A=^6$Li, $^7$Li, $^9$Be, $^{13}$C and $^{16}$O $p$-shell nuclei is presented. The data were collected by the FINUDA spectrometer operating at the DA$\Phi$NE $\phi$-factory (LNF-INFN, Italy). Emission rates for the reaction in the mentioned nuclei are measured and compared with the few existing data. The spectra of several observables are discussed; indications of Quasi-Free absorptions by a $(np)$ pair embedded in the $A$ nucleus can be obtained from the study of the missing mass distributions.Comment: Version accepted by PR

Production of Λ6^{6}_{\Lambda}H and Λ7^{7}_{\Lambda}H with the (Kstop−^{-}_{stop},π+\pi^+) reaction

The production of neutron rich $\Lambda$-hypernuclei via the ($K^-_stop$,$\pi^+$) reaction has been studied using data collected with the FINUDA spectrometer at the DA$\Phi$NE $\phi$-factory (LNF). The analysis of the inclusive $\pi^+$ momentum spectra is presented and an upper limit for the production of $^6_\Lambda$H and $^7_\Lambda$H from $^6$Li and $^7$Li, is assessed for the first time.Comment: 11 pages, 3 figures. Accepted for publication in PL

Inelastic Neutron Scattering from the Spin Ladder Compound (VO)2P2O7

We present results from an inelastic neutron scattering experiment on the candidate Heisenberg spin ladder vanadyl pyrophosphate, (VO)2P2O7. We find evidence for a spin-wave excitation gap of $E_{gap} = 3.7\pm 0.2$ meV, at a band minimum near $Q=0.8 A^{-1}$. This is consistent with expectations for triplet spin waves in (VO)2P2O7 in the spin-ladder model, and is to our knowledge the first confirmation in nature of a Heisenberg antiferromagnetic spin ladder.Comment: 11 pages and 2 figures (available as hard copy or postscript files from the authors, send request to [email protected] or [email protected]), TEX using jnl, reforder and eqnorder, ORNL-CCIP-94-05 / RAL-94-04

An experimental measurement of the staggered magnetization curve for a Haldane spin chain

Long-range magnetic ordering in R_2 Ba Ni O_5 (R=magnetic rare earth) quasi-1-dimensional mixed-spin antiferromagnets is described by a simple mean-field model that is based on the intrinsic staggered magnetization function of isolated Haldane spin chains for the Ni-subsystem, and single-ion magnetization functions for the rare earth ions. The model is applied to new experimental results obtained in powder diffraction experiments on Nd_2 Ba Ni O_5 and Nd Y Ba Ni O_5, and to previously published diffraction data for Er_2 Ba Ni O_5. From this analysis we extract the bare staggered magnetization curve for Haldane spin chains in these compounds.Comment: some revisions in text and figures 5 pages, 2 figures, PRL accepted for publicatio

The Framingham cardiovascular risk score in multiple sclerosis

Background and purpose: Cardiovascular risk factors can increase the risk of multiple sclerosis (MS) and modify its course. However, such factors possibly interact, determining a global cardiovascular risk. Our aim was to compare the global cardiovascular risk of subjects with and without MS with the simplified 10-year Framingham General Cardiovascular Disease Risk Score (FR) and to evaluate its importance on MS-related outcomes. Methods: Age, gender, smoking status, body mass index, systolic blood pressure, type II diabetes and use of antihypertensive medications were recorded in subjects with and without MS to estimate the FR, an individualized percentage risk score estimating the 10-year likelihood of cardiovascular events. Results: In total, 265 MS subjects were identified with 530 matched controls. A t test showed similar FR in cases and controls (P = 0.212). Secondary progressive MS presented significantly higher FR compared to relapsing-remitting MS (P < 0.001). Linear regression analysis showed a direct relationship between FR and Expanded Disability Status Scale (P < 0.001) and MS Severity Scale (P < 0.001). Conclusion: The FR, evaluating the global cardiovascular health by the interaction amongst different risk factors, relates to MS disability, severity and course