Long-term persistence of rituximab in patients with rheumatoid arthritis: an evaluation of the UCL cohort from 1998 to 2020

OBJECTIVES: B cell depletion therapy based on rituximab in patients with RA was pioneered at University College London Hospitals/University College London in 1998. The objective of this study was to evaluate long-term persistence of rituximab and identify factors associated with discontinuation of treatment. METHODS: Retrospective review of medical records from all rituximab-treated RA patients followed up in a dedicated clinic (1998–2020). Data collected included gender, disease duration, previous DMARDs, autoantibody status, age and concomitant therapy at first cycle, length of follow-up, and number of cycles. Drug survival and factors associated with drug discontinuation were analysed using Kaplan–Meier survival curves, log-rank test and Cox regression analysis. RESULTS: A total of 404 patients were included. Median disease duration and age at time of first rituximab cycle were 10 and 57 years, respectively. Median total follow-up was 55 months and median number of cycles five. 93.1% of patients were seropositive. Overall, 31.2% of patients stopped rituximab, with the largest reason for discontinuing being primary inefficacy (42.1%). Comparison of Kaplan–Meier curves showed that rituximab drug survival was lower in seronegative patients and in patients who had previously failed at least one biologic DMARD (bDMARD). Cox regression analysis revealed that rituximab discontinuation was associated with a greater number of previous bDMARDs. CONCLUSION: Many patients with RA achieve good control of their disease with repeated cycles of rituximab treatment. The most common reasons for treatment discontinuation were either primary or secondary inefficacy. Patients who were seronegative and who had previously failed other bDMARDs were more at risk of drug discontinuation

Crystal chemistry of type paulkerrite and establishment of the paulkerrite group nomenclature

A single-crystal structure determination and refinement has been conducted for the type specimen of paulkerrite. The structure analysis showed that the mineral has monoclinic symmetry, space group P21/c, not orthorhombic, Pbca, as originally reported. The unit-cell parameters are aCombining double low line10.569(2), bCombining double low line20.590(4), cCombining double low line12.413(2)Å, and βCombining double low line90.33(3)°. The results from the structure refinement were combined with electron microprobe analyses to establish the empirical structural formula A1[(H2O)0.98K0.02]ς1.00 A2K1.00 M1(Mg1.02Mn0.982+)ς2.00 M2(Fe1.203+Ti0.544+Al0.24Mg0.02)ς2.00 M3(Ti0.744+ Fe0.263+)ς1.00 (PO4)4.02X[O1.21F0.47(OH)0.32]ς2.00(H2O)10.3.95H2O, which leads to the end-member formula (H2O)KMg2Fe2Ti(PO4)4(OF)(H2O)10.4H2O. A proposal for a paulkerrite group, comprising orthorhombic members benyacarite, mantiennéite, pleysteinite, and hochleitnerite and monoclinic members paulkerrite and rewitzerite, has been approved by the International Mineralogical Association's Commission for New Minerals, Nomenclature and Classification. The general formulae are A2M12M22M3(PO4)4X2(H2O)10.4H2O and A1A2M12M22M3(PO4)4X2(H2O)10.4H2O for orthorhombic and monoclinic species, respectively, where ACombining double low lineK, H2O, (Combining double low linevacancy); M1Combining double low lineMn2+, Mg, Fe2+, Zn (rarely Fe3+); M2 and M3Combining double low lineFe3+, Al, Ti4+ (and very rarely Mg); XCombining double low lineO, OH, F. In monoclinic species, K and H2O show an ordering at the A1 and A2 sites, whereas O, (OH), and F show a disordering over the two non-equivalent X1 and X2 sites, which were hence merged as X2 in the general formula. In both monoclinic and orthorhombic species, a high degree of mixing of Fe3+, Al, and Ti occurs at the M2 and M3 sites of paulkerrite group members, making it difficult to get unambiguous end-member formulae from the structural determination of the constituents at individual sites. To deal with this problem an approach has been used that involves merging the compositions at the M2 and M3 sites and applying the site-total-charge method. The merged-site approach allows end-member formulae to be obtained directly from the chemical analysis without the need to conduct crystal-structure refinements to obtain the individual site species. Copyright

Ovine herpesvirus-2 encoded microRNAs target virus genes involved in virus latency

Herpesviruses encode miRNAs that target both virus and host genes; however their role in herpesvirus biology is poorly understood. We previously identified eight miRNAs encoded by OvHV-2; the causative agent of malignant catarrhal fever (MCF) and have now investigated the role of these miRNAs in regulating expression of OvHV-2 genes that play important roles in virus biology. ORF 20 (cell cycle inhibition), ORF 50 (reactivation) and ORF 73 (latency maintenance) each contain predicted targets for several OvHV-2 miRNAs. Co-transfection of miRNA mimics with luciferase reporter constructs containing the predicted targets showed the 5’ UTRs of ORF 20 and ORF 73 contain functional targets for ovhv-miR-2 and ovhv2-miR-8 respectively, and the 3’UTR of ORF 50 contains a functional target for ovhv2-miR-5. Transfection of BJ1035 cells (an OvHV-2 infected bovine T cell line) with the relevant miRNA mimic resulted in a significant decrease in ORF 50 and a smaller but non-significant decrease in ORF 20. However, we were unable to demonstrate a decrease in ORF 73. MCF is a disease of dysregulated lymphocyte proliferation, miRNA inhibition of ORF 20 expression may play a role in this aberrant lymphocyte proliferation. The proteins encoded by ORFs 50 and 73 play opposing roles in latency, it has been hypothesized that miRNA-induced inhibition of virus genes acts to ensure that fluctuations in virus mRNA levels do not result in reactivation in conditions that are unfavourable for viral replication, our data would support this hypothesis

STS in management education: connecting theory and practice

This paper explores the value of science and technology studies (STS) to management education. The work draws on an ethnographic study of second year management undergraduates studying decision making. The nature and delivery of the decision making module is outlined and the value of STS is demonstrated in terms of both teaching method and module content. Three particular STS contributions are identified and described: the social construction of technological systems; actor network theory; and ontological politics. Affordances and sensibilities are identified for each contribution and a discussion is developed that illustrates how these versions of STS are put to use in management education. It is concluded that STS has a pivotal role to play in critical management (education) and in the process offers opportunities for new forms of managin

STM induced hydrogen desorption via a hole resonance

We report STM-induced desorption of H from Si(100)-H(2$\times1$) at negative sample bias. The desorption rate exhibits a power-law dependence on current and a maximum desorption rate at -7 V. The desorption is explained by vibrational heating of H due to inelastic scattering of tunneling holes with the Si-H 5$\sigma$ hole resonance. The dependence of desorption rate on current and bias is analyzed using a novel approach for calculating inelastic scattering, which includes the effect of the electric field between tip and sample. We show that the maximum desorption rate at -7 V is due to a maximum fraction of inelastically scattered electrons at the onset of the field emission regime.Comment: 4 pages, 4 figures. To appear in Phys. Rev. Let

Crystal structure and proton conductivity of BaSn0.6Sc0.4O3-delta: insights from neutron powder diffraction and solid-state NMR spectroscopy

The solid-state synthesis and structural characterisation of perovskite BaSn(1–x)Sc(x)O(3–δ) (x = 0.0, 0.1, 0.2, 0.3, 0.4) and its corresponding hydrated ceramics are reported. Powder and neutron X-ray diffractions reveal the presence of cubic perovskites (space group Pm3m) with an increasing cell parameter as a function of scandium concentration along with some indication of phase segregation. (119)Sn and (45)Sc solid-state NMR spectroscopy data highlight the existence of oxygen vacancies in the dry materials, and their filling upon hydrothermal treatment with D(2)O. It also indicates that the Sn(4+) and Sc(3+) local distribution at the B-site of the perovskite is inhomogeneous and suggests that the oxygen vacancies are located in the scandium dopant coordination shell at low concentrations (x ≤ 0.2) and in the tin coordination shell at high concentrations (x ≥ 0.3). (17)O NMR spectra on (17)O enriched BaSn(1–x)Sc(x)O(3–δ) materials show the existence of Sn–O–Sn, Sn–O–Sc and Sc–O–Sc bridging oxygen environments. A further room temperature neutron powder diffraction study on deuterated BaSn(0.6)Sc(0.4)O(3–δ) refines the deuteron position at the 24k crystallographic site (x, y, 0) with x = 0.579(3) and y = 0.217(3) which leads to an O–D bond distance of 0.96(1) Å and suggests tilting of the proton towards the next nearest oxygen. Proton conduction was found to dominate in wet argon below 700 °C with total conductivity values in the range 1.8 × 10(–4) to 1.1 × 10(–3) S cm(–1) between 300 and 600 °C. Electron holes govern the conduction process in dry oxidizing conditions, whilst in wet oxygen they compete with protonic defects leading to a wide mixed conduction region in the 200 to 600 °C temperature region, and a suppression of the conductivity at higher temperature

D6-branes and torsion

The D6-brane spectrum of type IIA vacua based on twisted tori and RR background fluxes is analyzed. In particular, we compute the torsion factors of the (co)homology groups H_n and describe the effect that they have on D6-brane physics. For instance, the fact that H_3 contains Z_N subgroups explains why RR tadpole conditions are affected by geometric fluxes. In addition, the presence of torsional (co)homology shows why some D6-brane moduli are lifted, and it suggests how the D-brane discretum appears in type IIA flux compactifications. Finally, we give a clear, geometrical understanding of the Freed-Witten anomaly in the present type IIA setup, and discuss its consequences for the construction of semi-realistic flux vacua.Comment: 35 pages, 1 figure. One reference adde