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Sjögren's disease is characterised by mucosal dryness, fatigue, chronic pain, systemic organ involvement, and elevated autoreactive IgG antibodies. There are no approved disease-modifying treatments. Therefore, we aimed to evaluate nipocalimab, a neonatal Fc receptor blocker that reduces circulating IgG, including autoantibodies, in patients with Sjögren's disease. This phase 2, double-blind, multicentre trial enrolled individuals with moderate-to-severe, active Sjögren's disease (ie, Clinical European League Against Rheumatism Sjögren's Syndrome Disease Activity Index [ClinESSDAI] of at least 6) who were seropositive for anti-Ro IgG autoantibodies. Participants were recruited from 69 centres across France, Germany, Italy, Japan, the Netherlands, Poland, Portugal, Spain, Taiwan, and the USA. These centres included rheumatology centres, hospitals, and clinical research centres with experience conducting pharmaceutical company-sponsored phase 2 and phase 3 studies, which reported an ability to enrol eligible patients. Central randomisation assigned participants to one of three treatment groups using an Interactive Web Response System. Randomised (1:1:1) participants received intravenous nipocalimab 5 mg/kg, intravenous nipocalimab 15 mg/kg, or placebo every 2 weeks for 22 weeks. Schedules for administering the study intervention were the same across treatment groups, and labels on the study interventions were prepared by an unmasked pharmacist and were identical to maintain masking for the participants, investigators, site staff, and sponsor. The primary endpoint was change from baseline in ClinESSDAI score at week 24. The primary endpoint and other efficacy and safety analyses included participants who were randomly assigned and who received at least one dose of study intervention. For the primary endpoint, data from the time of discontinuation and onward were considered missing. The primary analysis approach used a mixed model for repeated measures to estimate the average outcome, taking into account the non-missing data and variability. DAHLIAS was registered with EudraCT (2021-000665-32) and ClinicalTrials.gov (NCT04968912) and has been completed. 163 participants were recruited between Sept 21, 2021, and April 3, 2023, (53 participants to nipocalimab 5 mg/kg, 54 to nipocalimab 15 mg/kg, and 56 to the placebo). The mean age of participants was 48·1 years (SD 12·12); 151 (93%) participants were female and 12 (7%) were male. The nipocalimab 15 mg/kg group had a significant reduction in ClinESSDAI score at week 24 versus the placebo group (least squares mean difference –2·65, 90% CI –4·03 to –1·28; p=0·0018), and the nipocalimab 5 mg/kg group had a non-significant reduction versus placebo (–0·34, –1·71 to 1·03; p=0·68). The safety profile of nipocalimab was comparable, for both doses, with that of placebo, with generally similar rates of adverse events and serious adverse events across groups. Fc receptor blockade by nipocalimab 15 mg/kg significantly improved clinical disease activity versus placebo and was safe and well tolerated in participants with moderate-to-severe, active Sjögren's disease. Reductions in IgG autoantibodies during nipocalimab treatment support their contribution to Sjögren's disease pathogenesis. Johnson & Johnson.

Infliximab has been shown to induce clinical response and remission in ulcerative colitis (UC). To characterize the biological response of patients to infliximab, we analyzed the mRNA expression patterns of mucosal colonic biopsies taken from UC patients enrolled in the Active Ulcerative Colitis Trial 1 (ACT1) study. Biopsies were obtained from 48 UC patients before treatment with 5 or 10 mg/kg infliximab, and at 8 and 30 weeks after treatment (n = 113 biopsies). Global gene expression profiling was performed using Affimetrix GeneChip Human Genome U133 Plus 2.0 arrays. Expression profiling results for selected genes were confirmed using qPCR. Infliximab had a significant effect on mRNA expression in treatment responders, with both infliximab dose and duration of treatment having an effect. Genes affected are primarily involved with inflammatory response, cell-mediated immune responses, and cell-to-cell signaling. Unlike responders, non-responders do not effectively modulate T(H₁), T(H₂), and T(H₁₇) pathways. Gene expression can differentiate placebo and infliximab responders. Analysis of mRNA expression in mucosal biopsies following infliximab treatment provided insight into the response to therapy and molecular mechanisms of non-response.

ObjectiveTo investigate serum protein expression in participants with psoriatic arthritis (PsA) and changes after guselkumab treatment.MethodsParticipants with PsA were treated with guselkumab or placebo in the DISCOVER-1 and DISCOVER-2 studies. Serum levels of acute phase reactants C reactive protein (CRP) and serum amyloid A (SAA) and inflammatory cytokines/chemokines were measured at weeks 0, 4 and 24 in 300 study participants and 34 healthy controls (HCs). The PSUMMIT studies measured serum interleukin (IL)-17A, IL-17F and CRP after ustekinumab treatment and levels with ustekinumab versus guselkumab treatment were compared.ResultsBaseline serum levels of CRP, SAA, IL-6, IL-17A and IL-17F were elevated in participants with active PsA vs HCs (p<0.05, geometric mean (GM) ≥40% higher). Baseline T-helper cell 17 (Th17) effector cytokines were significantly associated with baseline psoriasis but not joint disease activity. Compared with placebo, guselkumab treatment resulted in decreases in serum CRP, SAA, IL-6, IL-17A, IL-17F and IL-22 as early as week 4 and continued to decrease through week 24 (p<0.05, GM decrease from baseline ≥33%). At week 24, IL-17A and IL-17F levels were not significantly different from HCs, suggesting normalisation of peripheral IL-23/Th17 axis effector cytokines postguselkumab treatment. Reductions in IL-17A/IL-17F levels were greater in guselkumab-treated versus ustekinumab-treated participants, whereas effects on CRP levels were similar.ConclusionGuselkumab treatment reduced serum protein levels of acute phase and Th17 effector cytokines and achieved comparable levels to those in HCs. In participants with PsA, reductions of IL-17A and IL-17F were of greater magnitude after treatment with guselkumab than with ustekinumab.

ObjectivesTo investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and inadequate response or intolerance to ≥1 antitumour necrosis factor agent.MethodsIn this phase 2a study, participants with RA seropositive for anticitrullinated protein antibodies (ACPA) or rheumatoid factors were randomised 3:2 to nipocalimab (15 mg/kg intravenously every 2 weeks) or placebo from Weeks 0 to 10. Efficacy endpoints (primary endpoint: change from baseline in Disease Activity Score 28 using C reactive protein (DAS28-CRP) at Week 12) and patient-reported outcomes (PROs) were assessed through Week 12. Safety, pharmacokinetics and pharmacodynamics were assessed through Week 18.Results53 participants were enrolled (nipocalimab/placebo, n=33/20). Although the primary endpoint did not reach statistical significance for nipocalimab versus placebo, a numerically higher change from baseline in DAS28-CRP at Week 12 was observed (least squares mean (95% CI): –1.03 (–1.66 to –0.40) vs –0.58 (–1.24 to 0.07)), with numerically higher improvements in all secondary efficacy outcomes and PROs. Serious adverse events were reported in three participants (burn infection, infusion-related reaction and deep vein thrombosis). Nipocalimab significantly and reversibly reduced serum immunoglobulin G, ACPA and circulating immune complex levels but not serum inflammatory markers, including CRP. ACPA reduction was associated with DAS28-CRP remission and 50% response rate in American College of Rheumatology (ACR) criteria; participants with a higher baseline ACPA had greater clinical improvement.ConclusionsDespite not achieving statistical significance in the primary endpoint, nipocalimab showed consistent, numerical efficacy benefits in participants with moderate to severe active RA, with greater benefit observed for participants with a higher baseline ACPA.Trial registration numberNCT04991753.

The utilization of finite element technique is explored for an optimization problem by heat conduction equation with bilateral controls, which are the distributed and boundary control, respectively. The derivation of the co-state equation and optimality conditions is accomplished through the application of optimal control theory. To set up the fully discrete approximation schemes, piecewise linear continuous functions are employed for the approximation of state and co-state variables, whereas piecewise constant for control variable approximation. A priori error estimates are rigorously established for all considered variables under appropriate norms. Theoretical findings are validated by the presentation of comprehensive numerical experiments.

In this paper, we consider a non-overlapping domain decomposition method combined with the characteristic method for solving optimal control problems governed by linear convection–diffusion equations. The whole domain is divided into non-overlapping subdomains, and the global optimal control problem is decomposed into the local problems in these subdomains. The integral mean method is utilized for the diffusion term to present an explicit flux calculation on the inter-domain boundary in order to communicate the local problems on the interfaces between subdomains. The convection term is discretized along the characteristic direction. We establish the fully parallel and discrete schemes for solving these local problems. A priori error estimates in L2-norm are derived for the state, co-state and control variables. Finally, we present numerical experiments to show the validity of the schemes and verify the derived theoretical results.

Two types of approximation schemes are established for incompressible miscible displacements in porous media. First, standard mixed finite element method is used to approximate the velocity and pressure. And then parallel non-overlapping domain decomposition methods combined with the characteristics method are presented for the concentration. These methods use the characteristic method to handle the material derivative term of the concentration equation in the subdomains and explicit flux calculations on the interdomain boundaries by integral mean method or extrapolation method to predict the inner-boundary conditions. Thus, the velocity and pressure can be approximated simultaneously, and the parallelism can be achieved for the concentration equation. The explicit nature of the flux prediction induces a time step limitation that is necessary to preserve stability. These schemes hold the advantages of nonoverlapping domain decomposition methods and the characteristic method. Optimal error estimates in L2-norm are derived for these two schemes, respectively.

In this paper, we consider a non-overlapping domain decomposition method for solving optimal boundary control problems governed by parabolic equations. The whole domain is divided into non-overlapping subdomains, and the global optimal boundary control problem is decomposed into the local problems in these subdomains. The integral mean method is utilized to present an explicit flux calculation on the inter-domain boundary in order to communicate the local problems on the interface between subdomains. We establish the fully parallel and discrete schemes for solving these local problems. A priori error estimates in \\[L^2\\]-norm are derived for the state, co-state and control variables. Finally, we present numerical experiments to show the validity of the schemes and verify the derived theoretical results.

An approximation scheme is defined for incompressible miscible displacement in porous media. This scheme is constructed by two methods. Under the regularity assumption for the pressure, cubic Hermite finite element method is used for the pressure equation, which ensures the approximation of the velocity smooth enough. A second order characteristic finite element method is presented to handle the material derivative term of the concentration equation. It is of second order accuracy in time increment, symmetric, and unconditionally stable. The optimal L2-norm error estimates are derived for the scalar concentration.

The site attenuation deviation is an important index to evaluate the performance of a Semi-anechoic chamber used in an EMC laboratory. This index can be expressed by normalized site attenuation (NSA). There are clear measurement methods and measurement results requirements for site attenuation deviation in paper CISPR16-1-4:2020. In this paper, two measuring methods are used to measure the site attenuation deviation of the same Semi-anechoic chamber, compare the measured data, and analyze the difference between the two measured results.