The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for Crohn's disease are unknown.
In this randomized, double-blind trial, we evaluated the efficacy ...of infliximab monotherapy, azathioprine monotherapy, and the two drugs combined in 508 adults with moderate-to-severe Crohn's disease who had not undergone previous immunosuppressive or biologic therapy. Patients were randomly assigned to receive an intravenous infusion of 5 mg of infliximab per kilogram of body weight at weeks 0, 2, and 6 and then every 8 weeks plus daily oral placebo capsules; 2.5 mg of oral azathioprine per kilogram daily plus a placebo infusion on the standard schedule; or combination therapy with the two drugs. Patients received study medication through week 30 and could continue in a blinded study extension through week 50.
Of the 169 patients receiving combination therapy, 96 (56.8%) were in corticosteroid-free clinical remission at week 26 (the primary end point), as compared with 75 of 169 patients (44.4%) receiving infliximab alone (P=0.02) and 51 of 170 patients (30.0%) receiving azathioprine alone (P<0.001 for the comparison with combination therapy and P=0.006 for the comparison with infliximab). Similar numerical trends were found at week 50. At week 26, mucosal healing had occurred in 47 of 107 patients (43.9%) receiving combination therapy, as compared with 28 of 93 patients (30.1%) receiving infliximab (P=0.06) and 18 of 109 patients (16.5%) receiving azathioprine (P<0.001 for the comparison with combination therapy and P=0.02 for the comparison with infliximab). Serious infections developed in 3.9% of patients in the combination-therapy group, 4.9% of those in the infliximab group, and 5.6% of those in the azathioprine group.
Patients with moderate-to-severe Crohn's disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy. (ClinicalTrials.gov number, NCT00094458.)
A type I ribosome inactivating protein, gelonin, was linked to Lym-1, a murine monoclonal antibody reactive with a polymorphic determinant of class II HLA-DR histocompatibility leukocyte antigen ...(HLA) on human lymphoma cells, via a disulfide linkage using the heterobifunctional cross-linking agent, N-succinimidyl-3-(2-pyridyldithio) propionate. This immunotoxin was purified from unreacted gelonin and unconjugated Lym-1 by fast protein liquid chromatography using sephacryl S-300 gel filtration and blue sepharose affinity gradient separation. Binding of Lym-1-gelonin immunoconjugate to human Raji Burkitt's lymphoma cells was demonstrated by indirect immunofluorescence using flow cytometry. Lym-1-gelonin was very active in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium salt and sulforhodamine B in vitro cytotoxicity assays against the Raji lymphoma cell line and confirmed the fact that monoclonal antibody Lym-1 internalizes into human lymphoma cells. A weaker cytostatic antiproliferative effect was also noted for unconjugated Lym-1. gamma-interferon augmented the antiproliferative effects of Lym-1-gelonin conjugate and unconjugated Lym-1, by having a direct cytotoxic effect on the Raji cells. Tumor necrosis factor-alpha also enhanced the antiproliferative effect of unconjugated Lym-1, but did not significantly augment the cytotoxic activity of the Lym-1-gelonin conjugate. These results suggest that anti-HLA class II monoclonal antibodies may be useful in constructing immunotoxins for the treatment of human lymphomas and leukemias expressing HLA class II antigens, and that unconjugated anti-HLA class II monoclonal antibodies may be therapeutically useful in conjunction with recombinant cytokines, especially gamma-interferon.
Rapidly emerging SARS-CoV-2 variants jeopardize antibody-based countermeasures. Although cell culture experiments have demonstrated a loss of potency of several anti-spike neutralizing antibodies ...against variant strains of SARS-CoV-2
, the in vivo importance of these results remains uncertain. Here we report the in vitro and in vivo activity of a panel of monoclonal antibodies (mAbs), which correspond to many in advanced clinical development by Vir Biotechnology, AbbVie, AstraZeneca, Regeneron and Lilly, against SARS-CoV-2 variant viruses. Although some individual mAbs showed reduced or abrogated neutralizing activity in cell culture against B.1.351, B.1.1.28, B.1.617.1 and B.1.526 viruses with mutations at residue E484 of the spike protein, low prophylactic doses of mAb combinations protected against infection by many variants in K18-hACE2 transgenic mice, 129S2 immunocompetent mice and hamsters, without the emergence of resistance. Exceptions were LY-CoV555 monotherapy and LY-CoV555 and LY-CoV016 combination therapy, both of which lost all protective activity, and the combination of AbbVie 2B04 and 47D11, which showed a partial loss of activity. When administered after infection, higher doses of several mAb cocktails protected in vivo against viruses with a B.1.351 spike gene. Therefore, many-but not all-of the antibody products with Emergency Use Authorization should retain substantial efficacy against the prevailing variant strains of SARS-CoV-2.
Magnetohydrodynamic (MHD) turbulence on a \(\beta\)-plane with an in-plane mean field, a system which serves as a simple model for the solar tachocline, is investigated analytically and ...computationally. We first derive two useful analytic constraints: we express the mean turbulent cross-helicity in terms of the mean turbulent magnetic energy, and then show that (for weak turbulence) the time-averaged momentum transport in the system can be expressed in terms of the cross-helicity spectrum. We then complete a closure of the system using weak turbulence theory, appropriately extended to a system with multiple interacting eigenmodes. We use this closure to perturbatively solve for the spectra at lowest order in the Rossby parameter \(\beta\) and thereby show that the momentum transport in the system is \(O(\beta^2)\), thus quantifying the transition away from Alfvénized turbulence. Finally, we verify our theoretical results by performing direct numerical simulations of the system over a broad range of \(\beta\).
The self-organization is one of the most interesting phenomena in the
non-equilibrium complex system, generating ordered structures of different
sizes and durations. In tokamak plasmas, various ...self-organized phenomena have
been reported, and two of them, coexisting in the near-marginal (interaction
dominant) regime, are avalanches and the $E \times B$ staircase. Avalanches
mean the ballistic flux propagation event through successive interactions as it
propagates, and the $E \times B$ staircase means a globally ordered pattern of
self-organized zonal flow layers. Various models have been suggested to
understand their characteristics and relation, but experimental researches have
been mostly limited to the demonstration of their existence. Here we report
detailed analyses of their dynamics and statistics and explain their relation.
Avalanches influence the formation and the width distribution of the $E \times
B$ staircase, while the $E \times B$ staircase confines avalanches within its
mesoscopic width until dissipated or penetrated. Our perspective to consider
them the self-organization phenomena enhances our fundamental understanding of
them as well as links our findings with the self-organization of mesoscopic
structures in various complex systems.
•A stochastic hybrid blade tip timing approach is proposed and demonstrated.•Turbomachine blade damage is identified and classified using this approach.•Probabilistic damage identification is ...achieved through natural frequency tracking.•Damage classification utilises a K-means clustering approach.•The proactive scheduling of a turbomachine outage is thus demonstrated.
Blade Tip Timing (BTT) has been in existence for many decades as an attractive vibration based condition monitoring technique for turbomachine blades. The technique is non-intrusive and online monitoring is possible. For these reasons, BTT may be regarded as a feasible technique to track the condition of turbomachine blades, thus preventing unexpected and catastrophic failures. The processing of BTT data to find the associated vibration characteristics is however non-trivial. In addition, these vibration characteristics are difficult to validate, therefore resulting in great uncertainty of the reliability of BTT techniques. This article therefore proposes a hybrid approach comprising a stochastic Finite Element Model (FEM) based modal analysis and Bayesian Linear Regression (BLR) based BTT technique. The use of this stochastic hybrid approach is demonstrated for the identification and classification of turbomachine blade damage. For the purposes of this demonstration, discrete damage is incrementally introduced to a simplified test blade of an experimental rotor setup. The damage identification and classification processes are further used to determine whether a damage threshold has been reached, therefore providing sufficient evidence to schedule a turbomachine outage. It is shown that the proposed stochastic hybrid approach may offer many short- and long-term benefits for practical implementation.
To develop a computerized system to assist in the diagnosis of malignancy in breast fine needle aspiration cytology.
A Bayesian belief network was designed to control uncertainty and allow a ...diagnostic decision to be reached based on the sequential collection of cytologic information. Ten cytologic features were defined as clues that contribute to the diagnostic discrimination of benign and malignant aspirates. The impact of each feature on the diagnostic decision was quantified by a conditional probability matrix.
For the assessment of a new case, the computer guides the user through the diagnosis, prompting him or her for information on each of the diagnostic features in turn. For each feature, the user is presented with a series of digitally stored color microscopic images that have been selected to represent good examples of the different feature grades-e.g., pleomorphism: none, mild, moderate and severe. Each image is mapped to an overlapping curve, and by positioning a line on the spectrum where the user feels the case lies, a membership function vector is calculated and entered as evidence into the network. This results in an update in the belief in the diagnostic alternatives. After all the clues have been assessed, a final diagnostic probability is reported. In addition, a cumulative belief curve can be drawn that maps the change in the diagnostic probabilities after each piece of evidence has been submitted, providing unique insight into the diagnostic process.
Systems like this represent an important step forward in the use of descriptive classifiers. They impose consistency in terminology, improve reproducibility in the grading of cellular abnormalities and remove subjectivity in interpreting the significance of pvisual clues to diagnosis. As such, they represent a necessary tool in pathologic decision making.
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