ObjectiveTo investigate whether antidrug antibodies and/or drug non‐trough levels predict the long‐term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.MethodsA total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme‐linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non‐trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.ResultsAmong patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.ConclusionPharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months.
Background and Purpose Positron emission tomography (PET) imaging with [F-18] fluoromisonidazole (FMISO) has been validated as a hypoxic tracer [1, 2]. Head and neck cancer exhibits hypoxia, inducing aggressive biologic traits that impart resistance to treatment. Delivery of modestly higher radiation doses to tumors with stable areas of chronic hypoxia can improve tumor control [3]. Advanced radiation treatment planning (RTP) and delivery techniques such as Intensity Modulated Radiation Therapy (IMRT) can deliver higher doses to a small volume without increasing morbidity. We investigated the utility of co-registered FMISO-PET and CT images to develop clinically feasible RTPs with higher tumor control probabilities (TCP). Methods FMISO-PET images were used to determine hypoxic sub-volumes for boost planning. Example plans were generated for ten of the patients in the study who exhibited significant hypoxia. We created an IMRT plan for each patient with a simultaneous integrated boost (SIB) to the hypoxic sub-volumes. We also varied the boost for two patients. Results A significant (mean 17%, median 15%) improvement in TCP is predicted when the modest additional boost dose to the hypoxic sub-volume is included. Conclusions Combined FMISO-PET imaging and IMRT planning permits delivery of higher doses to hypoxic regions, increasing the predicted TCP (mean 17%) without increasing expected complications.
Detection of a single photon escaping an optical cavity QED system prepares a non-classical state of the electromagnetic field. The evolution of the state can be modified by changing the drive of the cavity. For the appropriate feedback, the conditional state can be captured (stabilized) and then released. This is observed by a conditional intensity measurement that shows suppression of vacuum Rabi oscillations for the length of the feedback pulse and their subsequent return.Feedback control of quantum systems was first studied about fifteen years ago [1][2][3], in the field of quantum optics. In these approaches, the feedback could be understood in an essentially classical way, with quantum field theory entering only to dictate the magnitude of the fluctuations. This is possible if fluctuations are small compared to the mean fields being detected. More recently, a different approach to quantum optical feedback has been developed [4,5], based on quantum trajectories [6][7][8], which specify the stochastic evolution of a quantum state conditioned on continuous monitoring (such as by photodetection). This theory allows the treatment of feedback in the deep quantum regime, where quantum fluctuations are not small compared to the mean. It is also arguably the best way to approach feedback, as the conditioned state by definition comprises all of the knowledge of the experimenter on which feedback could be based [9,10].So far, experiments in quantum feedback, such as Refs. [1,[11][12][13][14][15], have all been in the regime of small fluctuations [16]. Cavity QED is able to explore the opposite regime, where fluctuations in the conditional state are large. Furthermore, using the theory of quantum trajectories, Carmichael and coworkers [17,18] showed that such conditional quantum fluctuations are intrinsically related to the production of squeezing and antibunching. In this letter we present experimental results for the application of feedback in this regime. Following a photodetection, the conditioned quantum state of the system is |ψ c (τ ) . Given our knowledge of this evolution, we can, for certain times τ , change the parameters of the system dynamics so as to capture the system in that conditioned state. When the parameters are later restored to their usual values, the released system state resumes its interrupted evolution. This directly demonstrates both the reality of the conditioned state and its usefulness for quantum feedback.A Cavity quantum electrodynamical (QED) system consists of a single mode of the electromagnetic field of a cavity interacting with one or a collection of N two-level atoms [19]. Microwave Cavity QED systems have been used recently to prepare multiparticle entanglement [20], and to produce photon number states of the electromagnetic field [21]. Operated at optical frequencies, cavity QED systems can now trap single atoms in the electric field of the cavity when its average occupation is about one photon [22,23]. The system size and dynamics are characterized by two dimensionless numbers...
We carried out a resequencing project that examined 552 kb of sequence from each of 46 individual HLA haplotypes representing a diversity of HLA allele types, generating nearly 27 Mb of fully phased genomic sequence. Haplotype blocks were defined extending from telomeric of HLA-F to centromeric of HLA-DP including in total 5186 MHC SNPs. To investigate basic questions about the evolutionary origin of common HLA haplotypes, and to obtain an estimate of rare variation in the MHC, we similarly examined two additional sets of samples. In 19 independent HLA-A1, B8, DR3 chromosomes, the most common HLA haplotype in Northern European Caucasians, variation was found at 11 SNP positions in the 3600-kb region from HLA-A to DR. Partial resequencing of 282 individuals in the gene-dense class III region identified significant variability beyond what could have been detected by linkage to common SNPs.
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