Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: Results from the RA-BUILD study

Background Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor. Methods In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3. Results More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein. Conclusions In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage

Has the GZK suppression been discovered?

The energy spectra of ultra high energy cosmic rays reported by the AGASA, Fly's Eye, Haverah Park, HiRes, and Yakutsk experiments are all shown to be in agreement with each other for energies below 10^{20} eV (after small adjustments, within the known uncertainties, of the absolute energy scales). The data from HiRes, Fly's Eye, and Yakutsk are consistent with the expected flux suppression above 5\times 10^{19} eV due to interactions of cosmic rays with the cosmic microwave background, the Greisen-Zatsepin-Kuzmin (GZK) "supression," and are inconsistent with a smooth extrapolation of the observed cosmic ray energy spectrum to energies > 5\times 10^{19}$ eV. AGASA data show an excess of events above 10^{20} eV, compared to the predicted GZK suppression and to the flux measured by the other experiments.Comment: Editorial changes, including replacing 'cutoff' by 'supression

High Energy Neutrinos from Astrophysical Sources: An Upper Bound

We show that cosmic-ray observations set a model-independent upper bound to the flux of high-energy, > 10^14 eV, neutrinos produced by photo-meson (or p-p) interactions in sources of size not much larger than the proton photo-meson (or pp) mean-free-path. The bound applies, in particular, to neutrino production by either AGN jets or GRBs. This upper limit is two orders of magnitude below the flux predicted in some popular AGN jet models, but is consistent with our predictions from GRB models. We discuss the implications of these results for future km^2 high-energy neutrino detectors.Comment: Added discussion showing bound cannot be evaded by invoking magnetic fields. Accepted Phys Rev

Fractional quantum Hall effect in a quantum point contact at filling fraction 5/2

Recent theories suggest that the excitations of certain quantum Hall states may have exotic braiding statistics which could be used to build topological quantum gates. This has prompted an experimental push to study such states using confined geometries where the statistics can be tested. We study the transport properties of quantum point contacts (QPCs) fabricated on a GaAs/AlGaAs two dimensional electron gas that exhibits well-developed fractional quantum Hall effect, including at bulk filling fraction 5/2. We find that a plateau at effective QPC filling factor 5/2 is identifiable in point contacts with lithographic widths of 1.2 microns and 0.8 microns, but not 0.5 microns. We study the temperature and dc-current-bias dependence of the 5/2 plateau in the QPC, as well as neighboring fractional and integer plateaus in the QPC while keeping the bulk at filling factor 3. Transport near QPC filling factor 5/2 is consistent with a picture of chiral Luttinger liquid edge-states with inter-edge tunneling, suggesting that an incompressible state at 5/2 forms in this confined geometry

Cost-effectiveness analysis of pemetrexed versus docetaxel in the second-line treatment of non-small cell lung cancer in Spain: results for the non-squamous histology population

BackgroundThe objective of this study was to conduct a cost-effectiveness evaluation of pemetrexed compared to docetaxel in the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) for patients with predominantly non-squamous histology in the Spanish healthcare setting.MethodsA Markov model was designed consisting of stable, responsive, progressive disease and death states. Patients could also experience adverse events as long as they received chemotherapy. Clinical inputs were based on an analysis of a phase III clinical trial that identified a statistically significant improvement in overall survival for non-squamous patients treated with pemetrexed compared with docetaxel. Costs were collected from the Spanish healthcare perspective.ResultsOutcomes of the model included total costs, total quality-adjusted life years (QALYs), total life years gained (LYG) and total progression-free survival (PFS). Mean survival was 1.03 years for the pemetrexed arm and 0.89 years in the docetaxel arm; QALYs were 0.52 compared to 0.42. Per-patient lifetime costs were € 34677 and € 32343, respectively. Incremental cost-effectiveness ratios were € 23967 per QALY gained and € 17225 per LYG.ConclusionsPemetrexed as a second-line treatment option for patients with a predominantly non-squamous histology in NSCLC is a cost-effective alternative to docetaxel according to the € 30000/QALY threshold commonly accepted in Spain

Predictors and correlates for weight changes in patients co-treated with olanzapine and weight mitigating agents; a post-hoc analysis

<p>Abstract</p> <p>Background</p> <p>This study focuses on exploring the relationship between changes in appetite or eating behaviors and subsequent weight change for adult patients with schizophrenia or bipolar disorder treated with olanzapine and adjunctive potential weight mitigating pharmacotherapy. The aim is not to compare different weight mitigating agents, but to evaluate patients' characteristics and changes in their eating behaviors during treatment. Identification of patient subgroups with different degrees of susceptibility to the effect of weight mitigating agents during olanzapine treatment may aid clinicians in treatment decisions.</p> <p>Methods</p> <p>Data were obtained from 3 randomized, double-blind, placebo-controlled, 16-week clinical trials. Included were 158 patients with schizophrenia or bipolar disorder and a body mass index (BMI) ≥ 25 kg/m²who had received olanzapine treatment in combination with nizatidine (n = 68), sibutramine (n = 42), or amantadine (n = 48). Individual patients were analyzed for categorical weight loss ≥ 2 kg and weight gain ≥ 1 kg. Variables that were evaluated as potential predictors of weight outcomes included baseline patient characteristics, factors of the Eating Inventory, individual items of the Eating Behavior Assessment, and the Visual Analog Scale.</p> <p>Results</p> <p>Predictors/correlates of weight loss ≥ 2 kg included: high baseline BMI, low baseline interest in food, and a decrease from baseline to endpoint in appetite, hunger, or cravings for carbohydrates. Reduced cognitive restraint, increase in hunger, and increased overeating were associated with a higher probability of weight gain ≥ 1 kg.</p> <p>Conclusion</p> <p>The association between weight gain and lack of cognitive restraint in the presence of increased appetite suggests potential benefit of psychoeducational counseling in conjunction with adjunctive pharmacotherapeutic agents in limiting weight gain during antipsychotic drug therapy.</p> <p>Trial Registration</p> <p>This analysis was not a clinical trial and did not involve any medical intervention.</p