Etoricoxib in the treatment of osteoarthritis over 52-weeks: a double-blind, active-comparator controlled trial [NCT00242489]

BACKGROUND: The aim of this study was to evaluate the long-term efficacy and tolerability of etoricoxib, a COX-2 selective inhibitor, in osteoarthritis (OA) patients. METHODS: A double-blind, randomized, multicenter study was conducted in 617 patients with OA of the knee. The base study was 14 weeks in duration and consisted of 2 parts; in Part I (6 weeks), patients were allocated to once daily oral etoricoxib 5, 10, 30, 60, 90 mg or placebo. In Part II (8 weeks); the placebo, etoricoxib 5 and 10 mg groups were reallocated to etoricoxib 30, 60, or 90 mg qd or diclofenac 50 mg t.i.d. Treatment was continued for consecutive 12 and 26 week extensions. Primary efficacy endpoints were the WOMAC VA 3.0 pain subscale and investigator global assessment of disease status. Safety and tolerability were assessed by collecting adverse events throughout the study. RESULTS: Compared with placebo, the etoricoxib groups displayed significant (p < 0.05), dose-dependent efficacy for all primary endpoints in Part I; efficacy was maintained throughout the 52 weeks of the study. During the 46-week active-comparator controlled period, the etoricoxib groups demonstrated clinical efficacy that was similar to that of diclofenac 150 mg and was generally well tolerated, with a lower incidence of gastrointestinal (GI) nuisance symptoms compared with diclofenac (13.1, 14.7, and 13.5% for etoricoxib 30, 60, and 90 mg, respectively compared with 22.5% for diclofenac). CONCLUSION: In this extension study, etoricoxib, at doses ranging from 30 to 90 mg, demonstrated a maintenance of significant clinical efficacy in patients with OA through 52 weeks of treatment. Etoricoxib displayed clinical efficacy similar to diclofenac 150 mg and was generally well tolerated

Hemin availability induces coordinated DNA methylation and gene expression changes in Porphyromonas gingivalis.

Periodontal disease is a chronic inflammatory disease in which the oral pathogen Porphyromonas gingivalis plays an important role. Porphyromonas gingivalis expresses virulence determinants in response to higher hemin concentrations, but the underlying regulatory processes remain unclear. Bacterial DNA methylation has the potential to fulfil this mechanistic role. We characterized the methylome of P. gingivalis, and compared its variation to transcriptome changes in response to hemin availability. Porphyromonas gingivalis W50 was grown in chemostat continuous culture with excess or limited hemin, prior to whole-methylome and transcriptome profiling using Nanopore and Illumina RNA-Seq. DNA methylation was quantified for Dam/Dcm motifs and all-context N6-methyladenine (6mA) and 5-methylcytosine (5mC). Of all 1,992 genes analyzed, 161 and 268 were respectively over- and under-expressed with excess hemin. Notably, we detected differential DNA methylation signatures for the Dam "GATC" motif and both all-context 6mA and 5mC in response to hemin availability. Joint analyses identified a subset of coordinated changes in gene expression, 6mA, and 5mC methylation that target genes involved in lactate utilization and ABC transporters. The results identify altered methylation and expression responses to hemin availability in P. gingivalis, with insights into mechanisms regulating its virulence in periodontal disease. IMPORTANCE DNA methylation has important roles in bacteria, including in the regulation of transcription. Porphyromonas gingivalis, an oral pathogen in periodontitis, exhibits well-established gene expression changes in response to hemin availability. However, the regulatory processes underlying these effects remain unknown. We profiled the novel P. gingivalis epigenome, and assessed epigenetic and transcriptome variation under limited and excess hemin conditions. As expected, multiple gene expression changes were detected in response to limited and excess hemin that reflect health and disease, respectively. Notably, we also detected differential DNA methylation signatures for the Dam "GATC" motif and both all-context 6mA and 5mC in response to hemin. Joint analyses identified coordinated changes in gene expression, 6mA, and 5mC methylation that target genes involved in lactate utilization and ABC transporters. The results identify novel regulatory processes underlying the mechanism of hemin regulated gene expression in P. gingivalis, with phenotypic impacts on its virulence in periodontal disease

Changes in IgE- and antigen-dependent histamine-release in peripheral blood of Schistosoma mansoni-infected Ugandan fishermen after treatment with praziquantel.

BACKGROUND: Parasite-specific IgE levels correlate with human resistance to reinfection with Schistosoma spp. after chemotherapy. Although the role of eosinophils in schistosomiasis has been the focus of a great deal of important research, the involvement of other Fcepsilon receptor-bearing cells, such as mast cells and basophils, has not been investigated in relation to human immunity to schistosomes. Chemotherapy with praziquantel (PZQ) kills schistosomes living in an in vivo blood environment rich in IgE, eosinophils and basophils. This releases parasite Ags that have the potential to cross-link cell-bound IgE. However, systemic hypersensitivity reactions are not induced by treatment. Here, we describe the effects of schistosomiasis, and its treatment, on human basophil function by following changes in total cellular histamine and in vitro histamine-release induced by schistosome Ags or anti-IgE, in blood samples from infected Ugandan fishermen, who are continuously exposed to S. mansoni infection, before and 1-day and 21-days after PZQ treatment. RESULTS: There was a significant increase in the total cellular histamine in blood samples at 1-day post-treatment, followed by a very significant further increase by 21-days post-treatment. In vitro histamine-release induced by S. mansoni egg (SEA) or worm (SWA) Ags or anti-IgE antibody, was significantly reduced 1-day post-treatment. The degree of this reduction correlated with pre-treatment infection intensity. Twenty-1-days post-treatment, SEA-induced histamine-release was still significantly lower than at pretreatment. Histamine-release was not correlated to plasma concentrations of total or parasite-specific IgE, nor to specific IgG4 plasma concentrations. CONCLUSION: The biology of human blood basophils is modulated by S. mansoni infection and praziquantel treatment. Infection intensity-dependent suppression of basophil histamine-release, histamine-dependent resistance to infection, and similarities with allergen desensitisation are discussed as possible explanations of these observations

Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases.

Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases

Use of mechanical circulatory support devices among patients with acute myocardial infarction complicated by cardiogenic shock

Importance: Mechanical circulatory support (MCS) devices, including intravascular microaxial left ventricular assist devices (LVADs) and intra-aortic balloon pumps (IABPs), are used in patients who undergo percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) complicated by cardiogenic shock despite limited evidence of their clinical benefit. Objective: To examine trends in the use of MCS devices among patients who underwent PCI for AMI with cardiogenic shock, hospital-level use variation, and factors associated with use. Design, Setting, and Participants: This cross-sectional study used the CathPCI and Chest Pain-MI Registries of the American College of Cardiology National Cardiovascular Data Registry. Patients who underwent PCI for AMI complicated by cardiogenic shock between October 1, 2015, and December 31, 2017, were identified from both registries. Data were analyzed from October 2018 to August 2020. Exposures: Therapies to provide hemodynamic support were categorized as intravascular microaxial LVAD, IABP, TandemHeart, extracorporeal membrane oxygenation, LVAD, other devices, combined IABP and intravascular microaxial LVAD, combined IABP and other device (defined as TandemHeart, extracorporeal membrane oxygenation, LVAD, or another MCS device), or medical therapy only. Main Outcomes and Measures: Use of MCS devices overall and specific MCS devices, including intravascular microaxial LVAD, at both patient and hospital levels and variables associated with use. Results: Among the 28 304 patients included in the study, the mean (SD) age was 65.4 (12.6) years and 18 968 were men (67.0%). The overall MCS device use was constant from the fourth quarter of 2015 to the fourth quarter of 2017, although use of intravascular microaxial LVADs significantly increased (from 4.1% to 9.8%; P \u3c .001), whereas use of IABPs significantly decreased (from 34.8% to 30.0%; P \u3c .001). A significant hospital-level variation in MCS device use was found. The median (interquartile range [IQR]) proportion of patients who received MCS devices was 42% (30%-54%), and the median proportion of patients who received intravascular microaxial LVADs was 1% (0%-10%). In multivariable analyses, cardiac arrest at first medical contact or during hospitalization (odds ratio [OR], 1.82; 95% CI, 1.58-2.09) and severe left main and/or proximal left anterior descending coronary artery stenosis (OR, 1.36; 95% CI, 1.20-1.54) were patient characteristics that were associated with higher odds of receiving intravascular microaxial LVADs only compared with IABPs only. Conclusions and Relevance: This study found that, among patients who underwent PCI for AMI complicated by cardiogenic shock, overall use of MCS devices was constant, and a 2.5-fold increase in intravascular microaxial LVAD use was found along with a corresponding decrease in IABP use and a significant hospital-level variation in MCS device use. These trends were observed despite limited clinical trial evidence of improved outcomes associated with device use

Characterization of the Atmosphere of the Hot Jupiter HAT-P-32Ab and the M-dwarf Companion HAT-P-32B

Copyright © 2015 IOP PublishingWe report secondary eclipse photometry of the hot Jupiter HAT-P-32Ab, taken with Hale/Wide-field Infra-Red Camera (WIRC) in H and KS bands and with Spitzer/IRAC at 3.6 and 4.5 μm. We carried out adaptive optics imaging of the planet host star HAT-P-32A and its companion HAT-P-32B in the near-IR and the visible. We clearly resolve the two stars from each other and find a separation of 2.''923 ± 0.''004 and a position angle 110fdg64 ± 0fdg12. We measure the flux ratios of the binary in g'r'i'z' and H and KS bands, and determine T eff= 3565 ± 82 K for the companion star, corresponding to an M1.5 dwarf. We use PHOENIX stellar atmosphere models to correct the dilution of the secondary eclipse depths of the hot Jupiter due to the presence of the M1.5 companion. We also improve the secondary eclipse photometry by accounting for the non-classical, flux-dependent nonlinearity of the WIRC IR detector in the H band. We measure planet-to-star flux ratios of 0.090% ± 0.033%, 0.178% ± 0.057%, 0.364% ± 0.016%, and 0.438% ± 0.020% in the H, KS , 3.6 and 4.5 μm bands, respectively. We compare these with planetary atmospheric models, and find they prefer an atmosphere with a temperature inversion and inefficient heat redistribution. However, we also find that the data are equally well described by a blackbody model for the planet with T p = 2042 ± 50 K. Finally, we measure a secondary eclipse timing offset of 0.3 ± 1.3 minutes from the predicted mid-eclipse time, which constrains e = 0.0072 +0.0700}_-0.0064 when combined with radialNASACenter for Exoplanets and Habitable Worlds at the Pennsylvania State UniversityPennsylvania State UniversityEberly College of SciencePennsylvania Space Grant ConsortiumNational Science Foundation - Graduate Research Fellowship ProgramNatural Science and Engineering Research Council of CanadaJPL/SpitzerCalifornia Institute of Technology - NASA Sagan FellowshipAlfred P. Sloan FoundationCalifornia Institute of TechnologyInter-University Centre for Astronomy and AstrophysicsNational Science FoundationMt. Cuba Astronomical FoundationSamuel Oschi

Constraints on the Progenitor System of the Type Ia Supernova SN 2011fe/PTF11kly

Type Ia supernovae (SNe) serve as a fundamental pillar of modern cosmology, owing to their large luminosity and a well-defined relationship between light-curve shape and peak brightness. The precision distance measurements enabled by SNe Ia first revealed the accelerating expansion of the universe, now widely believed (though hardly understood) to require the presence of a mysterious "dark" energy. General consensus holds that Type Ia SNe result from thermonuclear explosions of a white dwarf (WD) in a binary system; however, little is known of the precise nature of the companion star and the physical properties of the progenitor system. Here we make use of extensive historical imaging obtained at the location of SN 2011fe/PTF11kly, the closest SN Ia discovered in the digital imaging era, to constrain the visible-light luminosity of the progenitor to be 10-100 times fainter than previous limits on other SN Ia progenitors. This directly rules out luminous red giants and the vast majority of helium stars as the mass-donating companion to the exploding white dwarf. Any evolved red companion must have been born with mass less than 3.5 times the mass of the Sun. These observations favour a scenario where the exploding WD of SN 2011fe/PTF11kly, accreted matter either from another WD, or by Roche-lobe overflow from a subgiant or main-sequence companion star.Comment: 22 pages, 6 figures, submitte