Budesonide Foam Has a Favorable Safety Profile for Inducing Remission in Mild-to-Moderate Ulcerative Proctitis or Proctosigmoiditis.

BackgroundBudesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis.AimThe aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam.MethodsData from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam.ResultsA similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0%, respectively). Adverse events occurred in 41.4 and 36.3% of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic-pituitary-adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration.ConclusionsThis integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis

Variance based weighting of multisensory head rotation signals for verticality perception

We tested the hypothesis that the brain uses a variance-based weighting of multisensory cues to estimate head rotation to perceive which way is up. The hypothesis predicts that the known bias in perceived vertical, which occurs when the visual environment is rotated in a vertical-plane, will be reduced by the addition of visual noise. Ten healthy participants sat head-fixed in front of a vertical screen presenting an annulus filled with coloured dots, which could rotate clockwise or counter-clockwise at six angular velocities (1, 2, 4, 6, 8, 16°/s) and with six levels of noise (0, 25, 50, 60, 75, 80%). Participants were required to keep a central bar vertical by rotating a hand-held dial. Continuous adjustments of the bar were required to counteract low-amplitude low-frequency noise that was added to the bar's angular position. During visual rotation, the bias in verticality perception increased over time to reach an asymptotic value. Increases in visual rotation velocity significantly increased this bias, while the addition of visual noise significantly reduced it, but did not affect perception of visual rotation velocity. The biasing phenomena were reproduced by a model that uses a multisensory variance-weighted estimate of head rotation velocity combined with a gravito-inertial acceleration signal (GIA) from the vestibular otoliths. The time-dependent asymptotic behaviour depends on internal feedback loops that act to pull the brain's estimate of gravity direction towards the GIA signal. The model's prediction of our experimental data furthers our understanding of the neural processes underlying human verticality perception

FUSE Measurements of Far Ultraviolet Extinction. I. Galactic Sight Lines

We present extinction curves that include data down to far ultraviolet wavelengths (FUV; 1050 - 1200 A) for nine Galactic sight lines. The FUV extinction was measured using data from the Far Ultraviolet Spectroscopic Explorer. The sight lines were chosen for their unusual extinction properties in the infrared through the ultraviolet; that they probe a wide range of dust environments is evidenced by the large spread in their measured ratios of total-to-selective extinction, R_V = 2.43 - 3.81. We find that extrapolation of the Fitzpatrick & Massa relationship from the ultraviolet appears to be a good predictor of the FUV extinction behavior. We find that predictions of the FUV extinction based upon the Cardelli, Clayton & Mathis (CCM) dependence on R_V give mixed results. For the seven extinction curves well represented by CCM in the infrared through ultraviolet, the FUV extinction is well predicted in three sight lines, over-predicted in two sight lines, and under-predicted in 2 sight lines. A Maximum Entropy Method analysis using a simple three component grain model shows that seven of the nine sight lines in the study require a larger fraction of grain materials to be in dust when FUV extinction is included in the models. Most of the added grain material is in the form of small (radii < 200 A) grains.Comment: Accepted for publication in the Astrophysical Journal. 31 pages with 7 figure

Quasi‐2‐Day Wave in Low‐Latitude Atmospheric Winds as Viewed From the Ground and Space During January–March, 2020

Horizontal winds from four low-latitude (±15°) specular meteor radars (SMRs) and the Michelson Interferometer for Global High-resolution Thermospheric Imaging (MIGHTI) instrument on the ICON satellite, are combined to investigate quasi-2-day waves (Q2DWs) in early 2020. SMRs cover 80–100 km altitude whereas MIGHTI covers 95–300 km. Q2DWs are the largest dynamical feature of the summertime middle atmosphere. At the overlapping altitudes, comparisons between the derived Q2DWs exhibit excellent agreement. The SMR sensor array analyses show that the dominant zonal wavenumbers are s = +2 and + 3, and help resolve ambiguities in MIGHTI results. We present the first Q2DW depiction for s = +2 and s = +3 between 95 and 200 km, and show that their amplitudes are almost invariant between 80 and 100 km. Above 106 km, Q2DW amplitudes and phases present structures that might result from the superposition of Q2DWs and their aliased secondary waves

Results of the combined U.S. multicenter postapproval study of the Nit‐Occlud PDA device for percutaneous closure of patent ductus arteriosus

ObjectivesTo report the results of the Nit‐Occlud PDA prospective postapproval study (PAS) along with a comparison to the results of the pivotal and continued access trials.BackgroundThe Nit‐Occlud PDA (PFM Medical, Cologne, Germany), a nitinol coil patent ductus arteriosus (PDA) occluder, was approved by the Food and Drug Administration in 2013.MethodsThe PAS enrolled a total of 184 subjects greater than 6 months of age, weighing at least 5 kg, with PDAs less than 4 mm by angiography at 11 centers. Patients were followed prospectively at 2 months, 12 months, and 24 months postprocedure. These outcomes were compared to the 357 subjects enrolled in the pivotal and continued access protocols. Efficacy and safety data were reported.ResultsAmong 184 subjects enrolled for the PAS between 2014 and 2017, 180 (97.8%) had successful device implantation. After 12 months, 98.7% (150/152) had trivial or no residual shunt by echocardiography and two subjects had only small residual shunts. There were three device embolizations that were all retrieved by snare without clinical consequence. Together with the pivotal and continued access study, 97.4% (449/461) had complete echocardiographic closure at 12 months in 541 enrolled subjects. The composite success was 94.4%. There were no mortalities and no serious device‐related adverse events.ConclusionsThe Nit‐Occlud PDA is a safe and effective device for closure of a small to moderate sized PDA. There were no serious device‐related adverse events in a large cohort of three clinical trials.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148398/1/ccd27995_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148398/2/ccd27995.pd

An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade

A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3-/- mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/ Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3-/- mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8 + T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. Significance: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade

Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform.

BACKGROUND: Hydroxychloroquine has been shown to inhibit entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into epithelial cells in vitro, but clinical studies found no evidence of reduced mortality when treating patients with COVID-19. We aimed to evaluate the effectiveness of hydroxychloroquine for prevention of COVID-19 mortality, as opposed to treatment for the disease. METHODS: We did a prespecified observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, which covers approximately 40% of the general population in England, UK. We included all adults aged 18 years and older registered with a general practice for 1 year or more on March 1, 2020. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use before the COVID-19 outbreak in England (considered as March 1, 2020) compared with non-users of hydroxychloroquine and risk of COVID-19 mortality among people with rheumatoid arthritis or systemic lupus erythematosus. Model adjustment was informed by a directed acyclic graph. FINDINGS: Between Sept 1, 2019, and March 1, 2020, of 194 637 people with rheumatoid arthritis or systemic lupus erythematosus, 30 569 (15·7%) received two or more prescriptions of hydroxychloroquine. Between March 1 and July 13, 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0·23% (95% CI 0·18 to 0·29) among users and 0·22% (0·20 to 0·25) among non-users; an absolute difference of 0·008% (-0·051 to 0·066). After accounting for age, sex, ethnicity, use of other immunosuppressive drugs, and geographical region, no association with COVID-19 mortality was observed (HR 1·03, 95% CI 0·80 to 1·33). We found no evidence of interactions with age or other immunosuppressive drugs. Quantitative bias analyses indicated that our observed associations were robust to missing information for additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality. INTERPRETATION: We found no evidence of a difference in COVID-19 mortality among people who received hydroxychloroquine for treatment of rheumatological disease before the COVID-19 outbreak in England. Therefore, completion of randomised trials investigating pre-exposure prophylactic use of hydroxychloroquine for prevention of severe outcomes from COVID-19 are warranted. FUNDING: Medical Research Council

Study protocol: Comparison of different risk prediction modelling approaches for COVID-19 related death using the OpenSAFELY platform

On March 11th 2020, the World Health Organization characterised COVID-19 as a pandemic. Responses to containing the spread of the virus have relied heavily on policies involving restricting contact between people. Evolving policies regarding shielding and individual choices about restricting social contact will rely heavily on perceived risk of poor outcomes from COVID-19. In order to make informed decisions, both individual and collective, good predictive models are required.   For outcomes related to an infectious disease, the performance of any risk prediction model will depend heavily on the underlying prevalence of infection in the population of interest. Incorporating measures of how this changes over time may result in important improvements in prediction model performance.  This protocol reports details of a planned study to explore the extent to which incorporating time-varying measures of infection burden over time improves the quality of risk prediction models for COVID-19 death in a large population of adult patients in England. To achieve this aim, we will compare the performance of different modelling approaches to risk prediction, including static cohort approaches typically used in chronic disease settings and landmarking approaches incorporating time-varying measures of infection prevalence and policy change, using COVID-19 related deaths data linked to longitudinal primary care electronic health records data within the OpenSAFELY secure analytics platform.</ns4:p

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine