Alimera Sciences

Purpose:To identify genetic variants associated with glucocorticoid (GC)-induced intraocular pressure (IOP) change using genome-wide association study (GWAS) and whole exome sequencing (WES) analyses. Design:A pharmacogenetic study within a clinical trial and cohort study. Participants:Five hundred thirty discovery cohort participants were included from the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) trials. Replication was performed in an independent cohort of 588 Mass Eye and Ear/Retina Health Center (MEE/RHC) participants. Participants were exposed to GC, primarily by intravitreal injection. Methods:Intraocular pressure was measured at baseline and serially within the first 6 months after GC exposure. Participants' DNA underwent genome-wide genotyping and WES. Genome-wide association study and WES rare variant gene burden analyses were applied to all ancestries and the European participants separately, adjusting for covariates. Expression and splicing quantitative trait loci colocalization analysis using eCAVIAR, and gene-level and pathway analyses using Multi-marker Analysis of GenoMic Annotation were performed. Main Outcome Measures:Genetic associations with the maximal change in IOP within 6 months after GC exposure. Results:Genetic associations for maximal IOP change within 6 months after GC exposure were evaluated. For the primary outcome across all ancestries in FAME, 1 variant, rs13425173 within the UBE2E3 locus, reached genome-wide significance (P = 2.88 × 10-8). In the FAME and MEE/RHC meta-analysis, variant rs1040227, also in the UBE2E3 locus, was significantly associated at the genome-wide level (P = 1.23 × 10-8). In the colocalization analyses, the significant FAME GWAS UBE2E3 locus was linked to expression regulation of this gene in 6 tissues including artery aorta. In gene-level analysis, UBE2E3 also demonstrated subthreshold significance (P = 6.6 × 10-6). Five hundred thirty-two FAME and 586 MEE/RHC participants were included in the WES gene burden analysis. One gene, MSTO1, passed false discovery rate correction for the primary outcome in FAME. Conclusions:We have identified genome-wide significant common variants associated with GC-IOP change, as well as genes and rare variants that may influence GC-induced IOP change. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The accretion flow in active galactic nuclei (AGN) is not well understood, motivating intensive monitoring campaigns of multiwavelength variability to probe its structure. One of the best of these is the 3 yr optical/UV/X-ray approximately daily monitoring campaign on Fairall 9, a fairly typical moderate accretion rate AGN. The UV light curve shows a clear increase over similar to 50 d between years 1 and 2, strongly coherent with the X-ray light curve rise. This changes the average spectral energy distribution (SED) such that the disc component is stronger while the X-ray spectrum steepens, so that the total X-ray power remains roughly constant. Outside of this global change, we apply a Fourier-resolved analysis to test stochastic models where intrinsic fluctuations in the UV disc propagate down into the hard X-ray emission region via both changing the seed photon flux for Compton scattering (short light travel time-scale) and changing the electron density (longer propagation time-scale). Unlike these models, the hard X-rays are not particularly well correlated with the UV, and also have the wrong sign in that the hard X-rays marginally lead the UV fluctuations. We show that this is instead consistent with uncorrelated stochastic fluctuations in both the UV (slow) and X-ray (fast), which are linked together only weakly via light travel time. These variability properties, as well as the changes in the SED, have implications for our understanding of AGN structure and physics, as well as future monitoring campaigns.

Reverberation mapping (RM) can measure black hole accretion disc sizes and radial structure through observable light travel time lags that should increase with wavelength as tau proportional to lambda(4/3 )due to the disc's T proportional to r(-3/4) temperature profile. Our 250-d RM campaign on NGC 7469 combines sub-day cadence 7-band photometry from the Las Cumbres Observatory robotic telescopes and weekly X-ray and UVOT data from Swift. By fitting these light curves, we measure the spectral energy distribution (SED) of the variable accretion disc, and inter-band lags of just 1.5 d across the UV to optical range. The disc SED is close to the expected f(nu)proportional to nu(1/3), and the lags are consistent with tau proportional to lambda(4/3), but three times larger than expected. We consider several possible modifications to standard disc assumptions. First, for a 9x10(6) M-circle dot black hole and two possible spins a(star)=(0,1), we fit the X-ray-ultraviolet (UV)-optical SED with a compact relativistic corona at height H-x similar to(46,27)R-g irradiating a flat disc with accretion rate m(Edd)(center dot)similar to(0.23,0.24) inclined to the line of sight by i<20(degrees). To fit the lags as well as the SED, this model requires a low spin a(star)approximate to 0 and boosts disc colour temperatures by a factor f(col)approximate to 1.8, which shifts reprocessed light to shorter wavelengths. Our Bowl model with f(col)=1 neglects relativity near the black hole, but fits the UV-optical lags and SEDs using a flat disc with m(Edd)(center dot)<0.06 and a steep outer rim at R-out/c similar to 5-10 d with H/R<1 per cent. This rim occurs near the 10(3)K dust sublimation temperature in the disc atmosphere, supporting models that invoke dust opacity to thicken the disc and launch failed radiatively driven dusty outflows at the inner edge of the broad line region (BLR). Finally, the disc lags and SEDs exhibit a significant excess in the u and r bands, suggesting Balmer continuum and H alpha emission, respectively, from the BLR.

The atmospheres of planets between the size of Earth and Neptune at short orbital periods have been under intense scrutiny. Of the approximately dozen planets in this regime with atmospheres studied so far, a few appear to have prominent molecular features, while others appear relatively void of detectable atmospheres. Further work is therefore needed to understand the atmospheres of these planets, starting with observing a larger sample. To this end, we present the 3–5 μ m transmission spectrum of TOI-776 c, a warm ( T _eq ∼ 420 K), ∼2 R _⊕ , ∼7 M _⊕ planet orbiting an M1V star, measured with JWST NIRSpec/G395H. By combining two visits, we measure a median transit precision of ∼18 and ∼32 ppm in the NRS1 and NRS2 detectors, respectively. We compare the transmission spectrum to both nonphysical and physical models and find no strong evidence for molecular features. For cloud-top pressures larger than 10 ^−3 bars, we rule out atmospheric metallicities less than 180–240× solar (depending on the reduction and modeling technique), which corresponds to a mean molecular weight of ∼6–8 g mol ^−1 . However, we find that simple atmosphere mixture models (H _2 O + H _2 /He or CO _2 + H _2 /He) give more pessimistic constraints, and we caution that mean molecular weight inferences are model dependent. We compare TOI-776 c to the similar planet TOI-270 d and discuss possible options for further constraining TOI-776 c’s atmospheric composition. Overall, we suggest that these TOI-776 c observations may represent a combination of planetary and stellar parameters that fall just below the threshold of detectable features in small-planet spectra; finding this boundary is one of the main goals of the COMPASS program.

Robust inference of galaxy stellar masses from photometry is crucial for constraints on galaxy assembly across cosmic time. Here, we test a commonly used spectral energy distribution (SED) fitting code using simulated galaxies from the S phinx 20 cosmological radiation hydrodynamics simulation with JWST NIRCam photometry forward-modeled with radiative transfer. Fitting the synthetic photometry with various star formation history models, we show that recovered stellar masses are, encouragingly, generally robust to within a factor of ∼3 for galaxies in the range M ⋆ ∼ 10 7 −10 9 M ⊙ at z = 5−10. These results are in stark contrast to recent work claiming that stellar masses can be underestimated by as much as an order of magnitude in these mass and redshift ranges. However, while >90% of masses are recovered to within 0.5 dex, there are notable systematic trends, with stellar masses typically overestimated for low-mass galaxies ( M ⋆ ≲ 10 8 M ⊙ ) and slightly underestimated for high-mass galaxies ( M ⋆ ≳ 10 9 M ⊙ ). We demonstrate that these trends arise due to the SED fitting code poorly modeling the impact of strong emission lines on broadband photometry. These systematic trends, which exist for all star formation history parameterizations tested, have a tilting effect on the inferred stellar mass function, with the number densities of massive galaxies underestimated (particularly at the lowest redshifts studied) and the number densities of lower-mass galaxies typically overestimated. Overall, this work suggests that we should be optimistic about our ability to infer the masses of high- z galaxies observed with JWST (notwithstanding contamination from active galactic nuclei) but careful when modeling the impact of strong emission lines on broadband photometry.