Do investors see through mistakes in reported earnings?

This study investigates whether investors see through materially misstated earnings, and whether they anticipate earnings restatements. For firms that restate at least one annual report, we find that investors are misled by mistakes in reported earnings at the time of initial earnings announcements. Investors react positively to the component of the favorable earnings surprise that will subsequently be restated, and attach the same valuation to it as to the true earnings surprise. We also find that investors anticipate the subsequent downward restatements and start marking stock prices down several months before a restatement announcement, so that the full impact of a restatement is about three times as large as the initial announcement effect. Overall our findings indicate that although investors anticipate restatements several months before its announcement, they are misled by misstated earnings for several years and therefore would benefit from better quality of financial information

Association of immune response with efficacy and safety outcomes in adults with phenylketonuria administered pegvaliase in phase 3 clinical trials

Background: This study assessed the immunogenicity of pegvaliase (recombinant Anabaena variabilis phenylalanine [Phe] ammonia lyase [PAL] conjugated with polyethylene glycol [PEG]) treatment in adults with phenylketonuria (PKU) and its impact on safety and efficacy. Methods: Immunogenicity was assessed during induction, upward titration, and maintenance dosing regimens in adults with PKU (n = 261). Total antidrug antibodies (ADA), neutralizing antibodies, immunoglobulin (Ig) M and IgG antibodies against PAL and PEG, IgG and IgM circulating immune complex (CIC) levels, complement components 3 and 4 (C3/C4), plasma Phe, and safety were assessed at baseline and throughout the study. Pegvaliase-specific IgE levels were measured in patients after hypersensitivity adverse events (HAE). Findings: All patients developed ADA against PAL, peaking by 6 months and then stabilizing. Most developed transient antibody responses against PEG, peaking by 3 months, then returning to baseline by 9 months. Binding of ADA to pegvaliase led to CIC formation and complement activation, which were highest during early treatment. Blood Phe decreased over time as CIC levels and complement activation declined and pegvaliase dosage increased. HAEs were most frequent during early treatment and declined over time. No patient with acute systemic hypersensitivity events tested positive for pegvaliase-specific IgE near the time of the event. Laboratory evidence was consistent with immune complex-mediated type III hypersensitivity. No evidence of pegvaliase-associated IC-mediated end organ damage was noted. Interpretation: Despite a universal ADA response post-pegvaliase administration, adult patients with PKU achieved substantial and sustained blood Phe reductions with a manageable safety profile. Fund: BioMarin Pharmaceutical Inc. Keywords: Enzyme replacement therapy, Antidrug antibody, Circulating immune complex, Hypersensitivity, Phenylalanin

Inhibition of macropinocytosis blocks antigen presentation of type II collagen in vitro and in vivo in HLA-DR1 transgenic mice

Professional antigen-presenting cells, such as dendritic cells, macrophages and B cells have been implicated in the pathogenesis of rheumatoid arthritis, constituting a possible target for antigen-specific immunotherapy. We addressed the possibility of blocking antigen presentation of the type II collagen (CII)-derived immunodominant arthritogenic epitope CII(259–273 )to specific CD4 T cells by inhibition of antigen uptake in HLA-DR1-transgenic mice in vitro and in vivo. Electron microscopy, confocal microscopy, subcellular fractionation and antigen presentation assays were used to establish the mechanisms of uptake, intracellular localization and antigen presentation of CII by dendritic cells and macrophages. We show that CII accumulated in membrane fractions of intermediate density corresponding to late endosomes. Treatment of dendritic cells and macrophages with cytochalasin D or amiloride prevented the intracellular appearance of CII and blocked antigen presentation of CII(259–273 )to HLA-DR1-restricted T cell hybridomas. The data suggest that CII was taken up by dendritic cells and macrophages predominantly via macropinocytosis. Administration of amiloride in vivo prevented activation of CII-specific polyclonal T cells in the draining popliteal lymph nodes. This study suggests that selective targeting of CII internalization in professional antigen-presenting cells prevents activation of autoimmune T cells, constituting a novel therapeutic strategy for the immunotherapy of rheumatoid arthritis

The HST Key Project on the Extragalactic Distance Scale. XV. A Cepheid Distance to the Fornax Cluster and Its Implications

Using the Hubble Space Telescope (HST) 37 long-period Cepheid variables have been discovered in the Fornax Cluster spiral galaxy NGC 1365. The resulting V and I period-luminosity relations yield a true distance modulus of 31.35 +/- 0.07 mag, which corresponds to a distance of 18.6 +/- 0.6 Mpc. This measurement provides several routes for estimating the Hubble Constant. (1) Assuming this distance for the Fornax Cluster as a whole yields a local Hubble Constant of 70 +/-18_{random} [+/-7]_{systematic} km/s/Mpc. (2) Nine Cepheid-based distances to groups of galaxies out to and including the Fornax and Virgo clusters yield Ho = 73 (+/-16)_r [+/-7]_s km/s/Mpc. (3) Recalibrating the I-band Tully-Fisher relation using NGC 1365 and six nearby spiral galaxies, and applying it to 15 galaxy clusters out to 100 Mpc gives Ho = 76 (+/-3)_r [+/-8]_s km/s/Mpc. (4) Using a broad-based set of differential cluster distance moduli ranging from Fornax to Abell 2147 gives Ho = 72 (+/-)_r [+/-6]_s km/s/Mpc. And finally, (5) Assuming the NGC 1365 distance for the two additional Type Ia supernovae in Fornax and adding them to the SnIa calibration (correcting for light curve shape) gives Ho = 67 (+/-6)_r [+/-7]_s km/s/Mpc out to a distance in excess of 500 Mpc. All five of these Ho determinations agree to within their statistical errors. The resulting estimate of the Hubble Constant combining all these determinations is Ho = 72 (+/-5)_r [+/-12]_s km/s/Mpc.Comment: Accepted for publication in the Astrophysical Journal, Apr. 10 issue 28 pages, 3 tables, 12 figures (Correct figures and abstract

Protein sequences bound to mineral surfaces persist into deep time

Proteins persist longer in the fossil record than DNA, but the longevity, survival mechanisms and substrates remain contested. Here, we demonstrate the role of mineral binding in preserving the protein sequence in ostrich (Struthionidae) eggshell, including from the palaeontological sites of Laetoli (3.8 Ma) and Olduvai Gorge (1.3 Ma) in Tanzania. By tracking protein diagenesis back in time we find consistent patterns of preservation, demonstrating authenticity of the surviving sequences. Molecular dynamics simulations of struthiocalcin-1 and -2, the dominant proteins within the eggshell, reveal that distinct domains bind to the mineral surface. It is the domain with the strongest calculated binding energy to the calcite surface that is selectively preserved. Thermal age calculations demonstrate that the Laetoli and Olduvai peptides are 50 times older than any previously authenticated sequence (equivalent to ~16 Ma at a constant 10°C)

Cross-Sectional Surveys of the Prevalence of Follicular Trachoma and Trichiasis in The Gambia: Has Elimination Been Reached?

BACKGROUND: The Gambia's National Eye Health Programme has made a concerted effort to reduce the prevalence of trachoma. The present study had two objectives. The first was to conduct surveillance following mass drug administrations to determine whether The Gambia has reached the World Health Organization's (WHO) criteria for trachoma elimination, namely a prevalence of trachomatous inflammation-follicular (TF) of less than 5% in children aged 1 to 9 years. The second was to determine the prevalence of trichiasis (TT) cases unknown to the programme and evaluate whether these meet the WHO criteria of less than 0.1% in the total population. METHODOLOGY/PRINCIPAL FINDINGS: Three cross-sectional surveys were conducted between 2011 and 2013 to determine the prevalence of TF and TT in each of nine surveillance zones. Each zone was of similar size, with a population of 60,000 to 90,000, once urban settlements were excluded. Trachoma grading was carried out according to the WHO's simplified trachoma grading system. The prevalence of TF in children aged 1 to 9 years was less than 5% in each surveillance zone at each of the three surveys. The prevalence of TT cases varied by zone from 0 to 1.7% of adults greater than 14 years while the prevalence of TT cases unknown to the country's National Eye Health Programme was estimated at 0.15% total population. CONCLUSIONS/SIGNIFICANCE: The Gambia has reached the elimination threshold for TF in children. Further work is needed to bring the number of unknown TT cases below the elimination threshold

The HST Key Project on the Extragalactic Distance Scale XVII. The Cepheid Distance to NGC 4725

The distance to NGC 4725 has been derived from Cepheid variables, as part of the Hubble Space Telescope Key Project on the Extragalactic Distance Scale. Thirteen F555W (V) and four F814W (I) epochs of cosmic-ray-split Wide Field and Planetary Camera 2 observations were obtained. Twenty Cepheids were discovered, with periods ranging from 12 to 49 days. Adopting a Large Magellanic Cloud distance modulus and extinction of 18.50+/-0.10 mag and E(V-I)=0.13 mag, respectively, a true reddening-corrected distance modulus (based on an analysis employing the ALLFRAME software package) of 30.50 +/- 0.16 (random) +/- 0.17 (systematic) mag was determined for NGC 4725. The corresponding of distance of 12.6 +/- 1.0 (random) +/- 1.0 (systematic) Mpc is in excellent agreement with that found with an independent analysis based upon the DoPHOT photometry package. With a foreground reddening of only E(V-I)=0.02, the inferred intrinsic reddening of this field in NGC 4725, E(V-I)=0.19, makes it one of the most highly-reddened, encountered by the HST Key Project, to date.Comment: To be published in The Astrophysical Journal, Vol. 512 (1999). 34 pages, LaTeX, 9 jpg figure