Methodological approaches to determining the marine radiocarbon reservoir effect

The marine radiocarbon reservoir effect is an offset in 14C age between contemporaneous organisms from the terrestrial environment and organisms that derive their carbon from the marine environment. Quantification of this effect is of crucial importance for correct calibration of the <sup>14</sup>C ages of marine-influenced samples to the calendrical timescale. This is fundamental to the construction of archaeological and palaeoenvironmental chronologies when such samples are employed in <sup>14</sup>C analysis. Quantitative measurements of temporal variations in regional marine reservoir ages also have the potential to be used as a measure of process changes within Earth surface systems, due to their link with climatic and oceanic changes. The various approaches to quantification of the marine radiocarbon reservoir effect are assessed, focusing particularly on the North Atlantic Ocean. Currently, the global average marine reservoir age of surface waters, R(t), is c. 400 radiocarbon years; however, regional values deviate from this as a function of climate and oceanic circulation systems. These local deviations from R(t) are expressed as +R values. Hence, polar waters exhibit greater reservoir ages (δR = c. +400 to +800 <sup>14</sup>C y) than equatorial waters (δR = c. 0 <sup>14</sup>C y). Observed temporal variations in δR appear to reflect climatic and oceanographic changes. We assess three approaches to quantification of marine reservoir effects using known age samples (from museum collections), tephra isochrones (present onshore/offshore) and paired marine/terrestrial samples (from the same context in, for example, archaeological sites). The strengths and limitations of these approaches are evaluated using examples from the North Atlantic region. It is proposed that, with a suitable protocol, accelerator mass spectrometry (AMS) measurements on paired, short-lived, single entity marine and terrestrial samples from archaeological deposits is the most promising approach to constraining changes over at least the last 5 ky BP

Small bound for birational automorphism groups of algebraic varieties (with an Appendix by Yujiro Kawamata)

We give an effective upper bound of |Bir(X)| for the birational automorphism group of an irregular n-fold (with n = 3) of general type in terms of the volume V = V(X) under an ''albanese smoothness and simplicity'' condition. To be precise, |Bir(X)| < d_3 V^{10}. An optimum linear bound |Bir(X)|-1 < (1/3)(42)^3 V is obtained for those 3-folds with non-maximal albanese dimension. For all n > 2, a bound |Bir(X)| < d_n V^{10} is obtained when alb_X is generically finite, alb(X) is smooth and Alb(X) is simple.Comment: Mathematische Annalen, to appea

Bronchoalveolar lavage in infants with recurrent lower respiratory symptoms

Background: Few data are available about the inflammatory cytokine profile of bronchoalveolar lavage (BAL) from young children with frequent wheeze. The first aim was to investigate the BAL cellular and cytokine profiles in infants with recurrent lower respiratory symptoms in whom bronchoscopy was indicated for clinical symptom evaluation. The second aim was to relate the BAL results with the histological findings of the endobronchial carina biopsies. Methods: Thirty-nine infants (median age 0.9 years) underwent lung function testing by whole-body plethysmography prior to the bronchoscopy. The BAL differential cell counts and cytokine levels were quantified. These findings were compared with the histological findings of the endobronchial carina biopsies. Results: The differential cytology reflected mainly that described for healthy infants with lymphocyte counts at the upper range level. A positive association between BAL CD8+ lymphocytes and neutrophils and endobronchial reticular basement membrane was found. Detectable levels of pro-inflammatory cytokine proteins IL-1 beta, IL-17A, IL-18, IL-23, and IL-33 were found, whereas levels of Th2-type cytokine proteins were low. Frequent wheeze was the only clinical characteristic significantly related to detectable combined pro-inflammatory cytokine profile. Lung function did not correlate with any cytokine. Conclusions: A positive association between BAL CD8+ lymphocytes and neutrophils and endobronchial reticular basement thickness was found. Detectable production of pro-inflammatory cytokines associated positively with frequent wheeze.Peer reviewe

Impact of Baseline Retinal Nonperfusion and Macular Retinal Capillary Nonperfusion on Outcomes in the COPERNICUS and GALILEO Studies

To evaluate the impact of baseline retinal capillary nonperfusion (RNP) and macular retinal capillary nonperfusion (MNP) status on outcomes at week&nbsp;24 (W24)

Safety and Efficacy of Risuteganib in Intermediate Non-exudative Age-Related Macular Degeneration

Purpose : Risuteganib is a small synthetic peptide that regulates select integrin functions involved in the pathogenesis of dry age-related macular degeneration (AMD). This study evaluated the safety and efficay of risuteganib for the treatment of dry AMD. Methods : Randomized, double-masked, placebo-controlled Phase 2 study in eyes with intermediate dry AMD presenting with best-corrected visual acuity (BCVA) between 20/40-20/200 was conducted across multiple centers in the United States. Patients were randomized to receive either intravitreal 1.0mg risuteganib or sham injection at baseline. At week 16, patients in the risuteganib group received a second dose and the sham group crossed over and receive a single dose of 1.0mg risuteganib. The primary endpoint was the percentage of population with ≥ 8 letters BCVA gain from baseline to week 28 in 1.0mg risuteganib vs baseline to week 12 for sham. Results : Forty-five patients were enrolled in the study. At baseline, mean patient age was 78.8 and 75.9 years and mean baseline BCVA was 67.1 and 64.4 letters in the sham and risuteganib groups, respectively. The primary endpoint was met; 48% of patients in the risuteganib group at week 28 and 7% of patients in the sham group at week 12 gained > 8 letters from baseline (p=0.013). Of the risuteganib treated patients, 20% gained > 15 letters at week 28; no patients in the sham group at week 12 had this gain. On a post-hoc masked analysis by 2 independent reading centers, greater outer retinal and photoreceptor thickness and volume and smaller ellipsoid zone defect area in the central 1 mm zone at baseline were associated with increased BCVA response to risuteganib. Risuteganib demonstrated a good safety profile in this study. Conclusions : Risuteganib showed significant benefit over sham in patients with dry AMD with respect to proportion of patients gaining > 8 letters of BCVA from baseline. Furthermore, post hoc analysis provides preliminary insights into baseline anatomic features that may help to determine likelihood of BCVA response to risuteganib. These findings will be confirmed in an upcoming larger trial

Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2) : 12-month results from a randomised, double-masked, phase 3 trial

Geographic atrophy is an advanced form of dry age-related macular degeneration that can lead to irreversible vision loss and high burden of disease. We aimed to assess efficacy and safety of avacincaptad pegol 2 mg in reducing geographic atrophy lesion growth.GATHER2 is a randomised, double-masked, sham-controlled, 24-month, phase 3 trial across 205 retina clinics, research hospitals, and academic institutions globally. To be eligible, patients had to be aged 50 years or older with non-centrepoint-involving geographic atrophy and best corrected visual acuity between 20/25 and 20/320 in the study eye. Eligible patients were randomly assigned (1:1) to monthly avacincaptad pegol 2 mg administered as a 100 μL intravitreal injection or sham for the first 12 months. Randomisation was performed using an interactive response technology system with stratification by factors known to be of prognostic importance in age-related macular degeneration. Patients, investigators, study centre staff, sponsor personnel, and data analysts were masked to treatment allocation. The primary endpoint was geographic atrophy lesion size measured by fundus autofluorescence at baseline, month 6, and month 12. Efficacy and safety analyses were done in the modified intention-to-treat and safety populations, respectively. This trial is registered with ClinicalTrials.gov, NCT04435366.Between June 22, 2020, and July 23, 2021, 1422 patients were screened for eligibility, of whom 448 were enrolled and randomly assigned to avacincaptad pegol 2 mg (n=225) or sham (n=223). One patient in the sham group did not receive study treatment and was excluded from analyses. There were 154 (68%) female patients and 71 (32%) male patients in the avacincaptad pegol 2 mg group, and 156 (70%) female patients and 66 (30%) male patients in the sham group. From baseline to month 12, the mean rate of square-root-transformed geographic atrophy area growth was 0·336 mm/year (SE 0·032) with avacincaptad pegol 2 mg and 0·392 mm/year (0·033) with sham, a difference in growth of 0·056 mm/year (95% CI 0·016-0·096; p=0·0064), representing a 14% difference between the avacincaptad pegol 2 mg group and the sham group. Ocular treatment-emergent adverse events in the study eye occurred in 110 (49%) patients in the avacincaptad pegol 2 mg group and 83 (37%) in the sham group. There were no endophthalmitis, intraocular inflammation, or ischaemic optic neuropathy events over 12 months. To month 12, macular neovascularisation in the study eye occurred in 15 (7%) patients in the avacincaptad pegol 2 mg group and nine (4%) in the sham group, with exudative macular neovascularisation occurring in 11 (5%) in the avacincaptad pegol 2 mg group and seven (3%) in the sham group.Monthly avacincaptad pegol 2 mg was well tolerated and showed significantly slower geographic atrophy growth over 12 months than sham treatment, suggesting that avacincaptad pegol might slow disease progression and potentially change the trajectory of disease for patients with geographic atrophy.Iveric Bio, An Astellas Company

Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration : A Randomized Phase 2 Trial

Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.Peer reviewedPublisher PD