Results of matching valve and root repair to aortic valve and root pathology

ObjectiveFor patients with aortic root pathology and aortic valve regurgitation, aortic valve replacement is problematic because no durable bioprosthesis exists, and mechanical valves require lifetime anticoagulation. This study sought to assess outcomes of combined aortic valve and root repair, including comparison with matched bioprosthesis aortic valve replacement.MethodsFrom November 1990 to January 2005, 366 patients underwent modified David reimplantation (n = 72), root remodeling (n = 72), or valve repair with sinotubular junction tailoring (n = 222). Active follow-up was 99% complete, with a mean of 5.6 ± 4.0 years (maximum 17 years); follow-up for vital status averaged 8.5 ± 3.6 years (maximum 19 years). Propensity-adjusted models were developed for fair comparison of outcomes.ResultsThirty-day and 5-, 10-, and 15-year survivals were 98%, 86%, 74%, and 58%, respectively, similar to that of the US matched population and better than that after bioprosthesis aortic valve replacement. Propensity-score–adjusted survival was similar across procedures (P > .3). Freedom from reoperation at 30 days and 5 and 10 years was 99%, 92%, and 89%, respectively, and was similar across procedures (P > .3) after propensity-score adjustment. Patients with tricuspid aortic valves were more likely to be free of reoperation than those with bicuspid valves at 10 years (93% vs 77%, P = .002), equivalent to bioprosthesis aortic valve replacement and superior after 12 years. Bioprostheses increasingly deteriorated after 7 years, and hazard functions for reoperation crossed at 7 years.ConclusionsValve preservation (rather than replacement) and matching root procedures have excellent early and long-term results, with increasing survival benefit at 7 years and fewer reoperations by 12 years. We recommend this procedure for experienced surgical teams

The Atacama Cosmology Telescope: Data Characterization and Map Making

We present a description of the data reduction and mapmaking pipeline used for the 2008 observing season of the Atacama Cosmology Telescope (ACT). The data presented here at 148 GHz represent 12% of the 90 TB collected by ACT from 2007 to 2010. In 2008 we observed for 136 days, producing a total of 1423 hours of data (11 TB for the 148 GHz band only), with a daily average of 10.5 hours of observation. From these, 1085 hours were devoted to a 850 deg^2 stripe (11.2 hours by 9.1 deg) centered on a declination of -52.7 deg, while 175 hours were devoted to a 280 deg^2 stripe (4.5 hours by 4.8 deg) centered at the celestial equator. We discuss sources of statistical and systematic noise, calibration, telescope pointing, and data selection. Out of 1260 survey hours and 1024 detectors per array, 816 hours and 593 effective detectors remain after data selection for this frequency band, yielding a 38% survey efficiency. The total sensitivity in 2008, determined from the noise level between 5 Hz and 20 Hz in the time-ordered data stream (TOD), is 32 micro-Kelvin sqrt{s} in CMB units. Atmospheric brightness fluctuations constitute the main contaminant in the data and dominate the detector noise covariance at low frequencies in the TOD. The maps were made by solving the least-squares problem using the Preconditioned Conjugate Gradient method, incorporating the details of the detector and noise correlations. Cross-correlation with WMAP sky maps, as well as analysis from simulations, reveal that our maps are unbiased at multipoles ell > 300. This paper accompanies the public release of the 148 GHz southern stripe maps from 2008. The techniques described here will be applied to future maps and data releases.Comment: 20 pages, 18 figures, 6 tables, an ACT Collaboration pape

Formation of Trans-Activation Competent HIV-1 Rev:RRE Complexes Requires the Recruitment of Multiple Protein Activation Domains

The HIV-1 Rev trans-activator is a nucleocytoplasmic shuttle protein that is essential for virus replication. Rev directly binds to unspliced and incompletely spliced viral RNA via the cis-acting Rev Response Element (RRE) sequence. Subsequently, Rev oligomerizes cooperatively and interacts with the cellular nuclear export receptor CRM1. In addition to mediating nuclear RNA export, Rev also affects the stability, translation and packaging of Rev-bound viral transcripts. Although it is established that Rev function requires the multimeric assembly of Rev molecules on the RRE, relatively little is known about how many Rev monomers are sufficient to form a trans-activation competent Rev:RRE complex, or which specific activity of Rev is affected by its oligomerization. We here analyzed by functional studies how homooligomer formation of Rev affects the trans-activation capacity of this essential HIV-1 regulatory protein. In a gain-of-function approach, we fused various heterologous dimerization domains to an otherwise oligomerization-defective Rev mutant and were able to demonstrate that oligomerization of Rev is not required per se for the nuclear export of this viral trans-activator. In contrast, however, the formation of Rev oligomers on the RRE is a precondition to trans-activation by directly affecting the nuclear export of Rev-regulated mRNA. Moreover, experimental evidence is provided showing that at least two protein activation domains are required for the formation of trans-activation competent Rev:RRE complexes. The presented data further refine the model of Rev trans-activation by directly demonstrating that Rev oligomerization on the RRE, thereby recruiting at least two protein activation domains, is required for nuclear export of unspliced and incompletely spliced viral RNA

A genomic storm in critically injured humans

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes

Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study

Objectives: To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naïve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX). Methods: In this open-label, multicentre, single-arm study, patients with RA (MTX inadequate responders) received intravenous abatacept (∼10 mg/kg) plus MTX for 24 weeks. A composite PDUS synovitis score, developed by the Outcome Measures in Rheumatology–European League Against Rheumatism (OMERACT–EULAR)-Ultrasound Task Force, was used to evaluate individual joints. The maximal score of each joint was added into a Global OMERACT–EULAR Synovitis Score (GLOESS) for bilateral metacarpophalangeal joints (MCPs) 2–5 (primary objective). The value of GLOESS containing other joint sets was explored, along with clinical efficacy. Results: Eighty-nine patients completed the 24-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2–5): −0.7 (95% CIs −1.2 to −0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia at week 2, joint effusion at week 4). Comparable changes were observed for 22 paired joints and minimal joint subsets. Mean Disease Activity Score 28 (C reactive protein) was significantly reduced from weeks 1 to 24, reaching clinical meaningful improvement (change ≥1.2) at week 8. Conclusions: In this first international prospective study, the composite PDUS score is responsive to abatacept. GLOESS demonstrated the rapid onset of action of abatacept, regardless of the number of joints examined. Ultrasound is an objective tool to monitor patients with RA under treatment. Trial registration number: NCT00767325

The NORMAN Suspect List Exchange (NORMAN-SLE): facilitating European and worldwide collaboration on suspect screening in high resolution mass spectrometry

The NORMAN Association (https://www.norman-network.com/) initiated the NORMAN Suspect List Exchange (NORMAN-SLE; https://www.norman-network.com/nds/SLE/) in 2015, following the NORMAN collaborative trial on non-target screening of environmental water samples by mass spectrometry. Since then, this exchange of information on chemicals that are expected to occur in the environment, along with the accompanying expert knowledge and references, has become a valuable knowledge base for "suspect screening" lists. The NORMAN-SLE now serves as a FAIR (Findable, Accessible, Interoperable, Reusable) chemical information resource worldwide.The NORMAN-SLE project has received funding from the NORMAN Association via its joint proposal of activities. HMT and ELS are supported by the Luxembourg National Research Fund (FNR) for project A18/BM/12341006. ELS, PC, SEH, HPHA, ZW acknowledge funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101036756, project ZeroPM: Zero pollution of persistent, mobile substances. The work of EEB, TC, QL, BAS, PAT, and JZ was supported by the National Center for Biotechnology Information of the National Library of Medicine (NLM), National Institutes of Health (NIH). JOB is the recipient of an NHMRC Emerging Leadership Fellowship (EL1 2009209). KVT and JOB acknowledge the support of the Australian Research Council (DP190102476). The Queensland Alliance for Environmental Health Sciences, The University of Queensland, gratefully acknowledges the financial support of the Queensland Department of Health. NR is supported by a Miguel Servet contract (CP19/00060) from the Instituto de Salud Carlos III, co-financed by the European Union through Fondo Europeo de Desarrollo Regional (FEDER). MM and TR gratefully acknowledge financial support by the German Ministry for Education and Research (BMBF, Bonn) through the project “Persistente mobile organische Chemikalien in der aquatischen Umwelt (PROTECT)” (FKz: 02WRS1495 A/B/E). LiB acknowledges funding through a Research Foundation Flanders (FWO) fellowship (11G1821N). JAP and JMcL acknowledge financial support from the NIH for CCSCompendium (S50 CCSCOMPEND) via grants NIH NIGMS R01GM092218 and NIH NCI 1R03CA222452-01, as well as the Vanderbilt Chemical Biology Interface training program (5T32GM065086-16), plus use of resources of the Center for Innovative Technology (CIT) at Vanderbilt University. TJ was (partly) supported by the Dutch Research Council (NWO), project number 15747. UFZ (TS, MaK, WB) received funding from SOLUTIONS project (European Union’s Seventh Framework Programme for research, technological development and demonstration under Grant Agreement No. 603437). TS, MaK, WB, JPA, RCHV, JJV, JeM and MHL acknowledge HBM4EU (European Union’s Horizon 2020 research and innovation programme under the grant agreement no. 733032). TS acknowledges funding from NFDI4Chem—Chemistry Consortium in the NFDI (supported by the DFG under project number 441958208). TS, MaK, WB and EMLJ acknowledge NaToxAq (European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Grant Agreement No. 722493). S36 and S63 (HPHA, SEH, MN, IS) were funded by the German Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU) Project No. (FKZ) 3716 67 416 0, updates to S36 (HPHA, SEH, MN, IS) by the German Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection (BMUV) Project No. (FKZ) 3719 65 408 0. MiK acknowledges financial support from the EU Cohesion Funds within the project Monitoring and assessment of water body status (No. 310011A366 Phase III). The work related to S60 and S82 was funded by the Swiss Federal Office for the Environment (FOEN), KK and JH acknowledge the input of Kathrin Fenner’s group (Eawag) in compiling transformation products from European pesticides registration dossiers. DSW and YDF were supported by the Canadian Institutes of Health Research and Genome Canada. The work related to S49, S48 and S77 was funded by the MAVA foundation; for S77 also the Valery Foundation (KG, JaM, BG). DML acknowledges National Science Foundation Grant RUI-1306074. YL acknowledges the National Natural Science Foundation of China (Grant No. 22193051 and 21906177), and the Chinese Postdoctoral Science Foundation (Grant No. 2019M650863). WLC acknowledges research project 108C002871 supported by the Environmental Protection Administration, Executive Yuan, R.O.C. Taiwan (Taiwan EPA). JG acknowledges funding from the Swiss Federal Office for the Environment. AJW was funded by the U.S. Environmental Protection Agency. LuB, AC and FH acknowledge the financial support of the Generalitat Valenciana (Research Group of Excellence, Prometeo 2019/040). KN (S89) acknowledges the PhD fellowship through Marie Skłodowska-Curie grant agreement No. 859891 (MSCA-ETN). Exposome-Explorer (S34) was funded by the European Commission projects EXPOsOMICS FP7-KBBE-2012 [308610]; NutriTech FP7-KBBE-2011-5 [289511]; Joint Programming Initiative FOODBALL 2014–17. CP acknowledges grant RYC2020-028901-I funded by MCIN/AEI/1.0.13039/501100011033 and “ESF investing in your future”, and August T Larsson Guest Researcher Programme from the Swedish University of Agricultural Sciences. The work of ML, MaSe, SG, TL and WS creating and filling the STOFF-IDENT database (S2) mostly sponsored by the German Federal Ministry of Education and Research within the RiSKWa program (funding codes 02WRS1273 and 02WRS1354). XT acknowledges The National Food Institute, Technical University of Denmark. MaSch acknowledges funding by the RECETOX research infrastructure (the Czech Ministry of Education, Youth and Sports, LM2018121), the CETOCOEN PLUS project (CZ.02.1.01/0.0/0.0/15_003/0000469), and the CETOCOEN EXCELLENCE Teaming 2 project supported by the Czech ministry of Education, Youth and Sports (No CZ.02.1.01/0.0/0.0/17_043/0009632).Peer reviewe

The impact of PICALM genetic variations on reserve capacity of posterior cingulate in AD continuum

Phosphatidylinositolbinding clathrin assembly protein (PICALM) gene is one novel genetic player associated with late-onset Alzheimer’s disease (LOAD), based on recent genome wide association studies (GWAS). However, how it affects AD occurrence is still unknown. Brain reserve hypothesis highlights the tolerant capacities of brain as a passive means to fight against neurodegenerations. Here, we took the baseline volume and/or thickness of LOAD-associated brain regions as proxies of brain reserve capacities and investigated whether PICALM genetic variations can influence the baseline reserve capacities and the longitudinal atrophy rate of these specific regions using data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. In mixed population, we found that brain region significantly affected by PICALM genetic variations was majorly restricted to posterior cingulate. In sub-population analysis, we found that one PICALM variation (C allele of rs642949) was associated with larger baseline thickness of posterior cingulate in health. We found seven variations in health and two variations (rs543293 and rs592297) in individuals with mild cognitive impairment were associated with slower atrophy rate of posterior cingulate. Our study provided preliminary evidences supporting that PICALM variations render protections by facilitating reserve capacities of posterior cingulate in non-demented elderly