Ubiquitous Molecular Outflows in z > 4 Massive, Dusty Galaxies I. Sample Overview and Clumpy Structure in Molecular Outflows on 500pc Scales

Massive galaxy-scale outflows of gas are one of the most commonly-invoked mechanisms to regulate the growth and evolution of galaxies throughout the universe. While the gas in outflows spans a large range of temperatures and densities, the cold molecular phase is of particular interest because molecular outflows may be capable of suppressing star formation in galaxies by removing the star-forming gas. We have conducted the first survey of molecular outflows at z > 4, targeting 11 strongly-lensed dusty, star-forming galaxies (DSFGs) with high-resolution Atacama Large Millimeter Array (ALMA) observations of OH 119um absorption as an outflow tracer. In this first paper, we give an overview of the survey, focusing on the detection rate and structure of molecular outflows. We find unambiguous evidence for outflows in 8/11 (73%) galaxies, more than tripling the number known at z > 4. This implies that molecular winds in z > 4 DSFGs must have both a near-unity occurrence rate and large opening angles to be detectable in absorption. Lensing reconstructions reveal that 500pc-scale clumpy structures in the outflows are common. The individual clumps are not directly resolved, but from optical depth arguments we expect that future observations will require 50-200pc spatial resolution to do so. We do not detect high-velocity [CII] wings in any of the sources with clear OH outflows, indicating that [CII] is not a reliable tracer of molecular outflows. Our results represent a first step toward characterizing molecular outflows at z > 4 at the population level, demonstrating that large-scale outflows are ubiquitous among early massive, dusty galaxies.Comment: ApJ accepted. 28 pages, 12 figures + appendix. Data and tables from Papers I and II available at https://github.com/spt-smg/publicdat

Apixaban for Prevention of Thromboembolism in Pediatric Heart Disease

BackgroundChildren with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages.ObjectivesThe authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease.MethodsPhase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thromboprophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis.Primary endpointa composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy.ResultsFrom 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference -4.0 [95% CI: -12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with ≥4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels.ConclusionsIn this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472)

Spatially Resolved [CII] Emission in SPT0346-52: A Hyper-starburst Galaxy Merger at z similar to 5.7

SPT0346-52 is one of the most most luminous and intensely star-forming galaxies in the universe, with LFIR > 10 L 13 and S » - - SFR 4200 yr kpc M 1 2. In this paper, we present ~ 0. 15 ALMA observations of the [ ] C II 158 μm emission line in this z = 5.7 dusty star-forming galaxy. We use a pixellated lensing reconstruction code to spatially and kinematically resolve the source-plane [ ] C II and rest-frame 158 μm dust continuum structure at ∼700 pc (∼0 12) resolution. We discuss the [ ] C II deficit with a pixellated study of the L[C II]/LFIR ratio in the source plane. We find that individual pixels within the galaxy follow the same trend found using unresolved observations of other galaxies, indicating that the deficit arises on scales 700 pc. The lensing reconstruction reveals two spatially and kinematically separated components (∼1 kpc and ∼500 km s−1 apart) connected by a bridge of gas. Both components are found to be globally unstable, with Toomre Q instability parameters 1 everywhere. We argue that SPT0346-52 is undergoing a major merger, which is likely driving the intense and compact star formation

Matrix Metalloproteinase-8 Mediates the Unfavorable Systemic Impact of Local Irradiation on Pharmacokinetics of Anti-Cancer Drug 5-Fluorouracil

Concurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for cancer treatment. However, the interactions between radiation and 5-FU remain unclear. Here, we evaluated the influence of local irradiation on the pharmacokinetics of 5-FU in rats. The single-fraction radiation was delivered to the whole pelvic fields of Sprague-Dawley rats after computerized tomography-based planning. 5-FU at 100 mg/kg was prescribed 24 hours after radiation. A high-performance liquid chromatography system was used to measure 5-FU in the blood. Matrix metalloproteinase-8 (MMP-8) inhibitor I was administered to examine whether or not RT modulation of 5-FU pharmacokinetic parameters could be blocked. Compared with sham-irradiated controls, whole pelvic irradiation reduced the area under the concentration versus time curve (AUC) of 5-FU in plasma and, in contrast, increased in bile with a radiation dose-dependent manner. Based on protein array analysis, the amount of plasma MMP-8 was increased by whole pelvic irradiation (2.8-fold by 0.5 Gy and 5.3-fold by 2 Gy) in comparison with controls. Pretreatment with MMP-8 inhibitor reversed the effect of irradiation on AUC of 5-FU in plasma. Our findings first indicate that local irradiation modulate the systemic pharmacokinetics of 5-FU through stimulating the release of MMP-8. The pharmacokinetics of 5-FU during concurrent chemoradiaiton therapy should be rechecked and the optimal 5-FU dose should be reevaluated, and adjusted if necessary, during CCRT

The Salinity of Coastal Waters as a Bellwether for Global Water Cycle Changes

Abstract While the global water cycle has been studied previously based on land and open ocean studies, here we use coastal satellite sea surface salinity (SSS) data to show that in global aggregate, SSS variations near coasts are strongly correlated with global water cycle variability driven by El Niño Southern Oscillation (ENSO). This is a significant finding as we demonstrate that open ocean SSS variability is not as sensitive to ENSO and global water cycle variability as the coastal oceans at interannual timescales. Aggregated global coastal SSS could therefore be used as a proxy for detection of changes in the large‐scale cycling of water between the oceans and continents. Moreover, we identify major potential “hotspots” on land and in the coastal ocean that tend to drive global coastal salinity variability, and which may consequently be most sensitive to future physical and biological impacts of water cycle changes on the coastal oceans

Optimizing Vancomycin Dosing and Monitoring in Neonates and Infants Using Population Pharmacokinetic Modeling

We determined optimal vancomycin starting dose regimens in infants ≤180 days of age to achieve the highest probability of target attainment with an area under the concentration-time curve for 24 h (AUC 24 ) of ≥400 using population pharmacokinetic (PK) modeling. Secondarily, determination of the relationship between serum creatinine (SCR) and vancomycin clearance in neonates was done. </jats:p