Misaligned Protoplanetary Disks in a Young Binary System

Many extrasolar planets follow orbits that differ from the nearly coplanar and circular orbits found in our solar system; orbits may be eccentric or inclined with respect to the host star's equator, and the population of giant planets orbiting close to their host stars suggests significant orbital migration. There is currently no consensus on what produces such orbits. Theoretical explanations often invoke interactions with a binary companion star on an orbit that is inclined relative to the planet's orbital plane. Such mechanisms require significant mutual inclinations between planetary and binary star orbital planes. The protoplanetary disks in a few young binaries are misaligned, but these measurements are sensitive only to a small portion of the inner disk, and the three-dimensional misalignment of the bulk of the planet-forming disk mass has hitherto not been determined. Here we report that the protoplanetary disks in the young binary system HK Tau are misaligned by 60{\deg}-68{\deg}, so one or both disks are significantly inclined to the binary orbital plane. Our results demonstrate that the necessary conditions exist for misalignment-driven mechanisms to modify planetary orbits, and that these conditions are present at the time of planet formation, apparently due to the binary formation process.Comment: Published in Nature, July 31 2014. 18 pages. This version has slight differences from the final published version. Final version is available at http://www.nature.com/nature/journal/v511/n7511/full/nature13521.htm

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Effect of evolocumab on lipoprotein particles

The level of low-density lipoprotein cholesterol (LDL-C) reflects the cholesterol carried mainly by low-density lipoprotein particles (LDL-P). LDL-C, however, does not always correlate with LDL-P because of the variable amounts of cholesterol per particle. Consideration of LDL-P concentrations in addition to LDL-C may help guide therapeutic decisions in a select number of patients. Evolocumab is a fully human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9 that lowers both LDL-C and cardiovascular events. To evaluate the effect of evolocumab on serum levels and size of lipoprotein particles, we conducted a post-hoc subanalysis of 619 patients from the DESCARTES trial, a 52-week, randomized, double-blind, placebo-controlled, global study of patients with hyperlipidemia. At baseline, mean LDL-P concentration was 1,077 nmol/L for the placebo group and 1,100 nmol/L for the evolocumab group. In patients receiving evolocumab, week 52 total LDL-P concentration decreased to 610 nmol/L, a treatment difference of 50% versus placebo. Evolocumab also reduced concentrations of medium VLDL-P, small VLDL-P, and IDL-P: median (Q1, Q3) changes were –15.2% (–48, 48), –29% (–54, 18), and –36% (–70, 22), respectively. Mean (95% CI) percent changes in total LDL particle size in the evolocumab group was –1.7 (–2.0, –1.4); percent changes in HDL and VLDL particle sizes were 1.1 (0.7, 1.5) and 8.7 (7.0, 10.5), respectively. Changes in total LDL, HDL, and VLDL particle sizes (versus placebo) were all significant (P < .001). In conclusion, evolocumab significantly lowers atherogenic lipoprotein particles including low-density and remnant lipoproteins

Evaluation of the efficacy, safety and glycaemic effects of evolocumab (AMG 145) in hypercholesterolaemic patients stratified by glycaemic status and metabolic syndrome.

Aim To examine the lipid and glycaemic effects of 52 weeks of evolocumab treatment. Materials and Methods DESCARTES was a 52-week placebo-controlled trial of evolocumab. DESCARTES randomised 905 patients from 88 study centres in nine countries with 901 receiving at least one dose of study drug. For this post-hoc analysis, DESCARTES patients were categorized by baseline glycaemic status – type 2 diabetes, impaired fasting glucose (IFG), metabolic syndrome (MetS), or none of these. Monthly subcutaneous evolocumab (420 mg) or placebo was administered. The main outcomes measured were percentage change in LDLcholesterol (LDL-C) at week 52 and safety. Results 413 patients had dysglycaemia (120 type 2 diabetes, 293 IFG), 289 MetS (194 also had IFG), and 393 none of these conditions. At week 52, evolocumab reduced LDL-C by &gt; 50% in all subgroups, with favourable effects on other lipids. No significant differences in fasting plasma glucose, HbA1c, insulin, C-peptide or HOMA indices were seen in any subgroup between evolocumab and placebo at week 52. The overall incidence of new-onset diabetes mellitus did not differ between placebo (6.6%) and evolocumab (5.6%); in those with baseline normoglycaemia, the incidences were 1.9% and 2.7%, respectively. Incidences of AEs were similar in evolocumab- and placebo-treated patients. Conclusions Evolocumab showed encouraging safety and efficacy at 52 weeks in patients with or without dysglycaemia or MetS. Changes in glycaemic parameters did not differ between evolocumab- and placebo-treated patients within the glycaemic subgroups examined.</p

Effect of evolocumab on lipoprotein particles

The level of low-density lipoprotein cholesterol (LDL-C) reflects the cholesterol carried mainly by low-density lipoprotein particles (LDL-P). LDL-C, however, does not always correlate with LDL-P because of the variable amounts of cholesterol per particle. Consideration of LDL-P concentrations in addition to LDL-C may help guide therapeutic decisions in a select number of patients. Evolocumab is a fully human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9 that lowers both LDL-C and cardiovascular events. To evaluate the effect of evolocumab on serum levels and size of lipoprotein particles, we conducted a post-hoc subanalysis of 619 patients from the DESCARTES trial, a 52-week, randomized, double-blind, placebo-controlled, global study of patients with hyperlipidemia. At baseline, mean LDL-P concentration was 1,077 nmol/L for the placebo group and 1,100 nmol/L for the evolocumab group. In patients receiving evolocumab, week 52 total LDL-P concentration decreased to 610 nmol/L, a treatment difference of 50% versus placebo. Evolocumab also reduced concentrations of medium VLDL-P, small VLDL-P, and IDL-P: median (Q1, Q3) changes were –15.2% (–48, 48), –29% (–54, 18), and –36% (–70, 22), respectively. Mean (95% CI) percent changes in total LDL particle size in the evolocumab group was –1.7 (–2.0, –1.4); percent changes in HDL and VLDL particle sizes were 1.1 (0.7, 1.5) and 8.7 (7.0, 10.5), respectively. Changes in total LDL, HDL, and VLDL particle sizes (versus placebo) were all significant (P &lt; .001). In conclusion, evolocumab significantly lowers atherogenic lipoprotein particles including low-density and remnant lipoproteins

Evaluation of the efficacy, safety and glycaemic effects of evolocumab (AMG 145) in hypercholesterolaemic patients stratified by glycaemic status and metabolic syndrome.

Aim To examine the lipid and glycaemic effects of 52 weeks of evolocumab treatment. Materials and Methods DESCARTES was a 52-week placebo-controlled trial of evolocumab. DESCARTES randomised 905 patients from 88 study centres in nine countries with 901 receiving at least one dose of study drug. For this post-hoc analysis, DESCARTES patients were categorized by baseline glycaemic status – type 2 diabetes, impaired fasting glucose (IFG), metabolic syndrome (MetS), or none of these. Monthly subcutaneous evolocumab (420 mg) or placebo was administered. The main outcomes measured were percentage change in LDLcholesterol (LDL-C) at week 52 and safety. Results 413 patients had dysglycaemia (120 type 2 diabetes, 293 IFG), 289 MetS (194 also had IFG), and 393 none of these conditions. At week 52, evolocumab reduced LDL-C by > 50% in all subgroups, with favourable effects on other lipids. No significant differences in fasting plasma glucose, HbA1c, insulin, C-peptide or HOMA indices were seen in any subgroup between evolocumab and placebo at week 52. The overall incidence of new-onset diabetes mellitus did not differ between placebo (6.6%) and evolocumab (5.6%); in those with baseline normoglycaemia, the incidences were 1.9% and 2.7%, respectively. Incidences of AEs were similar in evolocumab- and placebo-treated patients. Conclusions Evolocumab showed encouraging safety and efficacy at 52 weeks in patients with or without dysglycaemia or MetS. Changes in glycaemic parameters did not differ between evolocumab- and placebo-treated patients within the glycaemic subgroups examined.</p

Chronic oral study of myosin activation to increase contractility in heart failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial

Summary: Background: Impaired contractility is a fundamental abnormality in heart failure with reduced ejection fraction (HFrEF). We evaluated the pharmacokinetics of chronic therapy with the cardiac myosin activator omecamtiv mecarbil as well as its effect on cardiac function and structure in such patients. Methods: In this randomised, parallel-group, double-blind study, 448 patients from 87 sites in 13 countries with stable, symptomatic chronic heart failure and left ventricular ejection fraction ≤40% were randomly assigned (1:1:1) using an interactive web response system to oral omecamtiv mecarbil (25 mg twice daily; or 25 mg twice daily with pharmacokinetic-guided uptitration to 50 mg twice daily, PK-titration group) or placebo for 20 weeks. The primary endpoint was the maximal omecamtiv mecarbil plasma concentration (Cmax); secondary endpoints were changes from baseline in cardiac function and dimensions, heart rate and NT-proBNP at week 20. (ClinicalTrials.gov, NCT01786512) Findings: In patients enrolled from March 17, 2014 through March 5, 2015, Cmax (mean ± SD) at 12 weeks was 200±71 and 318±129 ng/mL in the 25 mg (n = 147) and PK-titration (n = 141) groups, respectively. Differences were seen in all secondary endpoints by 20 weeks in the PK titration group (n = 149) compared to placebo (n = 149): systolic ejection time [least square mean difference (95% CI); +25 (18, 32) msec, p<0·0001], stroke volume [+3·6 (0·5, 6·7) mL, p=0·0217], left ventricular end-systolic and end-diastolic dimensions [ 1·8 (-2·9, -0·6) mm, p=0·0027; 1·3 (-2·3, 0·3) mm, p=0·0128, respectively], heart rate [ 3·0 (-5·1, -0·8) bpm, p=0·0070] and NT-proBNP [ 970 (-1672, -268) pg/mL, p=0·0069). The maximum changes from baseline in plasma troponin-I concentrations were greater in patients assigned to omecamtiv mecarbil [PK titration: 0·020 ng/mL, (0·005, 0·038); median (Q1, Q3), p<0·0001] than placebo [0·010 ng/mL (0·000, 0·020)]. No important differences in adverse clinical events were observed. Interpretation: In patients with chronic HFrEF, pharmacokinetic-guided dosing of omecamtiv mecarbil achieved plasma concentrations associated with improvements in cardiac performance and ventricular dimensions

Complement Mediated Signaling on Pulmonary CD103+ Dendritic Cells Is Critical for Their Migratory Function in Response to Influenza Infection

10.1371/journal.ppat.1003115PLoS Pathogens91