Objectives This study sought to evaluate 4-year outcomes of percutaneous repair versus surgery for mitral regurgitation. Background Transcatheter therapies are being developed to treat valvular heart ...disease. In the EVEREST (Endovascular Valve Edge-to-Edge Repair Study) II trial, treatment of mitral valve regurgitation (MR) with a novel percutaneous device was compared with surgery and showed superior safety, but less reduction in MR at 1 year overall. We report the 4-year outcomes from the EVEREST II trial. Methods Patients with grade 3+ or 4+ MR were randomly assigned to percutaneous repair with the MitraClip (Abbott, Menlo Park, California) device or conventional mitral valve surgery in a 2:1 ratio (184:95). Patients prospectively consented to 5 years of follow-up. Results At 4 years, the rate of the composite endpoint of freedom from death, surgery, or 3+ or 4+ MR in the intention-to-treat population was 39.8% versus 53.4% in the percutaneous repair group and surgical groups, respectively (p = 0.070). Rates of death were 17.4% versus 17.8% (p = 0.914), and 3+ or 4+ MR was present in 21.7% versus 24.7% (p = 0.745) at 4 years of follow-up, respectively. Surgery for mitral valve dysfunction, however, occurred in 20.4% versus 2.2% (p < 0.001) at 1 year and 24.8% versus 5.5% (p < 0.001) at 4 years. Conclusions Patients treated with percutaneous repair of the mitral valve more commonly required surgery to treat residual MR; however, after the first year of follow-up, there were few surgeries required after either percutaneous or surgical treatment and no difference in the prevalence of moderate-severe and severe MR or mortality at 4 years. (Endovascular Valve Edge-to-Edge Repair Study EVEREST II; NCT00209274 )
Abstract
We measured the Rossiter–McLaughlin effect of WASP-107b during a single transit with Keck/HIRES. We found the sky-projected inclination of WASP-107b’s orbit, relative to its host star’s ...rotation axis, to be
degrees. This confirms the misaligned/polar orbit that was previously suggested from spot-crossing events and adds WASP-107b to the growing population of hot Neptunes in polar orbits around cool stars. WASP-107b is also the fourth such planet to have a known distant planetary companion. We examined several dynamical pathways by which this companion could have induced such an obliquity in WASP-107b. We find that nodal precession and disk dispersal-driven tilting can both explain the current orbital geometry while Kozai–Lidov cycles are suppressed by general relativity. While each hypothesis requires a mutual inclination between the two planets, nodal precession requires a much larger angle, which for WASP-107 is on the threshold of detectability with future Gaia astrometric data. As nodal precession has no stellar type dependence, but disk dispersal-driven tilting does, distinguishing between these two models is best done on the population level. Finding and characterizing more extrasolar systems like WASP-107 will additionally help distinguish whether the distribution of hot-Neptune obliquities is a dichotomy of aligned and polar orbits or if we are uniformly sampling obliquities during nodal precession cycles.
Abstract
TOI-561 is a galactic thick-disk star hosting an ultra-short-period (0.45-day-orbit) planet with a radius of 1.37
R
⊕
, making it one of the most metal-poor (Fe/H = −0.41) and oldest (≈10 ...Gyr) sites where an Earth-sized planet has been found. We present new simultaneous radial velocity (RV) measurements from Gemini-N/MAROON-X and Keck/HIRES, which we combined with literature RVs to derive a mass of
M
b
= 2.24 ± 0.20
M
⊕
. We also used two new sectors of TESS photometry to improve the radius determination, finding
R
b
= 1.37 ± 0.04
R
⊕
and confirming that TOI-561 b is one of the lowest-density super-Earths measured to date (
ρ
b
= 4.8 ± 0.5 g cm
−3
). This density is consistent with an iron-poor rocky composition reflective of the host star’s iron and rock-building element abundances; however, it is also consistent with a low-density planet with a volatile envelope. The equilibrium temperature of the planet (∼2300 K) suggests that this envelope would likely be composed of high mean molecular weight species, such as water vapor, carbon dioxide, or silicate vapor, and is likely not primordial. We also demonstrate that the composition determination is sensitive to the choice of stellar parameters and that further measurements are needed to determine whether TOI-561 b is a bare rocky planet, a rocky planet with an optically thin atmosphere, or a rare example of a nonprimordial envelope on a planet with a radius smaller than 1.5
R
⊕
.
Abstract Background In patients with acute heart failure (AHF), dyspnea relief is the most immediate goal. Renal dysfunction, diuretic resistance, and hyponatremia represent treatment impediments. ...Objectives It was hypothesized that the addition of tolvaptan to a background diuretic improved dyspnea early in patients selected for an enhanced vasopressin antagonism response. Methods In a double-blind trial, patients were randomized to tolvaptan 30 mg/day or placebo. Study entry required hospitalization within the previous 36 h, active dyspnea, and any of the following: 1) estimated glomerular filtration rate <60 ml/min/1.73 m2 ; 2) hyponatremia; or 3) diuretic resistance (urine output ≤125 ml/h following intravenous furosemide ≥40 mg). The primary endpoint was a 7-point change in self-assessed dyspnea at 8 and 16 h, using a novel standardized approach. Results We randomized 250 patients. There was no difference in the primary endpoint of day 1 dyspnea reduction, despite significantly greater weight reduction with tolvaptan (−2.4 ± 2.1 kg vs. −0.9 ± 1.8 kg; p < 0.001). At day 3, dyspnea reduction was greater with tolvaptan (p = 0.01). There were 2 significant treatment-by-subgroup interactions: patients without elevated jugular venous pressure and those without ascites showed directional favorability of tolvaptan over placebo for the primary endpoint compared with patients with these findings. Conclusions Despite rapid and persistent weight loss with tolvaptan compared with placebo, in patients with AHF who were selected for greater potential benefit from vasopressin receptor inhibition, tolvaptan was not associated with greater early improvement in dyspnea. Apparent subsequent differences in dyspnea warrant further exploration of the temporal relationship between diuresis and dyspnea relief and a possible clinical role for tolvaptan. (Randomized, Double-Blind, Placebo Controlled Study of the Short Term Clinical Effects of Tolvaptan in Patients Hospitalized for Worsening Heart Failure With Challenging Volume Management SECRET of CHF; NCT01584557 )
Abstract
Mass, radius, and age measurements of young (≲100 Myr) planets have the power to shape our understanding of planet formation. However, young stars tend to be extremely variable in both ...photometry and radial velocity (RV) measurements, which makes constraining these properties challenging. The V1298 Tau system of four ∼0.5
R
J
planets transiting a pre-main-sequence star presents an important, if stress-inducing, opportunity to observe and measure directly the properties of infant planets. Suárez Mascareño et al. published radial-velocity-derived masses for two of the V1298 Tau planets using a state-of-the-art Gaussian process regression framework. The planetary densities computed from these masses were surprisingly high, implying extremely rapid contraction after formation in tension with most existing planet-formation theories. In an effort to constrain further the masses of the V1298 Tau planets, we obtained 36 RVs using Keck/HIRES, and analyzed them in concert with published RVs and photometry. Through performing a suite of cross-validation tests, we found evidence that the preferred model of Suárez Mascareño et al. suffers from overfitting, defined as the inability to predict unseen data, rendering the masses unreliable. We detail several potential causes of this overfitting, many of which may be important for other RV analyses of other active stars, and recommend that additional time and resources be allocated to understanding and mitigating activity in active young stars such as V1298 Tau.
Abstract
Exoplanet systems with multiple transiting planets are natural laboratories for testing planetary astrophysics. One such system is HD 191939 (TOI 1339), a bright (
V
= 9) and Sun-like (G9V) ...star, which TESS found to host three transiting planets (b, c, and d). The planets have periods of 9, 29, and 38 days each with similar sizes from 3 to 3.4
R
⊕
. To further characterize the system, we measured the radial velocity (RV) of HD 191939 over 415 days with Keck/HIRES and APF/Levy. We find that
M
b
= 10.4 ± 0.9
M
⊕
and
M
c
= 7.2 ± 1.4
M
⊕
, which are low compared to most known planets of comparable radii. The RVs yield only an upper limit on
M
d
(<5.8
M
⊕
at 2
σ
). The RVs further reveal a fourth planet (e) with a minimum mass of 0.34 ± 0.01
M
Jup
and an orbital period of 101.4 ± 0.4 days. Despite its nontransiting geometry, secular interactions between planet e and the inner transiting planets indicate that planet e is coplanar with the transiting planets (Δ
i
< 10°). We identify a second high-mass planet (f) with 95% confidence intervals on mass between 2 and 11
M
Jup
and period between 1700 and 7200 days, based on a joint analysis of RVs and astrometry from Gaia and Hipparcos. As a bright star hosting multiple planets with well-measured masses, HD 191939 presents many options for comparative planetary astronomy, including characterization with JWST.
A general approach for heritably altering gene expression has the potential to enable many discovery and therapeutic efforts. Here, we present CRISPRoff—a programmable epigenetic memory writer ...consisting of a single dead Cas9 fusion protein that establishes DNA methylation and repressive histone modifications. Transient CRISPRoff expression initiates highly specific DNA methylation and gene repression that is maintained through cell division and differentiation of stem cells to neurons. Pairing CRISPRoff with genome-wide screens and analysis of chromatin marks establishes rules for heritable gene silencing. We identify single guide RNAs (sgRNAs) capable of silencing the large majority of genes including those lacking canonical CpG islands (CGIs) and reveal a wide targeting window extending beyond annotated CGIs. The broad ability of CRISPRoff to initiate heritable gene silencing even outside of CGIs expands the canonical model of methylation-based silencing and enables diverse applications including genome-wide screens, multiplexed cell engineering, enhancer silencing, and mechanistic exploration of epigenetic inheritance.
Display omitted
•CRISPRoff is a single fusion protein that programs heritable epigenetic memory•CRISPRoff can heritably silence most genes, including genes without CpG islands•CRISPRoff is highly specific and has a broad targeting window across gene promoters•CRISPRoff epigenetic memory persists through differentiation of iPSCs into neurons
CRISPRoff programs heritable epigenetic memory and is able to heritably silence most genes, including genes without CpG islands. This heritable silencing is highly specific and persists through differentiation of iPSCs into neurons.
Background/Purpose To date, studies examining polymicrobial infections in ocular disease have mostly been limited to keratitis or endophthalmitis. We characterized polybacterial infections compared ...to monobacterial infections in prior clinical studies evaluating besifloxacin ophthalmic suspension 0.6% for the treatment of bacterial conjunctivitis and report on associated microbiological outcomes. Methods In this post-hoc analysis, microbiological data for subjects with conjunctivitis due to one or more than one bacterial species in three previous studies (two vehicle-, one active-controlled) of besifloxacin were extracted. Bacterial species identified at baseline were deemed causative if their colony count equaled or exceeded species-specific prespecified threshold criteria. In subjects with polybacterial infections, the fold-increase over threshold was used to rank order the contribution of individual species. Baseline pathogens and their minimum inhibitory concentrations (MICs) for common ophthalmic antibiotics were compared by infection type, as were microbial eradication rates following treatment with besifloxacin. Results Of 1041 subjects with culture-confirmed conjunctivitis, 17% had polybacterial and 83% had monobacterial conjunctivitis at baseline. In polybacterial compared to monobacterial infections, Haemophilus influenzae and Streptococcus pneumoniae were identified less frequently as the dominant infecting species (P = 0.042 and P0.001, respectively), whereas Streptococcus mitis/S. mitis group was identified more frequently as dominant (P0.001). Viral coinfection was also identified more frequently in polybacterial infections (P0.001). Staphylococcus aureus was the most common coinfecting species in polybacterial infections and the second most common dominant species in such infections. With few exceptions, MICs for individual species were comparable regardless of infection type. Clinical microbial eradication rates with besifloxacin were high regardless of infection type (Pless than or equal to0.016 vs vehicle at follow-up visits). Conclusions Approximately one in five subjects with bacterial conjunctivitis are infected with more than one bacterial species underscoring the need for a broad-spectrum antibiotic for such infections. Besifloxacin treatment resulted in robust eradication rates of these infections comparable to monobacterial infections. Trial registration NCT000622908, NCT00347932, NCT00348348
Abstract Background Patients with frequent asthma exacerbations resulting in emergency department (ED) visits are at increased risk for future exacerbations. We examined the ability of 1 dose of ...benralizumab, an investigational antiinterleukin 5 receptor α monoclonal antibody, to reduce recurrence after acute asthma exacerbations. Methods In this randomized, double-blind, placebo-controlled study, eligible subjects presented to the ED with an asthma exacerbation, had partial response to treatment, and greater than or equal to 1 additional exacerbation within the previous year. Subjects received 1 intravenous infusion of placebo (n = 38) or benralizumab (0.3 mg/kg, n = 36 or 1.0 mg/kg, n = 36) added to outpatient management. The primary outcome was the proportion of subjects with greater than or equal to 1 exacerbation at 12 weeks in placebo vs the combined benralizumab groups. Other outcomes included the time-weighted rate of exacerbations at week 12, adverse events, blood eosinophil counts, asthma symptom changes, and health care resource utilization. Results The proportion of subjects with greater than or equal to 1 asthma exacerbation at 12 weeks was not different between placebo and the combined benralizumab groups (38.9% vs 33.3%; P = .67). However, compared with placebo, benralizumab reduced asthma exacerbation rates by 49% (3.59 vs 1.82; P = .01) and exacerbations resulting in hospitalization by 60% (1.62 vs 0.65; P = .02) in the combined groups. Benralizumab reduced blood eosinophil counts but did not affect other outcomes, while demonstrating an acceptable safety profile. Conclusions When added to usual care, 1 dose of benralizumab reduced the rate and severity of exacerbations experienced over 12 weeks by subjects who presented to the ED with acute asthma.
Abstract
An intriguing pattern among exoplanets is the lack of detected planets between approximately 1.5
R
⊕
and 2.0
R
⊕
. One proposed explanation for this “radius gap” is the photoevaporation of ...planetary atmospheres, a theory that can be tested by studying individual planetary systems. Kepler-105 is an ideal system for such testing due to the ordering and sizes of its planets. Kepler-105 is a Sun-like star that hosts two planets straddling the radius gap in a rare architecture with the larger planet closer to the host star (
R
b
= 2.53 ± 0.07
R
⊕
,
P
b
= 5.41 days,
R
c
= 1.44 ± 0.04
R
⊕
,
P
c
= 7.13 days). If photoevaporation sculpted the atmospheres of these planets, then Kepler-105b would need to be much more massive than Kepler-105c to retain its atmosphere, given its closer proximity to the host star. To test this hypothesis, we simultaneously analyzed radial velocities and transit-timing variations of the Kepler-105 system, measuring disparate masses of
M
b
= 10.8 ± 2.3
M
⊕
(
ρ
b
= 3.68 ± 0.84 g cm
−3
) and
M
c
= 5.6 ± 1.2
M
⊕
(
ρ
c
= 10.4 ± 2.39 g cm
−3
). Based on these masses, the difference in gas envelope content of the Kepler-105 planets could be entirely due to photoevaporation (in 76% of scenarios), although other mechanisms like core-powered mass loss could have played a role for some planet albedos.
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