We demonstrate improved operation of exchange-coupled semiconductor quantum dots by substantially reducing the sensitivity of exchange operations to charge noise. The method involves biasing a double ...dot symmetrically between the charge-state anticrossings, where the derivative of the exchange energy with respect to gate voltages is minimized. Exchange remains highly tunable by adjusting the tunnel coupling. We find that this method reduces the dephasing effect of charge noise by more than a factor of 5 in comparison to operation near a charge-state anticrossing, increasing the number of observable exchange oscillations in our qubit by a similar factor. Performance also improves with exchange rate, favoring fast quantum operations.
We report the first plausible optical electromagnetic counterpart to a (candidate) binary black hole merger. Detected by the Zwicky Transient Facility, the electromagnetic flare is consistent with ...expectations for a kicked binary black hole merger in the accretion disk of an active galactic nucleus B. McKernan, K. E. S. Ford, I. Bartoset al., Astrophys. J. Lett.884, L50 (2019) and is unlikely <O(0.01%)) due to intrinsic variability of this source. The lack of color evolution implies that it is not a supernova and instead is strongly suggestive of a constant temperature shock. Other false-positive events, such as microlensing ora tidal disruption event, are ruled out or constrained to be <O(0.1%). If the flare is associated withS190521g, we find plausible values of total mass M(BBH) ∼ 100 Mꙩ, kick velocity v(k) ∼ 200 km/s at θ ∼ 60° in a disk with aspect ratio H/a ∼ 0.01(i.e., disk height H at radius a) and gas density ρ ∼ 10^(−10)g/cu.cm. The merger could have occurred at a disk migration trap (a ∼ 700 r(g); r(g) ≡ GM(SMBH)/sq.c, where M(SMBH) is the mass of the active galactic nucleus supermassive black hole). The combination of parameters implies a significant spin for at least one of the black holes in S190521g. The timing of our spectroscopy prevents useful constraints on broad-line asymmetry due to an off-center flare. We predict a repeat flare in this source due to a reencountering with the disk in ∼ 1.6 yr(M(SMBH)/10^(8) Mꙩ)(a/10^(3)r(g))^(3/2).
Increased efficiency of energy harvest, due to alterations in the gut microbiota (increased Firmicutes and decreased Bacteroidetes), has been implicated in obesity in mice and humans. However, a ...causal relationship is unproven and contributory variables include diet, genetics and age. Therefore, we explored the effect of a high-fat (HF) diet and genetically determined obesity (ob/ob) for changes in microbiota and energy harvesting capacity over time.
Seven-week-old male ob/ob mice were fed a low-fat diet and wild-type mice were fed either a low-fat diet or a HF-diet for 8 weeks (n=8/group). They were assessed at 7, 11 and 15 weeks of age for: fat and lean body mass (by NMR); faecal and caecal short-chain fatty acids (SCFA, by gas chromatography); faecal energy content (by bomb calorimetry) and microbial composition (by metagenomic pyrosequencing).
A progressive increase in Firmicutes was confirmed in both HF-fed and ob/ob mice reaching statistical significance in the former, but this phylum was unchanged over time in the lean controls. Reductions in Bacteroidetes were also found in ob/ob mice. However, changes in the microbiota were dissociated from markers of energy harvest. Thus, although the faecal energy in the ob/ob mice was significantly decreased at 7 weeks, and caecal SCFA increased, these did not persist and faecal acetate diminished over time in both ob/ob and HF-fed mice, but not in lean controls. Furthermore, the proportion of the major phyla did not correlate with energy harvest markers.
The relationship between the microbial composition and energy harvesting capacity is more complex than previously considered. While compositional changes in the faecal microbiota were confirmed, this was primarily a feature of high-fat feeding rather than genetically induced obesity. In addition, changes in the proportions of the major phyla were unrelated to markers of energy harvest which changed over time. The possibility of microbial adaptation to diet and time should be considered in future studies.
The single-arm, phase 2 ENESTfreedom trial assessed the potential for treatment-free remission (TFR; i.e., the ability to maintain a molecular response after stopping therapy) following frontline ...nilotinib treatment. Patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with MR
(BCR-ABL1⩽0.0032% on the International Scale (BCR-ABL1
)) and ⩾2 years of frontline nilotinib therapy were enrolled. Patients with sustained deep molecular response during the 1-year nilotinib consolidation phase were eligible to stop treatment and enter the TFR phase. Patients with loss of major molecular response (MMR; BCR-ABL1
⩽0.1%) during the TFR phase reinitiated nilotinib. In total, 215 patients entered the consolidation phase, of whom 190 entered the TFR phase. The median duration of nilotinib before stopping treatment was 43.5 months. At 48 weeks after stopping nilotinib, 98 patients (51.6%; 95% confidence interval, 44.2-58.9%) remained in MMR or better (primary end point). Of the 86 patients who restarted nilotinib in the treatment reinitiation phase after loss of MMR, 98.8% and 88.4%, respectively, regained MMR and MR
by the data cutoff date. Consistent with prior reports of imatinib-treated patients, musculoskeletal pain-related events were reported in 24.7% of patients in the TFR phase (consolidation phase, 16.3%).
Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We ...undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS.
We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10-10 to 2 × 10-109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio OR = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10-5; I2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10-9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely.
A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.
We present the first joint analysis of cluster abundances and auto or cross-correlations of three cosmic tracer fields: galaxy density, weak gravitational lensing shear, and cluster density split by ...optical richness. From a joint analysis (4×2pt+N) of cluster abundances, three cluster cross-correlations, and the auto correlations of the galaxy density measured from the first year data of the Dark Energy Survey, we obtain Ω_{m}=0.305_{-0.038}^{+0.055} and σ_{8}=0.783_{-0.054}^{+0.064}. This result is consistent with constraints from the DES-Y1 galaxy clustering and weak lensing two-point correlation functions for the flat νΛCDM model. Consequently, we combine cluster abundances and all two-point correlations from across all three cosmic tracer fields (6×2pt+N) and find improved constraints on cosmological parameters as well as on the cluster observable-mass scaling relation. This analysis is an important advance in both optical cluster cosmology and multiprobe analyses of upcoming wide imaging surveys.
Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data ...connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment.
The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines.
Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy–treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated.
Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.
Objective To characterize the epidemiology of and identify risk factors for neonatal cardiac surgery–associated acute kidney injury (CS-AKI) and determine its impact on clinical outcomes. Study ...design Using secondary analysis of data from an ongoing multiprovincial prospective cohort study, we studied 264 neonates undergoing complex cardiac repair. CS-AKI was defined based on the Acute Kidney Injury Network (AKIN) definition. We used regression modeling and survival analysis (adjusting for covariates) to evaluate associations. Results CS-AKI occurred in 64% of the neonates in our study cohort. Lower age, longer cardiopulmonary bypass time, hypothermic circulatory arrest, type of repair, lower preoperative serum creatinine (SCr) level, lower gestational age, and preoperative ventilation were independent risk factors for developing CS-AKI. Neonates with CS-AKI had longer times to extubation, intensive care discharge, and hospital discharge, after adjusting for covariates. Mortality was significantly increased in neonates with AKIN stage 2 or higher CS-AKI. The neonates with CS-AKI had a lower z -score for height at 2-year follow-up and were seen by more specialists. Conclusion Neonatal CS-AKI is common and independently predicts important clinical outcomes, including mortality. Many risk factors are similar to those in older children, but some are unique to neonates. The observation that lower baseline SCr predicts CS-AKI merits further study. The AKIN definition, based on preoperative SCr value, is a reasonable method for defining CS-AKI in neonates. Many previous studies of CS-AKI have excluded neonates; we suggest that future intervention studies on approaches to reducing CS-AKI incidence and improving outcomes should include neonates.
We present angular diameter measurements obtained by measuring the position of baryon acoustic oscillations (BAO) in an optimized sample of galaxies from the first three years of Dark Energy Survey ...data (DES Y3). The sample consists of 7 million galaxies distributed over a footprint of 4100 deg2 with 0.6<zphoto<1.1 and a typical redshift uncertainty of 0.03(1+z). The sample selection is the same as in the BAO measurement with the first year of DES data, but the analysis presented here uses three times the area, extends to higher redshift, and makes a number of improvements, including a fully analytical BAO template, the use of covariances from both theory and simulations, and an extensive preunblinding protocol. We used two different statistics; angular correlation function and power spectrum, and validate our pipeline with an ensemble of over 1500 realistic simulations. Both statistics yield compatible results. We combine the likelihoods derived from angular correlations and spherical harmonics to constrain the ratio of comoving angular diameter distance DM at the effective redshift of our sample to the sound horizon scale at the drag epoch. We obtain DM(zeff=0.835)/rd=18.92±0.51, which is consistent with, but smaller than, the Planck prediction assuming flat ΛCDM, at the level of 2.3σ. The analysis was performed blind and is robust to changes in a number of analysis choices. It represents the most precise BAO distance measurement from imaging data to date, and is competitive with the latest transverse ones from spectroscopic samples at z>0.75. When combined with DES 3x2pt+SNIa, they lead to improvements in H0 and Ωm constraints by ∼20%.
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