The MiniBooNE experiment at Fermilab reports results from an analysis of ν_{e} appearance data from 12.84×10^{20} protons on target in neutrino mode, an increase of approximately a factor of 2 over ...previously reported results. A ν_{e} charged-current quasielastic event excess of 381.2±85.2 events (4.5σ) is observed in the energy range 200<E_{ν}^{QE}<1250 MeV. Combining these data with the νover ¯_{e} appearance data from 11.27×10^{20} protons on target in antineutrino mode, a total ν_{e} plus νover ¯_{e} charged-current quasielastic event excess of 460.5±99.0 events (4.7σ) is observed. If interpreted in a two-neutrino oscillation model, ν_{μ}→ν_{e}, the best oscillation fit to the excess has a probability of 21.1%, while the background-only fit has a χ^{2} probability of 6×10^{-7} relative to the best fit. The MiniBooNE data are consistent in energy and magnitude with the excess of events reported by the Liquid Scintillator Neutrino Detector (LSND), and the significance of the combined LSND and MiniBooNE excesses is 6.0σ. A two-neutrino oscillation interpretation of the data would require at least four neutrino types and indicate physics beyond the three neutrino paradigm. Although the data are fit with a two-neutrino oscillation model, other models may provide better fits to the data.
Objectives To assess whether the age of onset was associated with unique features or disease course in pediatric acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). Study design ...Demographic and clinical information on children with ARP or CP was collected at INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE) centers. The Cochran-Armitage trend test and Jonckheere-Terpstra test were used to examine for differences between pediatric age groups (<6, 6-11, and ≥12 years). Results Between September 2012 and March 2016, 342 children with ARP or CP were enrolled; 129 (38%) were <6 years of age at the time of first diagnosis of acute pancreatitis, 111 (32%) were 6-11 years of age, and 102 (30%) were ≥12 years of age. Early-onset disease was associated with mutations in cationic trypsinogen ( PRSS1 ) ( P < .01), chymotrypsin C ( CTRC ) ( P = .01), family history of acute pancreatitis ( P = .02), family history of CP ( P < .01), biliary cysts ( P = .04), or chronic renal failure ( P = .02). Later-onset disease was more commonly present with hypertriglyceridemia ( P = .04), ulcerative colitis ( P = .02), autoimmune diseases ( P < .0001), or medication use ( P < .01). Children with later-onset disease also were more likely to visit the emergency department ( P < .05) or have diabetes ( P < .01). Conclusions Early-onset pancreatitis is associated strongly with PRSS1 or CTRC mutations and family history of pancreatitis. Children with later-onset disease are more likely to have nongenetic risk factors. Future studies are needed to investigate whether the disease course, response to therapy, or clinical outcomes differ relative to the timing of disease onset.
Abstract Objectives The aims of this study were to: 1) use a novel method of late gadolinium enhancement (LGE) quantification that uses normalized intensity measures to confirm the association ...between LGE extent and atrial fibrillation (AF) recurrence following ablation; and 2) examine the presence of interaction and effect modification between LGE and AF persistence. Background Recurrent AF after catheter ablation has been reported to associate with the baseline extent of left atrial LGE on cardiac magnetic resonance. Traditional methods for measurement of intensity lack an objective threshold for quantification and interpatient comparisons of LGE. Methods The cohort included 165 participants (mean age 60.0 ± 10.2 years, 77% men, 57% with persistent AF) who underwent initial AF ablation. The association of baseline LGE extent with AF recurrence was examined using multivariable Cox proportional hazards models. Multiplicative and additive interactions between AF type and LGE extent were examined. Results During 10.2 ± 5.7 months of follow-up, 63 patients (38.2%) experienced AF recurrence. Baseline LGE extent was independently associated with AF recurrence after adjusting for confounders (hazard ratio: 1.5 per 10% increased LGE; p < 0.001). The hazard ratio for AF recurrence progressively increased as a function of LGE. The magnitude of association between LGE >35% and AF recurrence was greater among patients with persistent AF (hazard ratio: 6.5 p = 0.001 vs. 3.6 p = 0.001); however, there was no evidence for statistical interaction. Conclusions Regardless of AF persistence at baseline, participants with LGE ≤35% have favorable outcomes, whereas those with LGE >35% have a higher rate of AF recurrence in the first year after ablation. These findings suggest a role for: 1) patient selection for AF ablation using LGE extent; and 2) substrate modification in addition to pulmonary vein isolation in patients with LGE extent exceeding 35% of left atrial myocardium.
SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression and replication that depend on the structure and dynamics of its constituent proteins. Many protein structures ...have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate 0.1 seconds of the viral proteome. Our adaptive sampling simulations predict dramatic opening of the apo spike complex, far beyond that seen experimentally, explaining and predicting the existence of 'cryptic' epitopes. Different spike variants modulate the probabilities of open versus closed structures, balancing receptor binding and immune evasion. We also discover dramatic conformational changes across the proteome, which reveal over 50 'cryptic' pockets that expand targeting options for the design of antivirals. All data and models are freely available online, providing a quantitative structural atlas.
Cells from the same individual share common genetic and environmental backgrounds and are not statistically independent; therefore, they are subsamples or pseudoreplicates. Thus, single-cell data ...have a hierarchical structure that many current single-cell methods do not address, leading to biased inference, highly inflated type 1 error rates, and reduced robustness and reproducibility. This includes methods that use a batch effect correction for individual as a means of accounting for within-sample correlation. Here, we document this dependence across a range of cell types and show that pseudo-bulk aggregation methods are conservative and underpowered relative to mixed models. To compute differential expression within a specific cell type across treatment groups, we propose applying generalized linear mixed models with a random effect for individual, to properly account for both zero inflation and the correlation structure among measures from cells within an individual. Finally, we provide power estimates across a range of experimental conditions to assist researchers in designing appropriately powered studies.
Atrial fibrillation (AF) is an important cause of stroke. Given the morbidity and mortality associated with stroke, the risk stratification of patients based on left atrial appendage (LAA) ...characteristics is of great interest.
To explore the association between LAA morphology and LAA characteristics including the extent of trabeculations, orifice diameter, and length with prevalent stroke in a large cohort of patients with drug refractory AF who underwent AF ablation to develop mechanistic insight regarding the risk of stroke.
An institutional cohort of 1063 patients referred for AF ablation from 2003 to 2012 was reviewed to identify patients that underwent preprocedural cardiac computed tomography (CT). LAA morphology was characterized as chicken wing, cactus, windsock, or cauliflower by using previously reported methodology. Left atrial size and LAA trabeculations, morphology, orifice diameter, and length were compared between patients with prevalent stroke and patients without prevalent stroke.
Of 678 patients with CT images, 65 (10%) had prior stroke or transient ischemic attack. In univariate analyses, prevalent heart failure (7.7% in cases vs 2.8% in controls; P = .033), smaller LAA orifice (2.26 ± 0.52 cm vs 2.78 ± 0.71 cm ; P < .001), shorter LAA length (5.06 ± 1.17 cm vs 5.61 ± 1.17 cm; P < .001), and extensive LAA trabeculations (27.7% vs 14.4%; P = .019) were associated with stroke. LAA morphologies were unassociated with stroke risk. In multivariable analysis, smaller LAA orifice diameter and extensive LAA trabeculations remained independently associated with thromboembolic events.
The extent of LAA trabeculations and smaller LAA orifice diameter are associated with prevalent stroke and may mediate the previously described association of cauliflower LAA morphology with stroke.
The measurement of late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) intensity in arbitrary units limits the objectivity of thresholds for focal scar detection and interpatient ...comparisons of scar burden.
To develop and validate a normalized measure, the image intensity ratio (IIR), for the assessment of left atrial (LA) scar on LGE-MRI.
Electrocardiogram- and respiratory-gated 1.5 Tesla LGE-MRI was performed in 75 patients (75% men; 62 ± 8 years) before atrial fibrillation ablation. The local IIR was defined as LA myocardial signal intensity for each of the 20 sectors on contiguous axial image planes divided by the mean LA blood pool image intensity. Intracardiac point-by-point sampled electroanatomic map points were coregistered with the corresponding image sectors.
The average bipolar voltage for all 8153 electroanatomic map points was 0.9 ± 1.1 mV. In a mixed effects model accounting for within patient clustering, and adjusting for age, LA volume, mass, body mass index, sex, CHA2DS2-VASc score, atrial fibrillation type, history of previous ablations, and contrast delay time, each unit increase in local IIR was associated with 91.3% decrease in bipolar LA voltage (P < .001). Local IIR thresholds of >0.97 and >1.61 corresponded to bipolar voltage <0.5 and <0.1 mV, respectively.
Normalization of LGE-MRI intensity by the mean blood pool intensity results in a metric that is closely associated with intracardiac voltage as a surrogate of atrial fibrosis.
This paper asks whether elite colleges help students outside of historically advantaged groups reach top positions in the economy. I combine administrative data on income and leadership teams at ...publicly traded firms with a regression discontinuity design based on admissions rules at elite business-focused degree programs in Chile. The 1.8 percent of college students admitted to these programs account for 41 percent of leadership positions and 39 percent of top 0.1 percent incomes. Admission raises the number of leadership positions students hold by 44 percent and their probability of attaining a top 0.1 percent income by 51 percent. However, these gains are driven by male applicants from high-tuition private high schools, with zero effects for female students or students from other school types with similar admissions test scores. Admissions effects are equal to 38 percent of the gap in rates of top attainment by gender and 54 percent of the gap by high school background for male students. A difference-in-differences analysis of the rates at which pairs of students lead the same firms suggests that peer ties formed between college classmates from similar backgrounds may play an important role in driving the observed effects.
Summary Background Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival ...compared with the three commonest conventional care regimens. Methods In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m2 per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French–American–British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov , number NCT00071799. Findings Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21·1 months (IQR 15·1–26·9), median overall survival was 24·5 months (9·9–not reached) for the azacitidine group versus 15·0 months (5·6–24·1) for the conventional care group (hazard ratio 0·58; 95% CI 0·43–0·77; stratified log-rank p=0·0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50·8% (95% CI 42·1–58·8) of patients in the azacitidine group were alive compared with 26·2% (18·7–34·3) in the conventional care group (p<0·0001). Peripheral cytopenias were the most common grade 3–4 adverse events for all treatments. Interpretation Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care. Funding Celgene Corporation.
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