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.
The MiniBooNE-DM Collaboration searched for vector-boson mediated production of dark matter using the Fermilab 8-GeV Booster proton beam in a dedicated run with 1.86×10^{20} protons delivered to a ...steel beam dump. The MiniBooNE detector, 490 m downstream, is sensitive to dark matter via elastic scattering with nucleons in the detector mineral oil. Analysis methods developed for previous MiniBooNE scattering results were employed, and several constraining data sets were simultaneously analyzed to minimize systematic errors from neutrino flux and interaction rates. No excess of events over background was observed, leading to a 90% confidence limit on the dark matter cross section parameter, Y=ε^{2}α_{D}(m_{χ}/m_{V})^{4}≲10^{-8}, for α_{D}=0.5 and for dark matter masses of 0.01<m_{χ}<0.3 GeV in a vector portal model of dark matter. This is the best limit from a dedicated proton beam dump search in this mass and coupling range and extends below the mass range of direct dark matter searches. These results demonstrate a novel and powerful approach to dark matter searches with beam dump experiments.
Homologous recombination repair deficiency (HRD) is a frequent feature of high-grade serous ovarian, fallopian tube and peritoneal carcinoma (HGSC) and is associated with sensitivity to PARP ...inhibitor (PARPi) therapy. HRD testing provides an opportunity to optimise PARPi use in HGSC but methodologies are diverse and clinical application remains controversial.
To define best practice for HRD testing in HGSC the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project that incorporated a systematic review approach. The main aims were to (i) define the term ‘HRD test’; (ii) provide an overview of the biological rationale and the level of evidence supporting currently available HRD tests; (iii) provide recommendations on the clinical utility of HRD tests in clinical management of HGSC.
A broad range of repair genes, genomic scars, mutational signatures and functional assays are associated with a history of HRD. Currently, the clinical validity of HRD tests in ovarian cancer is best assessed, not in terms of biological HRD status per se, but in terms of PARPi benefit. Clinical trials evidence supports the use of BRCA mutation testing and two commercially available assays that also incorporate genomic instability for identifying subgroups of HGSCs that derive different magnitudes of benefit from PARPi therapy, albeit with some variation by clinical scenario. These tests can be used to inform treatment selection and scheduling but their use is limited by a failure to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies. Existing tests lack negative predictive value and inadequately address the complex and dynamic nature of the HRD phenotype.
Currently available HRD tests are useful for predicting likely magnitude of benefit from PARPis but better biomarkers are urgently needed to better identify current homologous recombination proficiency status and stratify HGSC management.
•Homologous recombination repair deficiency (HRD) is a common feature of high-grade serous gynaecological cancers (HGSC).•Currently, the clinical validity of HRD tests in ovarian cancer is best assessed in terms of PARPi benefit.•Germline and somatic BRCA mutation and genomic instability tests help to predict likely magnitude of benefit from a PARPi.•Existing HRD tests fail to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies.•HRD is a dynamic entity and better biomarkers that capture current homologous recombination proficiency status are needed.
We report the first measurement of coherent elastic neutrino-nucleus scattering (CEvNS) on argon using a liquid argon detector at the Oak Ridge National Laboratory Spallation Neutron Source. Two ...independent analyses prefer CEvNS over the background-only null hypothesis with greater than 3σ significance. The measured cross section, averaged over the incident neutrino flux, is (2.2±0.7)×10^{-39} cm^{2}-consistent with the standard model prediction. The neutron-number dependence of this result, together with that from our previous measurement on CsI, confirms the existence of the CEvNS process and provides improved constraints on nonstandard neutrino interactions.
In recurrent ovarian cancer, poly(ADP-ribose) polymerase (PARP)-inhibiting agents have transformed the treatment of platinum-sensitive disease. New data support use of PARP inhibitors earlier in the ...treatment algorithm.
We review results from recent phase III trials evaluating PARP inhibitors as treatment and/or maintenance therapy for patients with newly diagnosed ovarian cancer. We discuss the efficacy and safety of these agents in the all-comer and biomarker-selected populations studied in clinical trials, and compare the strengths and limitations of the various trial designs. We also consider priorities for future research, with a particular focus on patient selection and future regimens for populations with high unmet need.
Four phase III trials (SOLO-1, PAOLA-1/ENGOT-OV25, PRIMA/ENGOT-OV26 and VELIA/GOG-3005) demonstrated remarkable improvements in progression-free survival with PARP inhibitor therapy (olaparib, niraparib or veliparib) for newly diagnosed ovarian cancer. Differences in trial design (treatment and/or maintenance setting; single agent or combination; bevacizumab or no bevacizumab), patient selection (surgical outcome, biomarker eligibility, prognosis) and primary analysis population (intention-to-treat, BRCA mutated or homologous recombination deficiency positive) affect the conclusions that can be drawn from these trials. Overall survival data are pending and there is limited experience regarding long-term safety.
PARP inhibitors play a pivotal role in the management of newly diagnosed ovarian cancer, which will affect subsequent treatment choices. Refinement of testing for patient selection and identification of regimens to treat populations that appear to benefit less from PARP inhibitors are a priority.
•In four phase III trials in ovarian cancer, front-line PARP inhibition significantly improved progression-free survival.•Differences in trial design, patient selection and primary analysis population influence interpretation of these trials.•PARP inhibitors play a pivotal role in managing newly diagnosed ovarian cancer, affecting subsequent treatment choices.•Priorities include refining testing and identifying therapies for patients benefiting less from PARP inhibition.
Areas and layers of the cerebral cortex are specified by genetic programs that are initiated in progenitor cells and then, implemented in postmitotic neurons. Here, we report that Tbr1, a ...transcription factor expressed in postmitotic projection neurons, exerts positive and negative control over both regional (areal) and laminar identity. Tbr1 null mice exhibited profound defects of frontal cortex and layer 6 differentiation, as indicated by down-regulation of gene-expression markers such as Bcl6 and Cdh9. Conversely, genes that implement caudal cortex and layer 5 identity, such as Bhlhb5 and Fezf2, were up-regulated in Tbr1 mutants. Tbr1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism. Tbr1 regulates laminar identity in part by downstream activation or maintenance of Sox5, an important transcription factor controlling neuronal migration and corticofugal axon projections. Similar to Sox5 mutants, Tbr1 mutants exhibit ectopic axon projections to the hypothalamus and cerebral peduncle. Together, our findings show that Tbr1 coordinately regulates regional and laminar identity of postmitotic cortical neurons.
Childhood mortality remains high in sub-Saharan Africa. In this cluster-randomized, placebo-controlled trial, mortality among children younger than 5 years of age was lower among those who received ...azithromycin than among those who received placebo.
This paper describes the operation of the Coherent CAPTAIN-Mills (CCM) detector located at the Los Alamos Neutron Science Center at Los Alamos National Laboratory. CCM is a 10-ton liquid argon ...detector located 20 meters from a high flux neutron/neutrino source and is designed to search for sterile neutrinos (νs’s) and light dark matter (LDM). An engineering run was performed in fall 2019 to study the characteristics of the CCM120 detector by searching for coherent scattering signals consistent with νs’s and LDM resulting from the production and decays of π+ and π0 in the tungsten target. New parameter space in a leptophobic dark matter (DM) model was excluded for DM masses between ~2.0 and 30 MeV. The lessons learned from this run have guided the development and construction of the new CCM200 detector that will begin operations in 2021 and significantly improve on these searches.
This book is an introduction to the model-based approach to survey sampling. It consists of three parts, with Part I focusing on estimation of population totals. Chapters 1 and 2 introduce survey ...sampling, and the model-based approach, respectively. Chapter 3 considers the simplest possible model, the homogenous population model, which is then extended to stratified populations in Chapter 4. Chapter 5 discusses simple linear regression models for populations, and Chapter 6 considers clustered populations. The general linear population model is then used to integrate these results in Chapter 7. Part II of this book considers the properties of estimators based on incorrectly specified models. Chapter 8 develops robust sample designs that lead to unbiased predictors under model misspecification, and shows how flexible modelling methods like non-parametric regression can be used in survey sampling. Chapter 9 extends this development to misspecfication robust prediction variance
estimators and Chapter 10 completes Part II of the book with an exploration of outlier robust sample survey estimation. Chapters 11 to 17 constitute Part III of the book and show how model-based methods can be used in a variety of problem areas of modern survey sampling. They cover (in order) prediction of non-linear population quantities, sub-sampling approaches to prediction variance estimation, design and estimation for multipurpose surveys, prediction for domains, small area estimation, efficient prediction of population distribution functions and the use of transformations in survey inference. The book is designed to be accessible to undergraduate and graduate level students with a good grounding in statistics and applied survey statisticians seeking an introduction to model-based survey design and estimation.
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