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Imperfections in analog-to-digital conversion (ADC) cannot be ignored when signal digitization requirements demand both wide dynamic range and high resolution, as is the case for the Majorana Demonstrator 76Ge neutrinoless double-beta decay search. Enabling the experiment’s high-resolution spectral analysis and efficient pulse shape discrimination required careful measurement and correction of ADC nonlinearities. A simple measurement protocol was developed that did not require sophisticated equipment or lengthy data-taking campaigns. A slope-dependent hysteresis was observed and characterized. A correction applied to digitized waveforms prior to signal processing reduced the differential and integral nonlinearities by an order of magnitude, eliminating these as dominant contributions to the systematic energy uncertainty at the double-beta decay $Q$ value.

Background: As technology evolves, so does the integration of technology into health care delivery. Telemedicine, the use of information technology to provide remote health care, aims to i...

OBJECTIVES To measure the burden of delirium in older adults with or without Alzheimer disease or related disorders (ADRDs). DESIGN Prospective, observational cohort. SETTING Inpatient hospital and study participants' homes. PARTICIPANTS A subset (n = 267) of older medical and surgical patients and their caregivers enrolled in the Better Assessment of Illness study. MEASUREMENTS Delirium burden was measured using the DEL-B instrument (range = 0-40, with higher scores indicating greater burden) in caregivers (DEL-B-C) and patients 1 month after hospitalization. Severity of cognitive impairment (Montreal Cognitive Assessment [MoCA]), delirium presence (Confusion Assessment Method [CAM]), and delirium severity (CAM-Severity [CAM-S]) were measured during hospitalization and at 1-month follow-up. ADRD diagnosis was determined by a clinical consensus process. RESULTS For patients with (n = 56) and without (n = 211) ADRD, both DEL-B instruments had good internal consistency. DEL-B-C scores had a median (interquartile range) among caregivers of patients with and without ADRD of 9 (5-15) and 5 (1-11), respectively (P

Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is NewBackgroundPostoperative delirium and postoperative cognitive dysfunction share risk factors and may co-occur, but their relationship is not well established. The primary goals of this study were to describe the prevalence of postoperative cognitive dysfunction and to investigate its association with in-hospital delirium. The authors hypothesized that delirium would be a significant risk factor for postoperative cognitive dysfunction during follow-up.MethodsThis study used data from an observational study of cognitive outcomes after major noncardiac surgery, the Successful Aging after Elective Surgery study. Postoperative delirium was evaluated each hospital day with confusion assessment method–based interviews supplemented by chart reviews. Postoperative cognitive dysfunction was determined using methods adapted from the International Study of Postoperative Cognitive Dysfunction. Associations between delirium and postoperative cognitive dysfunction were examined at 1, 2, and 6 months.ResultsOne hundred thirty-four of 560 participants (24%) developed delirium during hospitalization. Slightly fewer than half (47%, 256 of 548) met the International Study of Postoperative Cognitive Dysfunction-defined threshold for postoperative cognitive dysfunction at 1 month, but this proportion decreased at 2 months (23%, 123 of 536) and 6 months (16%, 85 of 528). At each follow-up, the level of agreement between delirium and postoperative cognitive dysfunction was poor (kappa less than .08) and correlations were small (r less than .16). The relative risk of postoperative cognitive dysfunction was significantly elevated for patients with a history of postoperative delirium at 1 month (relative risk = 1.34; 95% CI, 1.07–1.67), but not 2 months (relative risk = 1.08; 95% CI, 0.72–1.64), or 6 months (relative risk = 1.21; 95% CI, 0.71–2.09).ConclusionsDelirium significantly increased the risk of postoperative cognitive dysfunction in the first postoperative month; this relationship did not hold in longer-term follow-up. At each evaluation, postoperative cognitive dysfunction was more common among patients without delirium. Postoperative delirium and postoperative cognitive dysfunction may be distinct manifestations of perioperative neurocognitive deficits.

Author(s): Arnquist, IJ; Avignone, FT; Barabash, AS; Barton, CJ; Bertrand, FE; Blalock, E; Bos, B; Busch, M; Buuck, M; Caldwell, TS; Chan, YD; Christofferson, CD; Chu, PH; Clark, ML; Cuesta, C; Detwiler, JA; Drobizhev, A; Edwards, TR; Edwins, DW; Efremenko, Y; Ejiri, H; Elliott, SR; Gilliss, T; Giovanetti, GK; Green, MP; Gruszko, J; Guinn, IS; Guiseppe, VE; Haufe, CR; Henning, R; Hervas Aguilar, D; Hoppe, EW; Hostiuc, A; Kidd, MF; Kim, I; Kouzes, RT; Lopez, AM; Lopez-Castano, JM; Martin, EL; Martin, RD; Massarczyk, R; Meijer, SJ; Mertens, S; Myslik, J; Oli, TK; Othman, G; Paudel, LS; Pettus, W; Poon, AWP; Radford, DC; Reine, AL; Rielage, K; Ruof, NW; Saykl, B; Stortini, MJ; Tedeschi, D; Varner, RL; Vasilyev, S; Wilkerson, JF; Wiseman, C; Xu, W; Yu, CH; Zhu, BX | Abstract: The majorana demonstrator is a neutrinoless double-β decay search consisting of a low-background modular array of high-purity germanium detectors, ∼2/3 of which are enriched to 88% in Ge76. The experiment is also searching for double-beta decay of Ge76 to excited states (e.s.) in Se76. Ge76 can decay into three daughter states of Se76, with clear event signatures consisting of a ββ-decay followed by the prompt emission of one or two γ rays. This results with high probability in multi-detector coincidences. The granularity of the demonstrator detector array enables powerful discrimination of this event signature from backgrounds. Using 41.9 kg yr of isotopic exposure, the demonstrator has set world leading limits for each e.s. decay of Ge76, with 90% CL lower half-life limits in the range of (0.75-4.0)×1024 yr. In particular, for the 2ν transition to the first 0+ e.s. of Se76, a lower half-life limit of 7.5×1023 yr at 90% CL was achieved.

Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.

Charges are incompatible with the hydrophobic interior of proteins, yet proteins use buried charges, often in pairs or networks, to drive energy transduction processes, catalysis, pH-sensing, and ion transport. The structural adaptations necessary to accommodate interacting charges in the protein interior are not well understood. According to continuum electrostatic calculations, the Coulomb interaction between two buried charges cannot offset the highly unfavorable penalty of dehydrating two charges. This was investigated experimentally with two variants of staphylococcal nuclease (SNase) with Glu:Lys or Lys:Glu pairs introduce at internal i, i+4 positions on an α-helix. Contrary to expectations from previous theoretical and experimental studies, the proteins tolerated the charged ion pairs in both orientations. Crystal structures and NMR spectroscopy studies showed that in both variants, side chains or backbone are reorganized. This leads to the exposure of at least one of the two buried groups to water. Comparison of these ion pairs with a highly stable buried ion pair in SNase shows that the location and the amplitude of structural reorganization can vary dramatically between ion pairs buried in the same general region of the protein. The propensity of the protein to populate alternative conformation states in which internal charges can contact water appears to be the factor that governs the magnitude of electrostatic effects in hydrophobic environments. The net effect of structural reorganization is to weaken the Coulomb interactions between charge pairs; however, the reorganized protein no longer has to pay the energetic penalty for burying charges. These results provide the framework necessary to understand the interplay between the dehydration of charges, Coulomb interactions and protein reorganization that tunes the functional properties of proteins.

The MAJORANA DEMONSTRATOR is an experiment constructed to search for neutrinoless double-beta decays in germanium-76 and to demonstrate the feasibility to deploy a ton-scale experiment in a phased and modular fashion. It consists of two modular arrays of natural and $^{76}\textrm{Ge}$-enriched germanium detectors totaling 44.1 kg (29.7 kg enriched detectors), located at the 4850' level of the Sanford Underground Research Facility in Lead, South Dakota, USA. Data taken with this setup since summer 2015 at different construction stages of the experiment show a clear reduction of the observed background index around the ROI for $0\nu\beta\beta$-decay search due to improvements in shielding. We discuss the statistical approaches to search for a $0\nu\beta\beta$-signal and derive the physics sensitivity for an expected exposure of $10\,\textrm{kg}{\cdot}\textrm{y}$ from enriched detectors using a profile likelihood based hypothesis test in combination with toy Monte Carlo data., Comment: 5 page, 2 figures, to appear in Proceedings of TAUP 2017 - XV International Conference on Topics in Astroparticle and Underground Physics, 24 - 28 July 2017, Sudbury, ON, Canada

The MAJORANA DEMONSTRATOR is an experiment constructed to search for neutrinoless double-beta decays in germanium-76 and to demonstrate the feasibility to deploy a large-scale experiment in a phased and modular fashion. It consists of two modular arrays of natural and $^{76}$Ge-enriched germanium detectors totalling 44.1 kg, located at the 4850' level of the Sanford Underground Research Facility in Lead, South Dakota, USA. Any neutrinoless double-beta decay search requires a thorough understanding of the background and the signal energy spectra. The various techniques employed to ensure the integrity of the measured spectra are discussed. Data collection is monitored with a thorough set of checks, and subsequent careful analysis is performed to qualify the data for higher level physics analysis. Instrumental background events are tagged for removal, and problematic channels are removed from consideration as necessary., Comment: 5 pages, 2 figures, Proceedings of TAUP 2017 - XV International Conference on Topics in Astroparticle and Underground Physics (Sudbury ON, Canada, July 24-28, 2017)

Neutrinoless double-beta decay searches seek to determine the nature of neutrinos, the existence of a lepton violating process, and the effective Majorana neutrino mass. The {\sc Majorana} Collaboration is assembling an array of high purity Ge detectors to search for neutrinoless double-beta decay in $^{76}$Ge. The {\sc Majorana Demonstrator} is composed of 44.8~kg (29.7 kg enriched in $^{76}$Ge) of Ge detectors in total, split between two modules contained in a low background shield at the Sanford Underground Research Facility in Lead, South Dakota. The initial goals of the {\sc Demonstrator} are to establish the required background and scalability of a Ge-based, next-generation, tonne-scale experiment. Following a commissioning run that began in 2015, the first detector module started physics data production in early 2016. We will discuss initial results of the Module 1 commissioning and first physics run, as well as the status and potential physics reach of the full {\sc Majorana Demonstrator} experiment. The collaboration plans to complete the assembly of the second detector module by mid-2016 to begin full data production with the entire array., Neutrino 2016 proceeding

This paper presents recent Lower Hybrid Current Drive (LHCD) progress in SWIP, including the experiments on HL-2A and system development on HL-2M. The 3.7GHz LHCD system was built on HL-2A, where the first Lower Hybrid Wave (LHW) coupling to H-mode plasma experiment via Passive-Active Multijunction (PAM) launcher was carried out. The coupled power has been increased much from 470kW to 1400kW since 2014. The LHW power became more and more important in the H-mode discharges on HL-2A in the past 4 years. In 2018, 1.1s ELMy H-mode was achieved with the help of Neutral Beam Injection (NBI) and LHW injection. However, The LHCD experiments showed distinct characteristic on HL-2A, i.e. no full non-inductive current drive (loop voltage never dropped below 0.3V) and counter-current drive effect found in the situation of co-current drive spectrum. Full non-inductive current drive was finally obtained after the spectrum turned opposite. Besides those achievements, the abnormal LHCD phenomenon discussion, full non-inductive current drive experiments, co-current and counter-current comparison, LHW deposition and mechanism of LHCD ELM mitigation are described. At the same time, a 4MW LHCD system is planned to be constructed on HL-2M. A 2MW LHCD system has been developed for HL-2M tokamak until now. Four TH2103C1 klystrons, transmission lines and a 4MW FAM antenna are included in this system. The other part will be built soon.

Background Extraskeletal osteosarcoma is an extremely rare disease, comprising less than 0.1% of all cancers diagnosed in the United States, of which less than 5% occur in the upper extremities. The management of two cases of pediatric upper extremity extraskeletal osteosarcoma is discussed. Case description Two children initially noticed painless left upper extremity masses at the ages of 16 and 13, respectively. Following a period of several months, both lesions became symptomatic, necessitating operative intervention, which revealed giant cell-rich extraskeletal osteosarcoma; PET staging following gross total resection revealed no residual or metastatic disease in either patient. After extensive discussion with the patients and family, adjuvant chemotherapy was initiated for one patient, and adjuvant radiation therapy was initiated in both patients. Conclusions Despite the rarity of these tumors, the importance of radiation therapy has been established by current and ongoing studies such as the Children's Oncology Group study ARST0332. Radiation therapy remains an important component of the multimodality therapy comprising optimal treatment of this disease, despite the relative paucity of long-term outcome data derived from level I evidence.