Comparison of an IgG-Specific Enzyme-Linked Immunosorbent Assay Cutoff of 0.4 Versus 0.8 and 1.0 Optical Density Units for Heparin-Induced Thrombocytopenia.

PubMed

Ritchie, Brianne M; Connors, Jean M; Sylvester, Katelyn W

2017-04-01

Previous studies have demonstrated optimized diagnostic accuracy in utilizing higher antiheparin-platelet factor 4 (PF4) enzyme-linked immunosorbent assay (ELISA) optical density (OD) thresholds for diagnosing heparin-induced thrombocytopenia (HIT). We describe the incidence of positive serotonin release assay (SRA) results, as well as performance characteristics, for antiheparin-PF4 ELISA thresholds ≥0.4, ≥0.8, and ≥1.0 OD units in the diagnosis of HIT at our institution. Following institutional review board approval, we conducted a single-center retrospective chart review on adult inpatients with a differential diagnosis of HIT evaluated by both antiheparin-PF4 ELISA and SRA from 2012 to 2014. The major endpoints were to assess incidence of positive SRA results, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy at antiheparin-PF4 ELISA values ≥0.4 OD units when compared to values ≥0.8 and ≥1.0 OD units. Clinical characteristics, including demographics, laboratory values, clinical and safety outcomes, length of stay, and mortality, were collected. A total of 140 patients with 140 antiheparin-PF4 ELISA and SRA values were evaluated, of which 23 patients were SRA positive (16.4%) and 117 patients were SRA negative (83.6%). We identified a sensitivity of 91.3% versus 82.6% and 73.9%, specificity of 61.5% versus 87.2% and 91.5%, PPV of 31.8% versus 55.9% and 63.0%, NPV of 97.3% versus 96.2% and 94.7%, and accuracy of 66.4% versus 86.4% and 88.6% at antiheparin-PF4 ELISA thresholds ≥0.4, ≥0.8, and ≥1.0 OD units, respectively. Our study suggests an increased antiheparin-PF4 ELISA threshold of 0.8 or 1.0 OD units enhances specificity, PPV, and accuracy while maintaining NPV with decreased sensitivity.

High sensitivity and specificity of a new functional flow cytometry assay for clinically significant heparin-induced thrombocytopenia antibodies.

PubMed

Garritsen, H S; Probst-Kepper, M; Legath, N; Eberl, W; Samaniego, S; Woudenberg, J; Schuitemaker, J H N; Kroll, H; Gurney, D A; Moore, G W; Zehnder, J L

2014-04-01

Heparin-induced thrombocytopenia (HIT) is a life-threatening condition, in which the anticoagulant heparin, platelet factor 4 (PF4), and platelet-activating antibodies form complexes with prothrombotic properties. Laboratory tests to support clinical diagnosis are subdivided into functional, platelet activation assays, which lack standardization, or immunological assays, which have moderate specificity toward HIT. In this study, clinical performance of HITAlert, a novel in vitro diagnostic (IVD) registered platelet activation assay, was tested in a large cohort of HIT-suspected patients and compared with immunological assays. From 346 HIT-suspected patients (single center), clinical data including 4T pretest probability results, citrated platelet-poor plasmas, and sera were collected, allowing direct comparison of clinical observations with HITAlert results. HITAlert performance was compared with PF4 IgG ELISA (246 patients, three centers) and PF4 PaGIA (298 patients, single center). HITAlert showed high sensitivity (88.2%) and specificity (99.1%) when compared with clinical diagnosis. Agreement of HITAlert with PF4 ELISA- and PF4 PaGIA-positive patients is low (52.7 and 23.2%, respectively), while agreement with PF4 IgG ELISA- and PF4 PaGIA-negative patients is very high (98.1 and 99.1%, respectively). HITAlert performance is excellent when compared with clinical HIT diagnosis, making it a suitable assay for rapid testing of platelet activation due to anticoagulant therapy. © 2013 John Wiley & Sons Ltd.

Maximizing the sensitivity and reliability of peptide identification in large-scale proteomic experiments by harnessing multiple search engines.

PubMed

Yu, Wen; Taylor, J Alex; Davis, Michael T; Bonilla, Leo E; Lee, Kimberly A; Auger, Paul L; Farnsworth, Chris C; Welcher, Andrew A; Patterson, Scott D

2010-03-01

Despite recent advances in qualitative proteomics, the automatic identification of peptides with optimal sensitivity and accuracy remains a difficult goal. To address this deficiency, a novel algorithm, Multiple Search Engines, Normalization and Consensus is described. The method employs six search engines and a re-scoring engine to search MS/MS spectra against protein and decoy sequences. After the peptide hits from each engine are normalized to error rates estimated from the decoy hits, peptide assignments are then deduced using a minimum consensus model. These assignments are produced in a series of progressively relaxed false-discovery rates, thus enabling a comprehensive interpretation of the data set. Additionally, the estimated false-discovery rate was found to have good concordance with the observed false-positive rate calculated from known identities. Benchmarking against standard proteins data sets (ISBv1, sPRG2006) and their published analysis, demonstrated that the Multiple Search Engines, Normalization and Consensus algorithm consistently achieved significantly higher sensitivity in peptide identifications, which led to increased or more robust protein identifications in all data sets compared with prior methods. The sensitivity and the false-positive rate of peptide identification exhibit an inverse-proportional and linear relationship with the number of participating search engines.

Acute vestibular syndrome: clinical head impulse test versus video head impulse test.

PubMed

Celebisoy, Nese

2018-03-05

HINTS battery involving head impulse test (HIT), nystagmus, and test of skew is the critical bedside examination to differentiate acute unilateral peripheral vestibulopathy from posterior circulation stroke (PCS) in acute vestibular syndrome (AVS). The highest sensitivity component of the battery has been reported to be the horizontal HIT, whereas skew deviation is defined as the most specific but non-sensitive sign for PCS. Video-oculography-based HIT (vHIT) may have an additional power in making the differentiation. If vHIT is undertaken, then both gain and gain asymmetry should be taken into account as anterior inferior cerebellar artery (AICA) strokes are at risk of being misclassified based on VOR gain alone. Further refinement in video technology, increased operator proficiency and incorporation with saccade analysis will increase the sensitivity of vHIT for PCS diagnosis. For the time being, clinical examination seems adequate in frontline diagnostic evaluation of AVS.

Comparative performance of aldolase and lactate dehydrogenase rapid diagnostic tests in Plasmodium vivax detection

PubMed Central

2014-01-01

Background Misdiagnosis of malaria by commercial rapid diagnostic tests (RDTs) is a major cause of concern in the diagnosis of malaria. This retrospective study was aimed at assessing the relative performance of four RDTs with emphasis on the detection of two Plasmodium vivax antigens: aldolase and lactate dehydrogenase (LDH). Methods Three commercially available Plasmodium LDH or aldolase antigen detection kits (One Step Malaria P.f/P.v, ParaHit Total ver. 1.0, SD Bioline Malaria) and an anti-P. vivax aldolase-specific monoclonal antibody (mAb) pair 1C3-12 F10 were evaluated with P. vivax positive as well as non-P. vivax samples and healthy samples using blood smear examination as standard. Each test was read according to the manufacturer’s instructions. Results MAb 1C3-12 F10 pair targeting P. vivax-specific aldolase exhibited very good specificity and sensitivity of 100 and 97.4%, respectively. Positive predictive value (PPV) and negative predictive value (NPV) of 100 and 99.5%, respectively, were also observed. The anti-P. vivax LDH in the One-Step Malaria P.f/P.v test showed sensitivity, specificity, PPV and NPV of 93.5, 98.0, 88.9 and 98.8%, respectively. ParaHit Total ver. 1.0 targeting the pan-aldolase antigen showed sensitivity, specificity of 97.4 and 99.6%, respectively. PPV and NPV were both 99.5%. SD Bioline had sensitivity, specificity, PPV and NPV of 93.5, 100, 100 and 98.8%, respectively. The overall sensitivity and specificity of all four RDTs were acceptable, especially for the aldolase detection tests. Five (6.5%) of the P. vivax-positive samples (n = 77) that were confirmed by microscopic examination as well as the two aldolase detection RDTs (mAb 1C3-12 F10 and ParaHit Total ver.1.0) were undetected by the two LDH detection RDTs (One Step Malaria P.f/P.v and SD Bioline). Similarly, two positive samples (2.6%) that were positively confirmed by the LDH detection RDTs were also undetected by the aldolase detection test kits. Conclusion Aldolase and LDH antigens perform differently in different P. vivax samples; hence there is a high risk of misdiagnosis when monoclonal antibodies are used against only one particular antigen in the test. A combination of both aldolase and LDH in RDTs for the rapid diagnosis of P. vivax will enhance the sensitivity of the assay and reduce misdiagnosis. PMID:25015737

Motif discovery and motif finding from genome-mapped DNase footprint data.

PubMed

Kulakovskiy, Ivan V; Favorov, Alexander V; Makeev, Vsevolod J

2009-09-15

Footprint data is an important source of information on transcription factor recognition motifs. However, a footprinting fragment can contain no sequences similar to known protein recognition sites. Inspection of genome fragments nearby can help to identify missing site positions. Genome fragments containing footprints were supplied to a pipeline that constructed a position weight matrix (PWM) for different motif lengths and selected the optimal PWM. Fragments were aligned with the SeSiMCMC sampler and a new heuristic algorithm, Bigfoot. Footprints with missing hits were found for approximately 50% of factors. Adding only 2 bp on both sides of a footprinting fragment recovered most hits. We automatically constructed motifs for 41 Drosophila factors. New motifs can recognize footprints with a greater sensitivity at the same false positive rate than existing models. Also we discuss possible overfitting of constructed motifs. Software and the collection of regulatory motifs are freely available at http://line.imb.ac.ru/DMMPMM.

Rapid immunoassays for diagnosis of heparin-induced thrombocytopenia: Comparison of diagnostic accuracy, reproducibility, and costs in clinical practice

PubMed Central

Bankova, Andriyana; Andres, Yvonne; Horn, Michael P.; Alberio, Lorenzo

2017-01-01

Background Immunoassays are crucial in the work-up of patients with suspected heparin-induced thrombocytopenia (HIT) and rapid tests have been recently developed. However, comparative data on diagnostic accuracy, reproducibility, and analytical costs of different immunoassays in clinical practice are limited. Methods Samples of 179 consecutive patients evaluated for suspected HIT in clinical practice using a polyspecific enzyme-linked immunoabsorbent assay (GTI diagnostics; ELISA) and a rapid particle gel immunoassay (PaGIA), were additionally analysed with a IgG-specific chemiluminescent immunoassay (AcuStar HIT-IgG). Presence of HIT was defined as a positive functional heparin-induced platelet aggregation test. Diagnostic accuracy was determined for low, intermediate and high thresholds as previously established (ELISA: optical density 0.4, 1.3, and 2.0 respectively; PaGIA: positive/negative, titre of 4, titre of 32; AcuStar HIT-IgG: 1.0 U/ml, 2.8, 9.4) and reproducibility was assessed by repeated measurements. Costs of test determination were calculated taking reagents, controls, and working time of technicians according to Swiss health care system into account. Results Data on PaGIA results were available for 171 patients (95.5%), ELISA for 144 patients (80.4%), and AcuStar HIT-IgG for 179 patients (100%). Sensitivity was above 95% for all assays at low and intermediate thresholds. Specificity increased with higher thresholds and was above 90% for all assays with intermediate and high thresholds. Specificity of AcuStar HIT-IgG (92.8%; 95% CI 87.7, 96.2) was significantly higher than PaGIA (83.0%; 95% CI 76.3, 88.5) and higher than ELISA (81.8%, 95% CI 74.2, 88.0) at low threshold (p<0.05). Reproducibility was adequate for all assays. Total costs per test were CHF 51.02 for ELISA, 117.70 for AcuStar HIT-IgG, and 83.13 for PaGIA. Conclusions We observed favourable diagnostic accuracy measures and a high reproducibility for PaGIA and AcuStar HIT-IgG. Implementation into 24-hours-service might improve patient care but the results must be confirmed in other settings and larger populations as well. PMID:28594835

Capacitively coupled hybrid pixel assemblies for the CLIC vertex detector

NASA Astrophysics Data System (ADS)

Tehrani, N. Alipour; Arfaoui, S.; Benoit, M.; Dannheim, D.; Dette, K.; Hynds, D.; Kulis, S.; Perić, I.; Petrič, M.; Redford, S.; Sicking, E.; Valerio, P.

2016-07-01

The vertex detector at the proposed CLIC multi-TeV linear e+e- collider must have minimal material content and high spatial resolution, combined with accurate time-stamping to cope with the expected high rate of beam-induced backgrounds. One of the options being considered is the use of active sensors implemented in a commercial high-voltage CMOS process, capacitively coupled to hybrid pixel ASICs. A prototype of such an assembly, using two custom designed chips (CCPDv3 as active sensor glued to a CLICpix readout chip), has been characterised both in the lab and in beam tests at the CERN SPS using 120 GeV/c positively charged hadrons. Results of these characterisation studies are presented both for single and dual amplification stages in the active sensor, where efficiencies of greater than 99% have been achieved at -60 V substrate bias, with a single hit resolution of 6.1 μm . Pixel cross-coupling results are also presented, showing the sensitivity to placement precision and planarity of the glue layer.

A prototype scintillating fibre beam profile monitor for Ion Therapy beams

NASA Astrophysics Data System (ADS)

Leverington, B. D.; Dziewiecki, M.; Renner, L.; Runze, R.

2018-05-01

A prototype plastic scintillating fibre based beam profile monitor was tested at the Heidelberg Ion Therapy Centre/Heidelberg Ionenstrahl Therapiezentrum (HIT) in 2016 to determine its beam property reconstruction performance and the feasibility of further developing an expanded system. At HIT protons, helium, carbon, and oxygen ions are available for therapy and experiments. The beam can be scanned in two dimensions using fast deflection magnets. A tracking system is used to monitor beam position and to adjust scanning magnet currents online. A new detector system with a finer granularity and without the drift time delay of the current MWPC system with a similar amount of material along the beamline would prove valuable in patient treatment. The sensitive detector components in the tested prototype detector are double-clad Kuraray SCSF-78MJ scintillating fibres with a diameter of 0.250 mm wound as a thin multi-layer ribbon. The scintillation light is detected at the end of the ribbon with Hamamatsu S11865-64 photodiode arrays with a pitch of 0.8 mm. Commercial or readily available readout electronics have been used to evaluate the system feasibility. The results shown in this paper include the linearity with respect to beam intensity, the RMS of the beam intensity as measured by two planes, along with the RMS of the mean position, and the measured beam width RMS. The Signal-to-Noise ratio of the current system is also measured as an indicator of potential performance. Additionally, the non-linear light yield of the scintillating fibres as measured by the photodiode arrays is compared to two models which describe the light yield as a function of the ion stopping power and Lorentz β.

Low-Volume High-Intensity Interval Training in a Gym Setting Improves Cardio-Metabolic and Psychological Health.

PubMed

Shepherd, Sam O; Wilson, Oliver J; Taylor, Alexandra S; Thøgersen-Ntoumani, Cecilie; Adlan, Ahmed M; Wagenmakers, Anton J M; Shaw, Christopher S

2015-01-01

Within a controlled laboratory environment, high-intensity interval training (HIT) elicits similar cardiovascular and metabolic benefits as traditional moderate-intensity continuous training (MICT). It is currently unclear how HIT can be applied effectively in a real-world environment. To investigate the hypothesis that 10 weeks of HIT, performed in an instructor-led, group-based gym setting, elicits improvements in aerobic capacity (VO2max), cardio-metabolic risk and psychological health which are comparable to MICT. Ninety physically inactive volunteers (42±11 y, 27.7±4.8 kg.m-2) were randomly assigned to HIT or MICT group exercise classes. HIT consisted of repeated sprints (15-60 seconds, >90% HRmax) interspersed with periods of recovery cycling (≤25 min.session-1, 3 sessions.week-1). MICT participants performed continuous cycling (~70% HRmax, 30-45 min.session-1, 5 sessions.week-1). VO2max, markers of cardio-metabolic risk, and psychological health were assessed pre and post-intervention. Mean weekly training time was 55±10 (HIT) and 128±44 min (MICT) (p<0.05), with greater adherence to HIT (83±14% vs. 61±15% prescribed sessions attended, respectively; p<0.05). HIT improved VO2max, insulin sensitivity, reduced abdominal fat mass, and induced favourable changes in blood lipids (p<0.05). HIT also induced beneficial effects on health perceptions, positive and negative affect, and subjective vitality (p<0.05). No difference between HIT and MICT was seen for any of these variables. HIT performed in a real-world gym setting improves cardio-metabolic risk factors and psychological health in physically inactive adults. With a reduced time commitment and greater adherence than MICT, HIT offers a viable and effective exercise strategy to target the growing incidence of metabolic disease and psychological ill-being associated with physical inactivity.

Low-Volume High-Intensity Interval Training in a Gym Setting Improves Cardio-Metabolic and Psychological Health

PubMed Central

Shepherd, Sam O.; Wilson, Oliver J.; Taylor, Alexandra S.; Thøgersen-Ntoumani, Cecilie; Adlan, Ahmed M.; Wagenmakers, Anton J. M.; Shaw, Christopher S.

2015-01-01

Background Within a controlled laboratory environment, high-intensity interval training (HIT) elicits similar cardiovascular and metabolic benefits as traditional moderate-intensity continuous training (MICT). It is currently unclear how HIT can be applied effectively in a real-world environment. Purpose To investigate the hypothesis that 10 weeks of HIT, performed in an instructor-led, group-based gym setting, elicits improvements in aerobic capacity (VO2max), cardio-metabolic risk and psychological health which are comparable to MICT. Methods Ninety physically inactive volunteers (42±11 y, 27.7±4.8 kg.m-2) were randomly assigned to HIT or MICT group exercise classes. HIT consisted of repeated sprints (15–60 seconds, >90% HRmax) interspersed with periods of recovery cycling (≤25 min.session-1, 3 sessions.week-1). MICT participants performed continuous cycling (~70% HRmax, 30–45 min.session-1, 5 sessions.week-1). VO2max, markers of cardio-metabolic risk, and psychological health were assessed pre and post-intervention. Results Mean weekly training time was 55±10 (HIT) and 128±44 min (MICT) (p<0.05), with greater adherence to HIT (83±14% vs. 61±15% prescribed sessions attended, respectively; p<0.05). HIT improved VO2max, insulin sensitivity, reduced abdominal fat mass, and induced favourable changes in blood lipids (p<0.05). HIT also induced beneficial effects on health perceptions, positive and negative affect, and subjective vitality (p<0.05). No difference between HIT and MICT was seen for any of these variables. Conclusions HIT performed in a real-world gym setting improves cardio-metabolic risk factors and psychological health in physically inactive adults. With a reduced time commitment and greater adherence than MICT, HIT offers a viable and effective exercise strategy to target the growing incidence of metabolic disease and psychological ill-being associated with physical inactivity. PMID:26402859

Breast mass detection in tomosynthesis projection images using information-theoretic similarity measures

NASA Astrophysics Data System (ADS)

Singh, Swatee; Tourassi, Georgia D.; Lo, Joseph Y.

2007-03-01

The purpose of this project is to study Computer Aided Detection (CADe) of breast masses for digital tomosynthesis. It is believed that tomosynthesis will show improvement over conventional mammography in detection and characterization of breast masses by removing overlapping dense fibroglandular tissue. This study used the 60 human subject cases collected as part of on-going clinical trials at Duke University. Raw projections images were used to identify suspicious regions in the algorithm's high-sensitivity, low-specificity stage using a Difference of Gaussian (DoG) filter. The filtered images were thresholded to yield initial CADe hits that were then shifted and added to yield a 3D distribution of suspicious regions. These were further summed in the depth direction to yield a flattened probability map of suspicious hits for ease of scoring. To reduce false positives, we developed an algorithm based on information theory where similarity metrics were calculated using knowledge databases consisting of tomosynthesis regions of interest (ROIs) obtained from projection images. We evaluated 5 similarity metrics to test the false positive reduction performance of our algorithm, specifically joint entropy, mutual information, Jensen difference divergence, symmetric Kullback-Liebler divergence, and conditional entropy. The best performance was achieved using the joint entropy similarity metric, resulting in ROC A z of 0.87 +/- 0.01. As a whole, the CADe system can detect breast masses in this data set with 79% sensitivity and 6.8 false positives per scan. In comparison, the original radiologists performed with only 65% sensitivity when using mammography alone, and 91% sensitivity when using tomosynthesis alone.

Process-to-Panel Modeling and Multiprobe Characterization of Silicon Heterojunction Solar Cell Technology

NASA Astrophysics Data System (ADS)

Chavali, Raghu Vamsi Krishna

The large-scale deployment of PV technology is very sensitive to the material and process costs. There are several potential candidates among p-n heterojunction (HJ) solar cells competing for higher efficiencies at lower material and process costs. These systems are, however, generally complex, involve diverse materials, and are not well understood. The direct translation of classical p-n homojunction theory to p-n HJ cells may not always be self-consistent and can lead, therefore, to misinterpretation of experimental results. Ultimately, this translation may not be useful for modeling and characterization of these solar cells. Hence, there is a strong need to redefine/reinterpret the modeling/characterization methodologies for HJ solar cells to produce a self-consistent framework for optimizing HJ solar cell designs. Towards this goal, we explore the physics and interpret characterization experiments of p-n HJs using Silicon HJ (HIT) solar cells. We will: (1) identify the key HJ properties that affect the cell efficiency; (2) analyze the dependence of key HJ properties on the carrier transport under light and dark conditions; (3) provide a selfconsistent multi-probe approach to extract the HJ parameters using several characterization techniques including dark I-V, light I-V, C-V, impedance spectroscopy, and Suns-Voc; (4) propose design guidelines to address the HJ bottlenecks of HIT cells; and (5) develop a process-to-module modeling framework to establish the module performance limits. The guidelines resulting from this multi-scale and self-consistent framework can be used to improve performance of HIT cells as well as other HJ based solar cells.

Coincidence electron/ion imaging with a fast frame camera

NASA Astrophysics Data System (ADS)

Li, Wen; Lee, Suk Kyoung; Lin, Yun Fei; Lingenfelter, Steven; Winney, Alexander; Fan, Lin

2015-05-01

A new time- and position- sensitive particle detection system based on a fast frame CMOS camera is developed for coincidence electron/ion imaging. The system is composed of three major components: a conventional microchannel plate (MCP)/phosphor screen electron/ion imager, a fast frame CMOS camera and a high-speed digitizer. The system collects the positional information of ions/electrons from a fast frame camera through real-time centroiding while the arrival times are obtained from the timing signal of MCPs processed by a high-speed digitizer. Multi-hit capability is achieved by correlating the intensity of electron/ion spots on each camera frame with the peak heights on the corresponding time-of-flight spectrum. Efficient computer algorithms are developed to process camera frames and digitizer traces in real-time at 1 kHz laser repetition rate. We demonstrate the capability of this system by detecting a momentum-matched co-fragments pair (methyl and iodine cations) produced from strong field dissociative double ionization of methyl iodide. We further show that a time resolution of 30 ps can be achieved when measuring electron TOF spectrum and this enables the new system to achieve a good energy resolution along the TOF axis.

Interspecialty communication supported by health information technology associated with lower hospitalization rates for ambulatory care-sensitive conditions.

PubMed

O'Malley, Ann S; Reschovsky, James D; Saiontz-Martinez, Cynthia

2015-01-01

Practice tools such as health information technology (HIT) have the potential to support care processes, such as communication between health care providers, and influence care for "ambulatory care-sensitive conditions" (ACSCs). ACSCs are conditions for which good outpatient care can potentially prevent the need for hospitalization. To date, associations between such primary care practice capabilities and hospitalizations for ambulatory care-sensitive conditions have been primarily limited to smaller, local studies or unique delivery systems rather than nationally representative studies of primary care physicians in the United States. We analyzed a nationally representative sample of 1,819 primary care physicians who responded to the Center for Studying Health System Change's Physician Survey. We linked 3 years of Medicare claims (2007 to 2009) with these primary care physician survey respondents. This linkage resulted in the identification of 123,760 beneficiaries with one or more of 4 ambulatory care-sensitive chronic conditions (diabetes, chronic obstructive pulmonary disease, asthma, and congestive heart failure) for whom these physicians served as the usual provider. Key independent variables of interest were physicians' practice capabilities, including communication with specialists, use of care managers, participation in quality and performance measurement, use of patient registries, and HIT use. The dependent variable was a summary measure of ambulatory care-sensitive hospitalizations for one or more of these 4 conditions. Higher provider-reported levels of communication between primary care and specialist physicians were associated with lower rates of potentially avoidable hospitalizations. While there was no significant main effect between HIT use and ACSC hospitalizations, the associations between interspecialty communication and ACSC hospitalizations were magnified in the presence of higher HIT use. For example, patients in practices with both the highest level of interspecialty communication and the highest level of HIT use had lower odds of ambulatory care-sensitive hospitalizations than did those in practices with lower interspecialty communication and high HIT use (adjusted odds ratio, 0.70; 95% confidence limits, 0.59, 0.82). Greater primary care and specialist communication is associated with reduced hospitalizations for ambulatory care-sensitive conditions. This effect was magnified in the presence of higher provider-reported HIT use, suggesting that coordination of care with support from HIT is important in the treatment of ambulatory care-sensitive conditions. © Copyright 2015 by the American Board of Family Medicine.

Fragment-Based Whole Cell Screen Delivers Hits against M. tuberculosis and Non-tuberculous Mycobacteria.

PubMed

Moreira, Wilfried; Lim, Jia Jie; Yeo, Si Ying; Ramanujulu, Pondy M; Dymock, Brian W; Dick, Thomas

2016-01-01

Reactive multi-target 'fragment drugs' represent critical components of current tuberculosis regimens. These compounds, such as pyrazinamide, are old synthetic antimycobacterials that are activated inside Mycobacterium tuberculosis bacilli and are smaller than the usual drug-like, single-target molecules. Based on the success of small 'dirty' drugs in the chemotherapy of tuberculosis, we suggested previously that fragment-based whole cell screens should be introduced in our current antimycobacterial drug discovery efforts. Here, we carried out such a screen and characterized bactericidal activity, selectivity and spectrum of hits we obtained. A library of 1725 fragments was tested at a single concentration for growth inhibitory activity against M. bovis BCG as screening strain and 38 of 116 primary hits were confirmed in dose response analyses to be active against virulent M. tuberculosis. Bacterial kill experiments showed that most hits displayed bactericidal activity at their minimal inhibitory concentration. Cytotoxicity assays established that a large proportion of hits displayed a favorable selectivity index for mammalian cells. Importantly, one third of M. tuberculosis active fragments were also active against M. abscessus and M. avium, two emerging non-tuberculous mycobacterial (NTM) pathogens, opening the opportunity to develop broad spectrum antimycobacterials. Activity determination against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa) bacteria, as well as fungi (Candida albicans, Cryptococcus neoformans) showed only a small overlap indicating a generally narrow spectrum of these novel antimicrobial hits for mycobacteria. In conclusion, we carried out the first fragment-based whole cell screen against bacteria and identified a substantial number of hits with excellent physicochemical properties and dual activity against M. tuberculosis and NTM pathogens. These hits will now be evaluated in animal models of mycobacterial infection to determine whether any of them can be moved forward as a new antimycobacterial fragment drug candidate.

Communications Patterns in a Symbolic Multiprocessor.

DTIC Science & Technology

1987-06-01

instruction references that Multilisp programs make. The cache hit ratio is greatest when instruction references have a high degree of -- locality. Another...future touches hit an undetermined future. N, The only exception is Consim, in which one third of future touches hit unde- termined futures. Task...Cambridge, MA, June 1985. [52] S. Sugimoto, K. Agusa, K. Tabata , and Y. Ohno. A multi-microprocessor system for concurrent Lisp. In Proceedings of

Formulation of the Multi-Hit Model With a Non-Poisson Distribution of Hits

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vassiliev, Oleg N., E-mail: Oleg.Vassiliev@albertahealthservices.ca

2012-07-15

Purpose: We proposed a formulation of the multi-hit single-target model in which the Poisson distribution of hits was replaced by a combination of two distributions: one for the number of particles entering the target and one for the number of hits a particle entering the target produces. Such an approach reflects the fact that radiation damage is a result of two different random processes: particle emission by a radiation source and interaction of particles with matter inside the target. Methods and Materials: Poisson distribution is well justified for the first of the two processes. The second distribution depends on howmore » a hit is defined. To test our approach, we assumed that the second distribution was also a Poisson distribution. The two distributions combined resulted in a non-Poisson distribution. We tested the proposed model by comparing it with previously reported data for DNA single- and double-strand breaks induced by protons and electrons, for survival of a range of cell lines, and variation of the initial slopes of survival curves with radiation quality for heavy-ion beams. Results: Analysis of cell survival equations for this new model showed that they had realistic properties overall, such as the initial and high-dose slopes of survival curves, the shoulder, and relative biological effectiveness (RBE) In most cases tested, a better fit of survival curves was achieved with the new model than with the linear-quadratic model. The results also suggested that the proposed approach may extend the multi-hit model beyond its traditional role in analysis of survival curves to predicting effects of radiation quality and analysis of DNA strand breaks. Conclusions: Our model, although conceptually simple, performed well in all tests. The model was able to consistently fit data for both cell survival and DNA single- and double-strand breaks. It correctly predicted the dependence of radiation effects on parameters of radiation quality.« less

Evaluation of flow cytometric HIT assays in relation to an IgG-Specific immunoassay and clinical outcome.

PubMed

Kerényi, Adrienne; Beke Debreceni, Ildikó; Oláh, Zsolt; Ilonczai, Péter; Bereczky, Zsuzsanna; Nagy, Béla; Muszbek, László; Kappelmayer, János

2017-09-01

Heparin-induced thrombocytopenia (HIT) is a severe side effect of heparin treatment caused by platelet activating IgG antibodies generated against the platelet factor 4 (PF4)-heparin complex. Thrombocytopenia and thrombosis are the leading clinical symptoms of HIT. The clinical pretest probability of HIT was evaluated by the 4T score system. Laboratory testing of HIT was performed by immunological detection of antibodies against PF4-heparin complex (EIA) and two functional assays. Heparin-dependent activation of donor platelets by patient plasma was detected by flow cytometry. Increased binding of Annexin-V to platelets and elevated number of platelet-derived microparticles (PMP) were the indicators of platelet activation. EIA for IgG isotype HIT antibodies was performed in 405 suspected HIT patients. Based on negative EIA results, HIT was excluded in 365 (90%) of cases. In 40 patients with positive EIA test result functional tests were performed. Platelet activating antibodies were detected in 17 cases by Annexin V binding. PMP count analysis provided nearly identical results. The probability of a positive flow cytometric assay result was higher in patients with elevated antibody titer. 71% of patients with positive EIA and functional assay had thrombosis. EIA is an important first line laboratory test in the diagnosis of HIT; however, HIT must be confirmed by a functional test. Annexin V binding and PMP assays using flow cytometry are functional HIT tests convenient in a clinical diagnostic laboratory. The positive results of functional assays may predict the onset of thrombosis. © 2016 International Clinical Cytometry Society. © 2016 International Clinical Cytometry Society.

The prognosis of MYC translocation positive diffuse large B-cell lymphoma depends on the second hit.

PubMed

Clipson, Alexandra; Barrans, Sharon; Zeng, Naiyan; Crouch, Simon; Grigoropoulos, Nicholas F; Liu, Hongxiang; Kocialkowski, Sylvia; Wang, Ming; Huang, Yuanxue; Worrillow, Lisa; Goodlad, John; Buxton, Jenny; Neat, Michael; Fields, Paul; Wilkins, Bridget; Grant, John W; Wright, Penny; Ei-Daly, Hesham; Follows, George A; Roman, Eve; Watkins, A James; Johnson, Peter W M; Jack, Andrew; Du, Ming-Qing

2015-07-01

A proportion of MYC translocation positive diffuse large B-cell lymphomas (DLBCL) harbour a BCL2 and/or BCL6 translocation, known as double-hit DLBCL, and are clinically aggressive. It is unknown whether there are other genetic abnormalities that cooperate with MYC translocation and form double-hit DLBCL, and whether there is a difference in clinical outcome between the double-hit DLBCL and those with an isolated MYC translocation. We investigated TP53 gene mutations along with BCL2 and BCL6 translocations in a total of 234 cases of DLBCL, including 81 with MYC translocation. TP53 mutations were investigated by PCR and sequencing, while BCL2 and BCL6 translocation was studied by interphase fluorescence in situ hybridization. The majority of MYC translocation positive DLBCLs (60/81 = 74%) had at least one additional genetic hit. In MYC translocation positive DLBCL treated by R-CHOP ( n  = 67), TP53 mutation and BCL2, but not BCL6 translocation had an adverse effect on patient overall survival. In comparison with DLBCL with an isolated MYC translocation, cases with MYC/TP53 double-hits had the worst overall survival, followed by those with MYC/BCL2 double-hits. In MYC translocation negative DLBCL treated by R-CHOP ( n  = 101), TP53 mutation, BCL2 and BCL6 translocation had no impact on patient survival. The prognosis of MYC translocation positive DLBCL critically depends on the second hit, with TP53 mutations and BCL2 translocation contributing to an adverse prognosis. It is pivotal to investigate both TP53 mutations and BCL2 translocations in MYC translocation positive DLBCL, and to distinguish double-hit DLBCLs from those with an isolated MYC translocation.

Impact of normalization methods on high-throughput screening data with high hit rates and drug testing with dose-response data.

PubMed

Mpindi, John-Patrick; Swapnil, Potdar; Dmitrii, Bychkov; Jani, Saarela; Saeed, Khalid; Wennerberg, Krister; Aittokallio, Tero; Östling, Päivi; Kallioniemi, Olli

2015-12-01

Most data analysis tools for high-throughput screening (HTS) seek to uncover interesting hits for further analysis. They typically assume a low hit rate per plate. Hit rates can be dramatically higher in secondary screening, RNAi screening and in drug sensitivity testing using biologically active drugs. In particular, drug sensitivity testing on primary cells is often based on dose-response experiments, which pose a more stringent requirement for data quality and for intra- and inter-plate variation. Here, we compared common plate normalization and noise-reduction methods, including the B-score and the Loess a local polynomial fit method under high hit-rate scenarios of drug sensitivity testing. We generated simulated 384-well plate HTS datasets, each with 71 plates having a range of 20 (5%) to 160 (42%) hits per plate, with controls placed either at the edge of the plates or in a scattered configuration. We identified 20% (77/384) as the critical hit-rate after which the normalizations started to perform poorly. Results from real drug testing experiments supported this estimation. In particular, the B-score resulted in incorrect normalization of high hit-rate plates, leading to poor data quality, which could be attributed to its dependency on the median polish algorithm. We conclude that a combination of a scattered layout of controls per plate and normalization using a polynomial least squares fit method, such as Loess helps to reduce column, row and edge effects in HTS experiments with high hit-rates and is optimal for generating accurate dose-response curves. john.mpindi@helsinki.fi. Supplementary information: R code and Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press.

PF4/heparin-antibody complex induces monocyte tissue factor expression and release of tissue factor positive microparticles by activation of FcγRI

PubMed Central

Glover, Sam L.; Jonas, William; McEachron, Troy; Pawlinski, Rafal; Arepally, Gowthami M.; Key, Nigel S.; Mackman, Nigel

2012-01-01

Heparin-induced thrombocytopenia (HIT) is a potentially devastating form of drug-induced thrombocytopenia that occurs in patients receiving heparin for prevention or treatment of thrombosis. Patients with HIT develop autoantibodies to the platelet factor 4 (PF4)/heparin complex, which is termed the HIT Ab complex. Despite a decrease in the platelet count, the most feared complication of HIT is thrombosis. The mechanism of thrombosis in HIT remains poorly understood. We investigated the effects of the HIT Ab complex on tissue factor (TF) expression and release of TF-positive microparticles in peripheral blood mononuclear cells and monocytes. To model these effects ex vivo, we used a murine mAb specific for the PF4/heparin complex (KKO), as well as plasma from patients with HIT. We found that the HIT Ab complex induced TF expression in monocytes and the release of TF-positive microparticles. Further, we found that induction of TF is mediated via engagement of the FcγRI receptor and activation of the MEK1-ERK1/2 signaling pathway. Our data suggest that monocyte TF may contribute to the development of thrombosis in patients with HIT. PMID:22394597

A novel method for the line-of-response and time-of-flight reconstruction in TOF-PET detectors based on a library of synchronized model signals

NASA Astrophysics Data System (ADS)

Moskal, P.; Zoń, N.; Bednarski, T.; Białas, P.; Czerwiński, E.; Gajos, A.; Kamińska, D.; Kapłon, Ł.; Kochanowski, A.; Korcyl, G.; Kowal, J.; Kowalski, P.; Kozik, T.; Krzemień, W.; Kubicz, E.; Niedźwiecki, Sz.; Pałka, M.; Raczyński, L.; Rudy, Z.; Rundel, O.; Salabura, P.; Sharma, N. G.; Silarski, M.; Słomski, A.; Smyrski, J.; Strzelecki, A.; Wieczorek, A.; Wiślicki, W.; Zieliński, M.

2015-03-01

A novel method of hit time and hit position reconstruction in scintillator detectors is described. The method is based on comparison of detector signals with results stored in a library of synchronized model signals registered for a set of well-defined positions of scintillation points. The hit position is reconstructed as the one corresponding to the signal from the library which is most similar to the measurement signal. The time of the interaction is determined as a relative time between the measured signal and the most similar one in the library. A degree of similarity of measured and model signals is defined as the distance between points representing the measurement- and model-signal in the multi-dimensional measurement space. Novelty of the method lies also in the proposed way of synchronization of model signals enabling direct determination of the difference between time-of-flights (TOF) of annihilation quanta from the annihilation point to the detectors. The introduced method was validated using experimental data obtained by means of the double strip prototype of the J-PET detector and 22Na sodium isotope as a source of annihilation gamma quanta. The detector was built out from plastic scintillator strips with dimensions of 5 mm×19 mm×300 mm, optically connected at both sides to photomultipliers, from which signals were sampled by means of the Serial Data Analyzer. Using the introduced method, the spatial and TOF resolution of about 1.3 cm (σ) and 125 ps (σ) were established, respectively.

Multi-Point Thomson Scattering Diagnostic for the Helicity Injected Torus

NASA Astrophysics Data System (ADS)

Liptac, J. E.; Smith, R. J.; Hoffman, C. S.; Jarboe, T. R.; Nelson, B. A.; Leblanc, B. P.; Phillips, P.

1999-11-01

The multi-point Thomson scattering system on the Helicity Injected Torus--II can determine electron temperature and density at 11 radial positions at a single time during the plasma discharge. The system includes components on loan from both PPPL and from the University of Texas. The collection optics and Littrow spectrometer from Princeton, and the 1 GW laser and multi-anode microchannel plate detector from Texas have been integrated into a compact structure, creating a mobile and reliable diagnostic. The mobility of the system allows alignment to occur in a room adjacent to the experiment, greatly reducing the disturbance to normal machine operation. The four main parts of the Thomson scattering system, namely, the laser, the beam line, the collection optics, and the mobile structure are presented and discussed.

First Plasma Results from the HIT-SI Spheromak

NASA Astrophysics Data System (ADS)

Sieck, P. E.; Hamp, W. T.; Izzo, V. A.; Jarboe, T. R.; Nelson, B. A.; O'Neill, R. G.; Redd, A. J.; Smith, R. J.

2003-10-01

HIT-SI is the newest device in the Helicity Injected Torus (HIT) program. HIT-SI is a ``bow tie'' spheromak formed and sustained by Steady Inductive Helicity Injection (SIHI) current drive. SIHI injects helicity at a nearly constant rate with no open field lines intersecting the boundary. (T. R. Jarboe, Fusion Technology 36) (1), p. 85, 1999 HIT-SI has been designed with a bow tie geometry to achieve stable high-β (>10%) spheromak equilibria. (U. Shumlak and T. R. Jarboe, Phys. Plasmas 7) (7), p. 2959, 2000 Diagnostics currently include surface magnetic probes and flux loops, visible light imaging, H-alpha line radiation monitors, voltage measurements across insulating breaks, injector current Rogowski coils, and injector flux loops. HIT-SI is currently operating in parallel with experiments on HIT-II. At the conclusion of HIT-II operations, HIT-SI will inherit a multi-point Thomson Scattering system, a scanning two-chord FIR interferometer, and other advanced diagnostics, as well as more power supplies to extend the discharge duration. Results are presented which characterize injector operation and possible evidence for spheromak formation.

Position and volume estimation of atmospheric nuclear detonations from video reconstruction

NASA Astrophysics Data System (ADS)

Schmitt, Daniel T.

Recent work in digitizing films of foundational atmospheric nuclear detonations from the 1950s provides an opportunity to perform deeper analysis on these historical tests. This work leverages multi-view geometry and computer vision techniques to provide an automated means to perform three-dimensional analysis of the blasts for several points in time. The accomplishment of this requires careful alignment of the films in time, detection of features in the images, matching of features, and multi-view reconstruction. Sub-explosion features can be detected with a 67% hit rate and 22% false alarm rate. Hotspot features can be detected with a 71.95% hit rate, 86.03% precision and a 0.015% false positive rate. Detected hotspots are matched across 57-109 degree viewpoints with 76.63% average correct matching by defining their location relative to the center of the explosion, rotating them to the alternative viewpoint, and matching them collectively. When 3D reconstruction is applied to the hotspot matching it completes an automated process that has been used to create 168 3D point clouds with 31.6 points per reconstruction with each point having an accuracy of 0.62 meters with 0.35, 0.24, and 0.34 meters of accuracy in the x-, y- and z-direction respectively. As a demonstration of using the point clouds for analysis, volumes are estimated and shown to be consistent with radius-based models and in some cases improve on the level of uncertainty in the yield calculation.

Improved human visuomotor performance and pupil constriction after choline supplementation in a placebo-controlled double-blind study.

PubMed

Naber, Marnix; Hommel, Bernhard; Colzato, Lorenza S

2015-08-14

Only few nutrients are known to enhance cognition. Here we explore whether visuomotor performance can be improved through the intake of the nutrient choline, an essential chemical compound in a vertebrate's diet. Choline is abundant in for example eggs and shrimps and many animal studies suggest that it serves as a cognitive enhancer. As choline is important for the communication between motor neurons and the control of skeletal muscles, we assumed that choline supplementation may have positive effects on action coordination in humans. A group of twenty-eight individuals ingested two grams of choline bitartrate or a placebo in two separate sessions. Seventy minutes post ingestion, participants performed a visuomotor aiming task in which they had to rapidly hit the centers of targets. Results showed that participants hit targets more centrally after choline supplementation. Pupil size (a cognition-sensitive biomarker) also significantly decreased after choline intake and correlated positively with the hit distance to the targets and the number of target misses, and negatively with reaction times. These findings point to a choline-induced bias towards action precision in the trade-off between speed and accuracy. The changes in pupil size suggest that choline uptake alters cholinergic functions in the nervous system.

Two-colored fluorescence correlation spectroscopy screening for LC3-P62 interaction inhibitors.

PubMed

Tsuganezawa, Keiko; Shinohara, Yoshiyasu; Ogawa, Naoko; Tsuboi, Shun; Okada, Norihisa; Mori, Masumi; Yokoyama, Shigeyuki; Noda, Nobuo N; Inagaki, Fuyuhiko; Ohsumi, Yoshinori; Tanaka, Akiko

2013-10-01

The fluorescence correlation spectroscopy (FCS)-based competitive binding assay to screen for protein-protein interaction inhibitors is a highly sensitive method as compared with the fluorescent polarization assay used conventionally. However, the FCS assay identifies many false-positive compounds, which requires specifically designed orthogonal screenings. A two-colored application of the FCS-based screening was newly developed, and inhibitors of a protein-protein interaction, involving selective autophagy, were selected. We focused on the interaction of LC3 with the adaptor protein p62, because the interaction is crucial to degrade the specific target proteins recruited by p62. First, about 10,000 compounds were subjected to the FCS-based competitive assay using a TAMRA-labeled p62-derived probe, and 29 hit compounds were selected. Next, the obtained hits were evaluated by the second FCS assay, using an Alexa647-labeled p62-derived probe to remove the false-positive compounds, and six hit compounds inhibited the interaction. Finally, we tested all 29 compounds by surface plasmon resonance-based competitive binding assay to evaluate their inhibition of the LC3-p62 interaction and selected two inhibitors with IC50 values less than 2 µM. The two-colored FCS-based screening was shown to be effective to screen for protein-protein interaction inhibitors.

Improved human visuomotor performance and pupil constriction after choline supplementation in a placebo-controlled double-blind study

PubMed Central

Naber, Marnix; Hommel, Bernhard; Colzato, Lorenza S.

2015-01-01

Only few nutrients are known to enhance cognition. Here we explore whether visuomotor performance can be improved through the intake of the nutrient choline, an essential chemical compound in a vertebrate’s diet. Choline is abundant in for example eggs and shrimps and many animal studies suggest that it serves as a cognitive enhancer. As choline is important for the communication between motor neurons and the control of skeletal muscles, we assumed that choline supplementation may have positive effects on action coordination in humans. A group of twenty-eight individuals ingested two grams of choline bitartrate or a placebo in two separate sessions. Seventy minutes post ingestion, participants performed a visuomotor aiming task in which they had to rapidly hit the centers of targets. Results showed that participants hit targets more centrally after choline supplementation. Pupil size (a cognition-sensitive biomarker) also significantly decreased after choline intake and correlated positively with the hit distance to the targets and the number of target misses, and negatively with reaction times. These findings point to a choline-induced bias towards action precision in the trade-off between speed and accuracy. The changes in pupil size suggest that choline uptake alters cholinergic functions in the nervous system. PMID:26271904

Biological characterization of adult MYC-translocation-positive mature B-cell lymphomas other than molecular Burkitt lymphoma.

PubMed

Aukema, Sietse M; Kreuz, Markus; Kohler, Christian W; Rosolowski, Maciej; Hasenclever, Dirk; Hummel, Michael; Küppers, Ralf; Lenze, Dido; Ott, German; Pott, Christiane; Richter, Julia; Rosenwald, Andreas; Szczepanowski, Monika; Schwaenen, Carsten; Stein, Harald; Trautmann, Heiko; Wessendorf, Swen; Trümper, Lorenz; Loeffler, Markus; Spang, Rainer; Kluin, Philip M; Klapper, Wolfram; Siebert, Reiner

2014-04-01

Chromosomal translocations affecting the MYC oncogene are the biological hallmark of Burkitt lymphomas but also occur in a subset of other mature B-cell lymphomas. If accompanied by a chromosomal break targeting the BCL2 and/or BCL6 oncogene these MYC translocation-positive (MYC(+)) lymphomas are called double-hit lymphomas, otherwise the term single-hit lymphomas is applied. In order to characterize the biological features of these MYC(+) lymphomas other than Burkitt lymphoma we explored, after exclusion of molecular Burkitt lymphoma as defined by gene expression profiling, the molecular, pathological and clinical aspects of 80 MYC-translocation-positive lymphomas (31 single-hit, 46 double-hit and 3 MYC(+)-lymphomas with unknown BCL6 status). Comparison of single-hit and double-hit lymphomas revealed no difference in MYC partner (IG/non-IG), genomic complexity, MYC expression or gene expression profile. Double-hit lymphomas more frequently showed a germinal center B-cell-like gene expression profile and had higher IGH and MYC mutation frequencies. Gene expression profiling revealed 130 differentially expressed genes between BCL6(+)/MYC(+) and BCL2(+)/MYC(+) double-hit lymphomas. BCL2(+)/MYC(+) double-hit lymphomas more frequently showed a germinal center B-like gene expression profile. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In this series of lymphomas, in which immunochemotherapy was administered in only a minority of cases, single-hit and double-hit lymphomas had a similar poor outcome in contrast to the outcome of molecular Burkitt lymphoma and lymphomas without the MYC break. Our data suggest that, after excluding molecular Burkitt lymphoma and pediatric cases, MYC(+) lymphomas are biologically quite homogeneous with single-hit and double-hit lymphomas as well as IG-MYC and non-IG-MYC(+) lymphomas sharing various molecular characteristics.

Heparin-independent, PF4-dependent binding of HIT antibodies to platelets: implications for HIT pathogenesis.

PubMed

Padmanabhan, Anand; Jones, Curtis G; Bougie, Daniel W; Curtis, Brian R; McFarland, Janice G; Wang, Demin; Aster, Richard H

2015-01-01

Antibodies specific for platelet factor 4 (PF4)/heparin complexes are the hallmark of heparin-induced thrombocytopenia and thrombosis (HIT), but many antibody-positive patients have normal platelet counts. The basis for this is not fully understood, but it is believed that antibodies testing positive in the serotonin release assay (SRA) are the most likely to cause disease. We addressed this issue by characterizing PF4-dependent binding of HIT antibodies to intact platelets and found that most antibodies testing positive in the SRA, but none of those testing negative, bind to and activate platelets when PF4 is present without any requirement for heparin (P < .0001). Binding of SRA-positive antibodies to platelets was inhibited by chondroitinase ABC digestion (P < .05) and by the addition of chondroitin-4-sulfate (CS) or heparin in excess quantities. The findings suggest that although all HIT antibodies recognize PF4 in a complex with heparin, only a subset of these antibodies recognize more subtle epitopes induced in PF4 when it binds to CS, the major platelet glycosaminoglycan. Antibodies having this property could explain "delayed HIT" seen in some individuals after discontinuation of heparin and the high risk for thrombosis that persists for weeks in patients recovered from HIT. © 2015 by The American Society of Hematology.

Evaluation of a pretest scoring system (4Ts) for the diagnosis of heparin-induced thrombocytopenia in a university hospital setting.

PubMed

Vatanparast, Rodina; Lantz, Sarah; Ward, Kristine; Crilley, Pamela Ann; Styler, Michael

2012-11-01

The initial diagnosis of heparin-induced thrombocytopenia (HIT) is made on clinical grounds because the assays with the highest sensitivity (eg, heparin-platelet factor 4 antibody enzyme-linked immunosorbent assay [ELISA]) and specificity (eg, serotonin release assay) may not be readily available. The clinical utility of the pretest scoring system, the 4Ts, was developed and validated by Lo et al in the Journal of Thrombosis and Haemostasis in 2006. The pretest scoring system looks at the degree and timing of thrombocytopenia, thrombosis, and the possibility of other etiologies. Based on the 4T score, patients can be categorized as having a high, intermediate, or low probability of having HIT. We conducted a retrospective study of 100 consecutive patients who were tested for HIT during their hospitalization at Hahnemann University Hospital (Philadelphia, PA) in 2009. Of the 100 patients analyzed, 72, 23, and 5 patients had 4T pretest probability scores of low, intermediate, and high, respectively. A positive HIT ELISA (optical density > 1.0 unit) was detected in 0 of 72 patients (0%) in the low probability group, in 5 of 23 patients (22%) in the intermediate probability group, and in 2 of 5 patients (40%) in the high probability group. The average turnaround time for the HIT ELISA was 4 to 5 days. Fourteen (19%) of the 72 patients with a low pretest probability of HIT were treated with a direct thrombin inhibitor. Ten (71%) of the 14 patients in the low probability group treated with a direct thrombin inhibitor had a major complication of bleeding requiring blood transfusion support. In this retrospective study, a low 4T score showed 100% correlation with a negative HIT antibody assay. We recommend incorporating the 4T scoring system into institutional core measures when assessing a patient with suspected HIT, selecting only patients with intermediate to high probability for therapeutic intervention, which may translate into reduced morbidity and lower health care costs.

Recovery of Vestibulo-Ocular Reflex Symmetry After an Acute Unilateral Peripheral Vestibular Deficit: Time Course and Correlation With Canal Paresis.

PubMed

Allum, John H J; Cleworth, T; Honegger, Flurin

2016-07-01

We investigated how response asymmetries and deficit side response amplitudes for head accelerations used clinically to test the vestibular ocular reflex (VOR) are correlated with caloric canal paresis (CP) values. 30 patients were examined at onset of an acute unilateral peripheral vestibular deficit (aUPVD) and 3, 6, and 13 weeks later with three different VOR tests: caloric, rotating chair (ROT), and video head impulse tests (vHIT). Response changes over time were fitted with an exponential decay model and compared with using linear regression analysis. Recovery times (to within 10% of steady state) were similar for vHIT-asymmetry and CP (>10 weeks) but shorter for ROT asymmetry (<4 weeks). Regressions with CP were similar (vHIT asymmetry, R = 0.68, ROT, R = 0.62). Responses to the deficit side were also equally well correlated with CP values (R = 0.71). Specificity for vHIT and 20 degrees/s ROT deficit side responses was 100% in comparison to CP values, sensitivity was 74% for vHIT, 75% for ROT. A decrease in normal side responses occurred for ROT but not for vHIT at 3 weeks. Normal side responses were weekly correlated with CP for ROT (R = 0.49) but not for vHIT (R = 0.17). These results indicate that vHIT deficit side VOR gains are slightly better correlated with CP values than ROT, probably because of similar recovery time courses of vHIT and caloric responses and the lack of normal side vHIT changes. However, specificity and sensitivity is the same for vHIT and ROT tests.

Prospective evaluation of a rapid nanoparticle-based lateral flow immunoassay (STic Expert(®) HIT) for the diagnosis of heparin-induced thrombocytopenia.

PubMed

Leroux, Dorothée; Hezard, Nathalie; Lebreton, Aurélien; Bauters, Anne; Suchon, Pierre; de Maistre, Emmanuel; Biron, Christine; Huisse, Marie-Genevieve; Ternisien, Catherine; Voisin, Sophie; Gruel, Yves; Pouplard, Claire

2014-09-01

A rapid lateral flow immunoassay (LFIA) (STic Expert(®) HIT), recently developed for the diagnosis of heparin-induced thrombocytopenia (HIT), was evaluated in a prospective multicentre cohort of 334 consecutive patients. The risk of HIT was estimated by the 4Ts score as low, intermediate and high in 28·7%, 61·7% and 9·6% of patients, respectively. Definite HIT was diagnosed in 40 patients (12·0%) with positive results on both enzyme-linked immunosorbent assay (Asserachrom(®) HPIA IgG) and serotonin release assay. The inter-reader reproducibility of results obtained was excellent (kappa ratio > 0·9). The negative predictive value of LFIA with plasma samples was 99·6% with a negative likelihood ratio (LR) of 0·03, and was comparable to those of the particle gel immunoassay (H/PF4-PaGIA(®) ) performed in 124 cases. Positive predictive value and positive LR were 44·4% and 5·87, respectively, and the results were similar for serum samples. The probability of HIT in intermediate risk patients decreased from 11·2% to 0·4% when the LFIA result was negative and increased to 42·5% when it was positive. In conclusion, the STic Expert(®) HIT combined with the 4Ts score is a reliable tool to rule out the diagnosis of HIT. © 2014 John Wiley & Sons Ltd.

Video Head Impulse Test for Early Diagnosis of Vestibular Neuritis Among Acute Vertigo.

PubMed

Guan, Qiongfeng; Zhang, Lisan; Hong, Wenke; Yang, Yi; Chen, Zhaoying; Lu, Peilin; Zhang, Dan; Hu, Xingyue

2017-09-01

This study assesses the value of the video head impulse test (vHIT) for early diagnosis of vestibular neuritis (VN) among acute vertigo. Thirty-three cases of vestibular neuritis (VN), 96 patients with other acute vertigo (AV), and 50 cases of normal controls used vHIT to quantitatively test a pair of horizontal vestibulo-ocular reflection (VOR) gains, two pairs of vertical VOR gains, and the corresponding three pairs of VOR gain asymmetry. The peculiarity of VOR gains in VN and the differences between VN and other AV, normal controls by vHIT, were collected and analyzed. There were statistically significant differences in the three pairs of VOR gains asymmetry between VN and other AV, and normal controls (P<0.01). The sensitivity was 87.9% and specificity was 94.3% in differentiating VN from normal and other acute vertigo by vHIT. This study shows vHIT has advantages in the diagnosis of VN in acute vertigo with good sensitivity and specificity and indicates a widespread clinical application.

Comprehensive Mechanistic Analysis of Hits from High-Throughput and Docking Screens against β-Lactamase

PubMed Central

Babaoglu, Kerim; Simeonov, Anton; Irwin, John J.; Nelson, Michael E.; Feng, Brian; Thomas, Craig J.; Cancian, Laura; Costi, M. Paola; Maltby, David A.; Jadhav, Ajit; Inglese, James; Austin, Christopher P.; Shoichet, Brian K.

2009-01-01

High-throughput screening (HTS) is widely used in drug discovery. Especially for screens of unbiased libraries, false positives can dominate “hit lists”; their origins are much debated. Here we determine the mechanism of every active hit from a screen of 70,563 unbiased molecules against β-lactamase using quantitative HTS (qHTS). Of the 1274 initial inhibitors, 95% were detergent-sensitive and were classified as aggregators. Among the 70 remaining were 25 potent, covalent-acting β-lactams. Mass spectra, counter-screens, and crystallography identified 12 as promiscuous covalent inhibitors. The remaining 33 were either aggregators or irreproducible. No specific reversible inhibitors were found. We turned to molecular docking to prioritize molecules from the same library for testing at higher concentrations. Of 16 tested, 2 were modest inhibitors. Subsequent X-ray structures corresponded to the docking prediction. Analog synthesis improved affinity to 8 µM. These results suggest that it may be the physical behavior of organic molecules, not their reactivity, that accounts for most screening artifacts. Structure-based methods may prioritize weak-but-novel chemotypes in unbiased library screens. PMID:18333608

Using multi-stakeholder alliances to accelerate the adoption of health information technology by physician practices.

PubMed

McHugh, Megan; Shi, Yunfeng; McClellan, Sean R; Shortell, Stephen M; Fareed, Naleef; Harvey, Jillian; Ramsay, Patricia; Casalino, Lawrence P

2016-06-01

Multi-stakeholder alliances - groups of payers, purchasers, providers, and consumers that work together to address local health goals - are frequently used to improve health care quality within communities. Under the Aligning Forces for Quality (AF4Q) initiative, multi-stakeholder alliances were given funding and technical assistance to encourage the use of health information technology (HIT) to improve quality. We investigated whether HIT adoption was greater in AF4Q communities than in other communities. Drawing upon survey data from 782 small and medium-sized physician practices collected as part of the National Study of Physician Organizations during July 2007 - March 2009 and January 2012-November 2013, we used weighted fixed effects models to detect relative changes in four measures representing three domains: use of electronic health records (EHRs), receipt of electronic information from hospitals, and patients' online access to their medical records. Improvement on a composite EHR adoption measure was 7.6 percentage points greater in AF4Q communities than in non-AF4Q communities, and the increase in the probability of adopting all five EHR capabilities was 23.9 percentage points greater in AF4Q communities. There was no significant difference in improvement in receipt of electronic information from hospitals or patients' online access to medical records between AF4Q and non-AF4Q communities. By linking HIT to quality improvement efforts, AF4Q alliances may have facilitated greater adoption of EHRs in small and medium-sized physician practices, but not receipt of electronic information from hospitals or patients' online access to medical records. Multi-stakeholder alliances charged with promoting HIT to advance quality improvement may accelerate adoption of EHRs. Copyright © 2016 Elsevier Inc. All rights reserved.

Implementation of a rapid HIT immunoassay at a university hospital - Retrospective analysis of HIT laboratory orders in patients with thrombocytopenia.

PubMed

Black, Anne; Heimerl, Susanne; Oertli, Linnéa; Wilczek, Wolf; Greinacher, Andreas; Spannagl, Michael; Herr, Wolfgang; Hart, Christina

2017-10-01

Heparin-induced thrombocytopenia (HIT) is a rare cause of thrombocytopenia and a potentially life-threatening adverse drug reaction. Clinical overdiagnosis of HIT results in costly laboratory tests and anticoagulation. Criteria and algorithms for diagnosis are established, but their translation into clinical practice is still challenging. In a retrospective approach we studied all HIT related laboratory test requests within four years and evaluated data before (1st period, 24month) and after (2nd period, 24month) replacing particle gel immunoassay (PaGIA) and enzyme-linked immunosorbent assay (ELISA) by a chemiluminescent immunoassay (CLIA). HIT was confirmed by heparin-induced platelet activation (HIPA) test. Clinical pretest probability for HIT using an implemented simplified 4Ts score and platelet count were evaluated. Costs for laboratory tests and alternative anticoagulation were calculated. In 1850 patients with suspected HIT, 2327 laboratory orders were performed. In 87.2% of these orders an intermediate/high simplified 4Ts score was found. Thrombocytopenia was present in 87.1%. After replacing PaGIA and ELISA by CLIA the number of immunological and functional laboratory tests was reduced by 38.2%. The number of positive HIT immunoassays declined from 22.6% to 6.0%, while the number of positive HIPA tests among positive immunological tests increased by 19%. Altogether, acute HIT was confirmed in 59 patients. A decline in the use of alternative anticoagulants was observed in the 2nd period. Our study shows that in a university hospital setting HIT is well-known, but diagnosis requires a precise laboratory confirmation. Replacing PaGIA and ELISA by CLIA did not influence laboratory order behavior but results in reduced overall costs for laboratory diagnostics and alternative anticoagulation. Copyright © 2017 Elsevier Ltd. All rights reserved.

High intensity interval training is associated with greater impact on physical fitness, insulin sensitivity and muscle mitochondrial content in males with overweight/obesity, as opposed to continuous endurance training: a randomized controlled trial.

PubMed

De Strijcker, Dorien; Lapauw, Bruno; Ouwens, D Margriet; Van de Velde, Dominique; Hansen, Dominique; Petrovic, Mirko; Cuvelier, Claude; Tonoli, Cajsa; Calders, Patrick

2018-06-01

To evaluate the effect of high intensity training (HIT) on physical fitness, basal respiratory exchange ratio (bRER), insulin sensitivity and muscle histology in overweight/obese men compared to continuous aerobic training (CAT). 16 male participants with overweight/obesity (age: 42-57 years, body mass index: 28-36 kg/m2) were randomized to HIT (n=8) or CAT (n=8) for 10 weeks, twice a week. HIT was composed of 10 minutes high intensity, 10 minutes continuous aerobic, 10 minutes high intensity exercises. CAT was composed of three times 10 minutes continuous exercising. Changes in anthropometry, physical and metabolic fitness were evaluated. Muscle histology (mitochondria and lipid content) was evaluated by transmission electron microscopy (TEM). HIT showed a significant increase for peak VO2 (P=0.01), for insulin sensitivity (AUC glucose (P<0,001), AUC insulin (P<0,001), OGTT composite score (P=0.007)) and a significant decrease of bRER (P<0.001) compared to CAT. Muscle mitochondrial content was significantly increased after HIT at the subsarcolemmal (P=0.004 number and P=0.001 surface) as well as the intermyofibrillar site (P<0.001 number and P=0.001 surface). High intensity training elicits stronger beneficial effects on physical fitness, basal RER, insulin sensitivity, and muscle mitochondrial content, as compared to continuous aerobic training.

Multiple-hit parameter estimation in monolithic detectors.

PubMed

Hunter, William C J; Barrett, Harrison H; Lewellen, Tom K; Miyaoka, Robert S

2013-02-01

We examine a maximum-a-posteriori method for estimating the primary interaction position of gamma rays with multiple interaction sites (hits) in a monolithic detector. In assessing the performance of a multiple-hit estimator over that of a conventional one-hit estimator, we consider a few different detector and readout configurations of a 50-mm-wide square cerium-doped lutetium oxyorthosilicate block. For this study, we use simulated data from SCOUT, a Monte-Carlo tool for photon tracking and modeling scintillation- camera output. With this tool, we determine estimate bias and variance for a multiple-hit estimator and compare these with similar metrics for a one-hit maximum-likelihood estimator, which assumes full energy deposition in one hit. We also examine the effect of event filtering on these metrics; for this purpose, we use a likelihood threshold to reject signals that are not likely to have been produced under the assumed likelihood model. Depending on detector design, we observe a 1%-12% improvement of intrinsic resolution for a 1-or-2-hit estimator as compared with a 1-hit estimator. We also observe improved differentiation of photopeak events using a 1-or-2-hit estimator as compared with the 1-hit estimator; more than 6% of photopeak events that were rejected by likelihood filtering for the 1-hit estimator were accurately identified as photopeak events and positioned without loss of resolution by a 1-or-2-hit estimator; for PET, this equates to at least a 12% improvement in coincidence-detection efficiency with likelihood filtering applied.

Factors influencing nurses' attitudes towards healthcare information technology.

PubMed

Huryk, Laurie A

2010-07-01

This literature review examines the current trend in nurses' attitudes toward healthcare information technology (HIT). HIT implementation and expansion are at the core of global efforts to improve healthcare quality and patient safety. As a large portion of the healthcare workforce, nurses' attitudes towards HIT are likely to have a major impact on the electronic health record (EHR) implementation process. A search of PubMed, CINAHL and Medline databases produced 1930 combined hits. Returned articles were scanned for relevancy and applicability. Thirteen articles met all criteria and were subsequently reviewed in their entirety. In accordance with two change theories, if HIT implementation projects are to be successful, nurses must recognize that incorporating EHRs into their daily practice is beneficial to patient outcomes. Overall, the attitudes of nurses toward HIT are positive. Increased computer experience is the main demographic indicator for positive attitudes. The most common detractors are poor system design, system slowdown and system downtime. Nurses are also fearful that the use of technology will dehumanize patient care. Involving nurses in system design is likely to improve post-implementation satisfaction. Creating a positive, supportive atmosphere appears to be instrumental to sustainability.

Plasma exchange to remove HIT antibodies: dissociation between enzyme-immunoassay and platelet activation test reactivities.

PubMed

Warkentin, Theodore E; Sheppard, Jo-Ann I; Chu, F Victor; Kapoor, Anil; Crowther, Mark A; Gangji, Azim

2015-01-01

Repeated therapeutic plasma exchange (TPE) has been advocated to remove heparin-induced thrombocytopenia (HIT) IgG antibodies before cardiac/vascular surgery in patients who have serologically-confirmed acute or subacute HIT; for this situation, a negative platelet activation assay (eg, platelet serotonin-release assay [SRA]) has been recommended as the target serological end point to permit safe surgery. We compared reactivities in the SRA and an anti-PF4/heparin IgG-specific enzyme immunoassay (EIA), testing serial serum samples in a patient with recent (subacute) HIT who underwent serial TPE precardiac surgery, as well as for 15 other serially-diluted HIT sera. We observed that post-TPE/diluted HIT sera-when first testing SRA-negative-continue to test strongly positive by EIA-IgG. This dissociation between the platelet activation assay and a PF4-dependent immunoassay for HIT antibodies indicates that patients with subacute HIT undergoing repeated TPE before heparin reexposure should be tested by serial platelet activation assays even when their EIAs remain strongly positive. © 2015 by The American Society of Hematology.

Heparin-independent, PF4-dependent binding of HIT antibodies to platelets: implications for HIT pathogenesis

PubMed Central

Jones, Curtis G.; Bougie, Daniel W.; Curtis, Brian R.; McFarland, Janice G.; Wang, Demin; Aster, Richard H.

2015-01-01

Antibodies specific for platelet factor 4 (PF4)/heparin complexes are the hallmark of heparin-induced thrombocytopenia and thrombosis (HIT), but many antibody-positive patients have normal platelet counts. The basis for this is not fully understood, but it is believed that antibodies testing positive in the serotonin release assay (SRA) are the most likely to cause disease. We addressed this issue by characterizing PF4-dependent binding of HIT antibodies to intact platelets and found that most antibodies testing positive in the SRA, but none of those testing negative, bind to and activate platelets when PF4 is present without any requirement for heparin (P < .0001). Binding of SRA-positive antibodies to platelets was inhibited by chondroitinase ABC digestion (P < .05) and by the addition of chondroitin-4-sulfate (CS) or heparin in excess quantities. The findings suggest that although all HIT antibodies recognize PF4 in a complex with heparin, only a subset of these antibodies recognize more subtle epitopes induced in PF4 when it binds to CS, the major platelet glycosaminoglycan. Antibodies having this property could explain “delayed HIT” seen in some individuals after discontinuation of heparin and the high risk for thrombosis that persists for weeks in patients recovered from HIT. PMID:25342714

Assessment of the performances of AcuStar HIT and the combination with heparin-induced multiple electrode aggregometry: a retrospective study.

PubMed

Minet, V; Bailly, N; Douxfils, J; Osselaer, J C; Laloy, J; Chatelain, C; Elalamy, I; Chatelain, B; Dogné, J M; Mullier, F

2013-09-01

Early diagnosis of immune heparin-induced thrombocytopenia (HIT) is challenging. HemosIL® AcuStar HIT and heparin-induced multiple electrode aggregometry (HIMEA) were recently proposed as rapid diagnostic methods. We conducted a study to assess performances of AcuStar HIT-IgG (PF4-H) and AcuStar HIT-Ab (PF4-H). The secondary objective was to compare the performances of the combination of Acustar HIT and HIMEA with standardised clinical diagnosis. Sera of 104 suspected HIT patients were retrospectively tested with AcuStar HIT. HIMEA was performed on available sera (n=81). The clinical diagnosis was established by analysing in a standardized manner the patient's medical records. These tests were also compared with PF4-Enhanced®, LTA, and SRA in subsets of patients. Thresholds were determined using ROC curve analysis with clinical outcome as reference. Using the recommended thresholds (1.00AU), the negative predictive value (NPV) of HIT-IgG and HIT-Ab were 100.0% (95% CI: 95.9%-100.0% and 95.7%-100.0%). The positive predictive value (PPV) were 64.3% (95% CI: 35.1%-87.2.2%) and 45.0% (95% CI: 23.2%-68.6%), respectively. Using our thresholds (HIT-IgG: 2.89AU, HIT-Ab: 9.41AU), NPV of HIT-IgG and HIT-Ab were 100.0% (95% CI: 96.0%-100.0% and 96.1%-100.0%). PPV were 75.0% (95% CI: 42.7%-94.5%) and 81.8% (95% CI: 48.3%-97.7%), respectively. Of the 79 patients with a medium-high pretest probability score, 67 were negative using HIT-IgG (PF4-H) test at our thresholds. HIMEA was performed on HIT-IgG positive patients. Using this combination, only one patient on 79 was incorrectly diagnosed. Acustar HIT showed good performances to exclude the diagnosis of HIT. Combination with HIMEA improves PPV. Copyright © 2013 Elsevier Ltd. All rights reserved.

Synthesis and SAR of novel tricyclic quinoxalinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miyashiro, Julie; Woods, Keith W.; Park, Chang H.

2010-09-03

Based on screening hit 1, a series of tricyclic quinoxalinones have been designed and evaluated for inhibition of PARP-1. Substitutions at the 7- and 8-positions of the quinoxalinone ring led to a number of compounds with good enzymatic and cellular potency. The tricyclic quinoxalinone class is sensitive to modifications of both the amine substituent and the tricyclic core. The synthesis and structure-activity relationship studies are presented.

Highly sensitive detection of individual HEAT and ARM repeats with HHpred and COACH.

PubMed

Kippert, Fred; Gerloff, Dietlind L

2009-09-24

HEAT and ARM repeats occur in a large number of eukaryotic proteins. As these repeats are often highly diverged, the prediction of HEAT or ARM domains can be challenging. Except for the most clear-cut cases, identification at the individual repeat level is indispensable, in particular for determining domain boundaries. However, methods using single sequence queries do not have the sensitivity required to deal with more divergent repeats and, when applied to proteins with known structures, in some cases failed to detect a single repeat. Testing algorithms which use multiple sequence alignments as queries, we found two of them, HHpred and COACH, to detect HEAT and ARM repeats with greatly enhanced sensitivity. Calibration against experimentally determined structures suggests the use of three score classes with increasing confidence in the prediction, and prediction thresholds for each method. When we applied a new protocol using both HHpred and COACH to these structures, it detected 82% of HEAT repeats and 90% of ARM repeats, with the minimum for a given protein of 57% for HEAT repeats and 60% for ARM repeats. Application to bona fide HEAT and ARM proteins or domains indicated that similar numbers can be expected for the full complement of HEAT/ARM proteins. A systematic screen of the Protein Data Bank for false positive hits revealed their number to be low, in particular for ARM repeats. Double false positive hits for a given protein were rare for HEAT and not at all observed for ARM repeats. In combination with fold prediction and consistency checking (multiple sequence alignments, secondary structure prediction, and position analysis), repeat prediction with the new HHpred/COACH protocol dramatically improves prediction in the twilight zone of fold prediction methods, as well as the delineation of HEAT/ARM domain boundaries. A protocol is presented for the identification of individual HEAT or ARM repeats which is straightforward to implement. It provides high sensitivity at a low false positive rate and will therefore greatly enhance the accuracy of predictions of HEAT and ARM domains.

Highly Sensitive Detection of Individual HEAT and ARM Repeats with HHpred and COACH

PubMed Central

Kippert, Fred; Gerloff, Dietlind L.

2009-01-01

Background HEAT and ARM repeats occur in a large number of eukaryotic proteins. As these repeats are often highly diverged, the prediction of HEAT or ARM domains can be challenging. Except for the most clear-cut cases, identification at the individual repeat level is indispensable, in particular for determining domain boundaries. However, methods using single sequence queries do not have the sensitivity required to deal with more divergent repeats and, when applied to proteins with known structures, in some cases failed to detect a single repeat. Methodology and Principal Findings Testing algorithms which use multiple sequence alignments as queries, we found two of them, HHpred and COACH, to detect HEAT and ARM repeats with greatly enhanced sensitivity. Calibration against experimentally determined structures suggests the use of three score classes with increasing confidence in the prediction, and prediction thresholds for each method. When we applied a new protocol using both HHpred and COACH to these structures, it detected 82% of HEAT repeats and 90% of ARM repeats, with the minimum for a given protein of 57% for HEAT repeats and 60% for ARM repeats. Application to bona fide HEAT and ARM proteins or domains indicated that similar numbers can be expected for the full complement of HEAT/ARM proteins. A systematic screen of the Protein Data Bank for false positive hits revealed their number to be low, in particular for ARM repeats. Double false positive hits for a given protein were rare for HEAT and not at all observed for ARM repeats. In combination with fold prediction and consistency checking (multiple sequence alignments, secondary structure prediction, and position analysis), repeat prediction with the new HHpred/COACH protocol dramatically improves prediction in the twilight zone of fold prediction methods, as well as the delineation of HEAT/ARM domain boundaries. Significance A protocol is presented for the identification of individual HEAT or ARM repeats which is straightforward to implement. It provides high sensitivity at a low false positive rate and will therefore greatly enhance the accuracy of predictions of HEAT and ARM domains. PMID:19777061

Change blindness, aging, and cognition

PubMed Central

Rizzo, Matthew; Sparks, JonDavid; McEvoy, Sean; Viamonte, Sarah; Kellison, Ida; Vecera, Shaun P.

2011-01-01

Change blindness (CB), the inability to detect changes in visual scenes, may increase with age and early Alzheimer’s disease (AD). To test this hypothesis, participants were asked to localize changes in natural scenes. Dependent measures were response time (RT), hit rate, false positives (FP), and true sensitivity (d′). Increased age correlated with increased sensitivity and RT; AD predicted even slower RT. Accuracy and RT were negatively correlated. Differences in FP were nonsignificant. CB correlated with impaired attention, working memory, and executive function. Advanced age and AD were associated with increased CB, perhaps due to declining memory and attention. CB could affect real-world tasks, like automobile driving. PMID:19051127

Change blindness, aging, and cognition.

PubMed

Rizzo, Matthew; Sparks, Jondavid; McEvoy, Sean; Viamonte, Sarah; Kellison, Ida; Vecera, Shaun P

2009-02-01

Change blindness (CB), the inability to detect changes in visual scenes, may increase with age and early Alzheimer's disease (AD). To test this hypothesis, participants were asked to localize changes in natural scenes. Dependent measures were response time (RT), hit rate, false positives (FP), and true sensitivity (d'). Increased age correlated with increased sensitivity and RT; AD predicted even slower RT. Accuracy and RT were negatively correlated. Differences in FP were nonsignificant. CB correlated with impaired attention, working memory, and executive function. Advanced age and AD were associated with increased CB, perhaps due to declining memory and attention. CB could affect real-world tasks, like automobile driving.

Multi-physics modelling contributions to investigate the atmospheric cosmic rays on the single event upset sensitivity along the scaling trend of CMOS technologies.

PubMed

Hubert, G; Regis, D; Cheminet, A; Gatti, M; Lacoste, V

2014-10-01

Particles originating from primary cosmic radiation, which hit the Earth's atmosphere give rise to a complex field of secondary particles. These particles include neutrons, protons, muons, pions, etc. Since the 1980s it has been known that terrestrial cosmic rays can penetrate the natural shielding of buildings, equipment and circuit package and induce soft errors in integrated circuits. Recently, research has shown that commercial static random access memories are now so small and sufficiently sensitive that single event upsets (SEUs) may be induced from the electronic stopping of a proton. With continued advancements in process size, this downward trend in sensitivity is expected to continue. Then, muon soft errors have been predicted for nano-electronics. This paper describes the effects in the specific cases such as neutron-, proton- and muon-induced SEU observed in complementary metal-oxide semiconductor. The results will allow investigating the technology node sensitivity along the scaling trend. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Multiple-Hit Parameter Estimation in Monolithic Detectors

PubMed Central

Barrett, Harrison H.; Lewellen, Tom K.; Miyaoka, Robert S.

2014-01-01

We examine a maximum-a-posteriori method for estimating the primary interaction position of gamma rays with multiple interaction sites (hits) in a monolithic detector. In assessing the performance of a multiple-hit estimator over that of a conventional one-hit estimator, we consider a few different detector and readout configurations of a 50-mm-wide square cerium-doped lutetium oxyorthosilicate block. For this study, we use simulated data from SCOUT, a Monte-Carlo tool for photon tracking and modeling scintillation- camera output. With this tool, we determine estimate bias and variance for a multiple-hit estimator and compare these with similar metrics for a one-hit maximum-likelihood estimator, which assumes full energy deposition in one hit. We also examine the effect of event filtering on these metrics; for this purpose, we use a likelihood threshold to reject signals that are not likely to have been produced under the assumed likelihood model. Depending on detector design, we observe a 1%–12% improvement of intrinsic resolution for a 1-or-2-hit estimator as compared with a 1-hit estimator. We also observe improved differentiation of photopeak events using a 1-or-2-hit estimator as compared with the 1-hit estimator; more than 6% of photopeak events that were rejected by likelihood filtering for the 1-hit estimator were accurately identified as photopeak events and positioned without loss of resolution by a 1-or-2-hit estimator; for PET, this equates to at least a 12% improvement in coincidence-detection efficiency with likelihood filtering applied. PMID:23193231

MYC/BCL2/BCL6 triple hit lymphoma: a study of 40 patients with a comparison to MYC/BCL2 and MYC/BCL6 double hit lymphomas.

PubMed

Huang, Wenting; Medeiros, L Jeffrey; Lin, Pei; Wang, Wei; Tang, Guilin; Khoury, Joseph; Konoplev, Sergej; Yin, C Cameron; Xu, Jie; Oki, Yasuhiro; Li, Shaoying

2018-05-21

High-grade B-cell lymphomas with MYC, BCL2, and BCL6 rearrangements (triple hit lymphoma) are uncommon. We studied the clinicopathologic features of 40 patients with triple hit lymphoma and compared them to 157 patients with MYC/BCL2 double hit lymphoma and 13 patients with MYC/BCL6 double hit lymphoma. The triple hit lymphoma group included 25 men and 15 women with a median age of 61 years (range, 34-85). Nine patients had a history of B-cell lymphoma. Histologically, 23 (58%) cases were diffuse large B-cell lymphoma and 17 cases had features of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Most cases of triple hit lymphoma were positive for CD10 (100%), BCL2 (95%), BCL6 (82%), MYC (74%), and 71% with MYC and BCL2 coexpression. P53 was overexpressed in 29% of triple hit lymphoma cases. The clinicopathological features of triple hit lymphoma patients were similar to patients with MYC/BCL2 and MYC/BCL6 double hit lymphoma, except that triple hit lymphoma cases were more often CD10 positive compared with MYC/BCL6 double hit lymphoma (p < 0.05). Induction chemotherapy used was similar for patients with triple hit lymphoma and double hit lymphoma and overall survival in triple hit lymphoma patients was 17.6 months, similar to the overall survival of patients with double hit lymphoma (p = 0.67). Patients with triple hit lymphoma showing P53 overexpression had significantly worse overall survival compared with those without P53 overexpression (p = 0.04). On the other hand, double expressor status and prior history of B-cell lymphoma did not correlate with overall survival. In conclusion, most patients with triple hit lymphoma have an aggressive clinical course and poor prognosis and these tumors have a germinal center B-cell immunophenotype, similar to patients with double hit lymphomas. P53 expression is a poor prognostic factor in patients with triple hit lymphoma.

Analysis of Physical Collisions in Elite National Rugby League Match Play.

PubMed

Cummins, Cloe; Orr, Rhonda

2015-09-01

To investigate the impact forces of collision events during both attack and defense in elite rugby league match play and to compare the collision profiles between playing positions. 26 elite rugby league players. Player collisions were recorded using an integrated accelerometer in global positioning system units (SPI-Pro X, GPSports). Impact forces of collisions in attack (hit-ups) and defense (tackles) were analyzed from 359 files from outside backs (n = 78), adjustables (n = 97), wide-running forwards (n = 136), and hit-up forwards (n = 48) over 1 National Rugby League season. Hit-up forwards were involved in 0.8 collisions/min, significantly more than all other positional groups (wide-running forwards P = .050, adjustables P = .042, and outside backs P = .000). Outside backs experienced 25% fewer collisions per minute than hit-up forwards. Hit-up forwards experienced a collision within the 2 highest classifications of force (≥ 10 g) every 2.5 min of match play compared with 1 every 5 and 9 min for adjustables and outside backs, respectively. Hit-up forwards performed 0.5 tackles per minute of match play, 5 times that of outside backs (ES = 1.90; 95% CI [0.26,3.16]), and 0.2 hit-ups per minute of match play, twice as many as adjustables. During a rugby league match, players are exposed to a significant number of collision events. Positional differences exist, with hit-up and wide-running forwards experiencing greater collision events than adjustables and outside backs. Although these results may be unique to the individual team's defensive- and attacking-play strategies, they are indicative of the significant collision profiles in professional rugby league.

Low-volume high-intensity swim training is superior to high-volume low-intensity training in relation to insulin sensitivity and glucose control in inactive middle-aged women.

PubMed

Connolly, Luke J; Nordsborg, Nikolai B; Nyberg, Michael; Weihe, Pál; Krustrup, Peter; Mohr, Magni

2016-10-01

We tested the hypothesis that low-volume high-intensity swimming has a larger impact on insulin sensitivity and glucose control than high-volume low-intensity swimming in inactive premenopausal women with mild hypertension. Sixty-two untrained premenopausal women were randomised to an inactive control (n = 20; CON), a high-intensity low-volume (n = 21; HIT) or a low-intensity high-volume (n = 21; LIT) training group. During the 15-week intervention period, HIT performed 3 weekly 6-10 × 30-s all-out swimming intervals (average heart rate (HR) = 86 ± 3 % HRmax) interspersed by 2-min recovery periods and LIT swam continuously for 1 h at low intensity (average HR = 73 ± 3 % HRmax). Fasting blood samples were taken and an oral glucose tolerance test (OGTT) was conducted pre- and post-intervention. After HIT, resting plasma [insulin] was lowered (17 ± 34 %; P < 0.05) but remained similar after LIT and CON. Following HIT, 60-min OGTT plasma [insulin] and [glucose] was lowered (24 ± 30 % and 10 ± 16 %; P < 0.05) but remained similar after LIT and CON. Total area under the curve for plasma [glucose] was lower (P < 0.05) after HIT than LIT (660 ± 141 vs. 860 ± 325 mmol min L(-1)). Insulin sensitivity (HOMA-IR) had increased (P < 0.05) by 22 ± 34 % after HIT, with no significant change after LIT or CON, respectively. Plasma soluble intracellular cell adhesion molecule 1 was lowered (P < 0.05) by 4 ± 8 and 3 ± 9 % after HIT and CON, respectively, while plasma soluble vascular cell adhesion molecule 1 had decreased (P < 0.05) by 8 ± 23 % after HIT only. These findings suggest that low-volume high-intensity intermittent swimming is an effective and time-efficient training strategy for improving insulin sensitivity, glucose control and biomarkers of vascular function in inactive, middle-aged mildly hypertensive women.

Health Information Technology Continues to Show Positive Effect on Medical Outcomes: Systematic Review.

PubMed

Kruse, Clemens Scott; Beane, Amanda

2018-02-05

Health information technology (HIT) has been introduced into the health care industry since the 1960s when mainframes assisted with financial transactions, but questions remained about HIT's contribution to medical outcomes. Several systematic reviews since the 1990s have focused on this relationship. This review updates the literature. The purpose of this review was to analyze the current literature for the impact of HIT on medical outcomes. We hypothesized that there is a positive association between the adoption of HIT and medical outcomes. We queried the Cumulative Index of Nursing and Allied Health Literature (CINAHL) and Medical Literature Analysis and Retrieval System Online (MEDLINE) by PubMed databases for peer-reviewed publications in the last 5 years that defined an HIT intervention and an effect on medical outcomes in terms of efficiency or effectiveness. We structured the review from the Primary Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), and we conducted the review in accordance with the Assessment for Multiple Systematic Reviews (AMSTAR). We narrowed our search from 3636 papers to 37 for final analysis. At least one improved medical outcome as a result of HIT adoption was identified in 81% (25/37) of research studies that met inclusion criteria, thus strongly supporting our hypothesis. No statistical difference in outcomes was identified as a result of HIT in 19% of included studies. Twelve categories of HIT and three categories of outcomes occurred 38 and 65 times, respectively. A strong majority of the literature shows positive effects of HIT on the effectiveness of medical outcomes, which positively supports efforts that prepare for stage 3 of meaningful use. This aligns with previous reviews in other time frames. ©Clemens Scott Kruse, Amanda Beane. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 05.02.2018.

High intensity aerobic exercise training improves chronic intermittent hypoxia-induced insulin resistance without basal autophagy modulation.

PubMed

Pauly, Marion; Assense, Allan; Rondon, Aurélie; Thomas, Amandine; Dubouchaud, Hervé; Freyssenet, Damien; Benoit, Henri; Castells, Josiane; Flore, Patrice

2017-03-03

Chronic intermittent hypoxia (IH) associated with obstructive sleep apnea (OSA) is a major risk factor for cardiovascular and metabolic diseases (insulin resistance: IR). Autophagy is involved in the pathophysiology of IR and high intensity training (HIT) has recently emerged as a potential therapy. We aimed to confirm IH-induced IR in a tissue-dependent way and to explore the preventive effect of HIT on IR-induced by IH. Thirty Swiss 129 male mice were randomly assigned to Normoxia (N), Intermittent Hypoxia (IH: 21-5% FiO 2 , 30 s cycle, 8 h/day) or IH associated with high intensity training (IH HIT). After 8 days of HIT (2*24 min, 50 to 90% of Maximal Aerobic Speed or MAS on a treadmill) mice underwent 14 days IH or N. We found that IH induced IR, characterized by a greater glycemia, an impaired insulin sensitivity and lower AKT phosphorylation in adipose tissue and liver. Nevertheless, MAS and AKT phosphorylation were greater in muscle after IH. IH associated with HIT induced better systemic insulin sensitivity and AKT phosphorylation in liver. Autophagy markers were not altered in both conditions. These findings suggest that HIT could represent a preventive strategy to limit IH-induced IR without change of basal autophagy.

High intensity aerobic exercise training improves chronic intermittent hypoxia-induced insulin resistance without basal autophagy modulation

PubMed Central

Pauly, Marion; Assense, Allan; Rondon, Aurélie; Thomas, Amandine; Dubouchaud, Hervé; Freyssenet, Damien; Benoit, Henri; Castells, Josiane; Flore, Patrice

2017-01-01

Chronic intermittent hypoxia (IH) associated with obstructive sleep apnea (OSA) is a major risk factor for cardiovascular and metabolic diseases (insulin resistance: IR). Autophagy is involved in the pathophysiology of IR and high intensity training (HIT) has recently emerged as a potential therapy. We aimed to confirm IH-induced IR in a tissue-dependent way and to explore the preventive effect of HIT on IR-induced by IH. Thirty Swiss 129 male mice were randomly assigned to Normoxia (N), Intermittent Hypoxia (IH: 21–5% FiO2, 30 s cycle, 8 h/day) or IH associated with high intensity training (IH HIT). After 8 days of HIT (2*24 min, 50 to 90% of Maximal Aerobic Speed or MAS on a treadmill) mice underwent 14 days IH or N. We found that IH induced IR, characterized by a greater glycemia, an impaired insulin sensitivity and lower AKT phosphorylation in adipose tissue and liver. Nevertheless, MAS and AKT phosphorylation were greater in muscle after IH. IH associated with HIT induced better systemic insulin sensitivity and AKT phosphorylation in liver. Autophagy markers were not altered in both conditions. These findings suggest that HIT could represent a preventive strategy to limit IH-induced IR without change of basal autophagy. PMID:28255159

Sci—Thur PM: Imaging — 01: Position-sensitive noise characteristics in multi-pinhole cardiac SPECT imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cuddy-Walsh, SG; University of Ottawa Heart Institute; Wells, RG

2014-08-15

Myocardial perfusion imaging (MPI) with Single Photon Emission Computed Tomography (SPECT) is invaluable in the diagnosis and management of heart disease. It provides essential information on myocardial blood flow and ischemia. Multi-pinhole dedicated cardiac-SPECT cameras offer improved count sensitivity, and spatial and energy resolutions over parallel-hole camera designs however variable sensitivity across the field-of-view (FOV) can lead to position-dependent noise variations. Since MPI evaluates differences in the signal-to-noise ratio, noise variations in the camera could significantly impact the sensitivity of the test for ischemia. We evaluated the noise characteristics of GE Healthcare's Discovery NM530c camera with a goal of optimizingmore » the accuracy of our patient assessment and thereby improving outcomes. Theoretical sensitivity maps of the camera FOV, including attenuation effects, were estimated analytically based on the distance and angle between the spatial position of a given voxel and each pinhole. The standard deviation in counts, σ was inferred for each voxel position from the square root of the sensitivity mapped at that position. Noise was measured experimentally from repeated (N=16) acquisitions of a uniform spherical Tc-99m-water phantom. The mean (μ) and standard deviation (σ) were calculated for each voxel position in the reconstructed FOV. Noise increased ∼2.1× across a 12 cm sphere. A correlation of 0.53 is seen when experimental noise is compared with theory suggesting that ∼53% of the noise is attributed to the combined effects of attenuation and the multi-pinhole geometry. Further investigations are warranted to determine the clinical impact of the position-dependent noise variation.« less

Validating a strategy for psychosocial phenotyping using a large corpus of clinical text.

PubMed

Gundlapalli, Adi V; Redd, Andrew; Carter, Marjorie; Divita, Guy; Shen, Shuying; Palmer, Miland; Samore, Matthew H

2013-12-01

To develop algorithms to improve efficiency of patient phenotyping using natural language processing (NLP) on text data. Of a large number of note titles available in our database, we sought to determine those with highest yield and precision for psychosocial concepts. From a database of over 1 billion documents from US Department of Veterans Affairs medical facilities, a random sample of 1500 documents from each of 218 enterprise note titles were chosen. Psychosocial concepts were extracted using a UIMA-AS-based NLP pipeline (v3NLP), using a lexicon of relevant concepts with negation and template format annotators. Human reviewers evaluated a subset of documents for false positives and sensitivity. High-yield documents were identified by hit rate and precision. Reasons for false positivity were characterized. A total of 58 707 psychosocial concepts were identified from 316 355 documents for an overall hit rate of 0.2 concepts per document (median 0.1, range 1.6-0). Of 6031 concepts reviewed from a high-yield set of note titles, the overall precision for all concept categories was 80%, with variability among note titles and concept categories. Reasons for false positivity included templating, negation, context, and alternate meaning of words. The sensitivity of the NLP system was noted to be 49% (95% CI 43% to 55%). Phenotyping using NLP need not involve the entire document corpus. Our methods offer a generalizable strategy for scaling NLP pipelines to large free text corpora with complex linguistic annotations in attempts to identify patients of a certain phenotype.

Validating a strategy for psychosocial phenotyping using a large corpus of clinical text

PubMed Central

Gundlapalli, Adi V; Redd, Andrew; Carter, Marjorie; Divita, Guy; Shen, Shuying; Palmer, Miland; Samore, Matthew H

2013-01-01

Objective To develop algorithms to improve efficiency of patient phenotyping using natural language processing (NLP) on text data. Of a large number of note titles available in our database, we sought to determine those with highest yield and precision for psychosocial concepts. Materials and methods From a database of over 1 billion documents from US Department of Veterans Affairs medical facilities, a random sample of 1500 documents from each of 218 enterprise note titles were chosen. Psychosocial concepts were extracted using a UIMA-AS-based NLP pipeline (v3NLP), using a lexicon of relevant concepts with negation and template format annotators. Human reviewers evaluated a subset of documents for false positives and sensitivity. High-yield documents were identified by hit rate and precision. Reasons for false positivity were characterized. Results A total of 58 707 psychosocial concepts were identified from 316 355 documents for an overall hit rate of 0.2 concepts per document (median 0.1, range 1.6–0). Of 6031 concepts reviewed from a high-yield set of note titles, the overall precision for all concept categories was 80%, with variability among note titles and concept categories. Reasons for false positivity included templating, negation, context, and alternate meaning of words. The sensitivity of the NLP system was noted to be 49% (95% CI 43% to 55%). Conclusions Phenotyping using NLP need not involve the entire document corpus. Our methods offer a generalizable strategy for scaling NLP pipelines to large free text corpora with complex linguistic annotations in attempts to identify patients of a certain phenotype. PMID:24169276

Development of a health information technology-based data system in community-based hospice and palliative care.

PubMed

Abernethy, Amy P; Wheeler, Jane L; Bull, Janet

2011-05-01

Few hospice and palliative care organizations use health information technology (HIT) for data collection and management; the feasibility and utility of a HIT-based approach in this multi-faceted, interdisciplinary context is unclear. To develop a HIT-based data infrastructure that serves multiple hospice and palliative care sites, meeting clinical and administrative needs with data, technical, and analytic support. Through a multi-site academic/community partnership, a data infrastructure was collaboratively developed, pilot-tested at a community-based site, refined, and demonstrated for data collection and preliminary analysis. Additional sites, which participated in system development, became prepared to contribute data to the growing aggregate database. Electronic data collection proved feasible in community-based hospice and palliative care. The project highlighted "success factors" for implementing HIT in this field: engagement of site-based project "champions" to promote the system from within; involvement of stakeholders at all levels of the organization, to promote culture change and buy-in; attention to local needs (e.g., data for quality reporting) and requirements (e.g., affordable cost, efficiency); consideration of practical factors (e.g., potential to interfere with clinical flow); provision of adequate software, technical, analytic, and statistical support; availability of flexible HIT options (e.g., different data-collection platforms); and adoption of a consortium approach in which sites can support one another, learn from each others' experiences, pool data, and benefit from economies of scale. In hospice and palliative care, HIT-based data collection/management has potential to generate better understanding of populations and outcomes, support quality assessment/quality improvement, and prepare sites to participate in research. Copyright © 2011 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Pharmacophore based design of some multi-targeted compounds targeted against pathways of diabetic complications.

PubMed

Chadha, Navriti; Silakari, Om

2017-09-01

Diabetic complications is a complex metabolic disorder developed primarily due to prolonged hyperglycemia in the body. The complexity of the disease state as well as the unifying pathophysiology discussed in the literature reports exhibited that the use of multi-targeted agents with multiple complementary biological activities may offer promising therapy for the intervention of the disease over the single-target drugs. In the present study, novel thiazolidine-2,4-dione analogues were designed as multi-targeted agents implicated against the molecular pathways involved in diabetic complications using knowledge based as well as in-silico approaches such as pharmacophore mapping, molecular docking etc. The hit molecules were duly synthesized and biochemical estimation of these molecules against aldose reductase (ALR2), protein kinase Cβ (PKCβ) and poly (ADP-ribose) polymerase 1 (PARP-1) led to identification of compound 2 that showed good potency against PARP-1 and ALR2 enzymes. These positive results support the progress of a low cost multi-targeted agent with putative roles in diabetic complications. Copyright © 2017 Elsevier Inc. All rights reserved.

Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review.

PubMed

Warkentin, Theodore E; Pai, Menaka; Linkins, Lori-Ann

2017-08-31

Direct oral anticoagulants (DOACs) are attractive options for treatment of heparin-induced thrombocytopenia (HIT). We report our continuing experience in Hamilton, ON, Canada, since January 1, 2015 (when we completed our prospective study of rivaroxaban for HIT), using rivaroxaban for serologically confirmed HIT (4Ts score ≥4 points; positive platelet factor 4 [PF4]/heparin immunoassay, positive serotonin-release assay). We also performed a literature review of HIT treatment using DOACs (rivaroxaban, apixaban, dabigatran, edoxaban). We focused on patients who received DOAC therapy for acute HIT as either primary therapy (group A) or secondary therapy (group B; initial treatment using a non-DOAC/non-heparin anticoagulant with transition to a DOAC during HIT-associated thrombocytopenia). Our primary end point was occurrence of objectively documented thrombosis during DOAC therapy for acute HIT. We found that recovery without new, progressive, or recurrent thrombosis occurred in all 10 Hamilton patients with acute HIT treated with rivaroxaban. Data from the literature review plus these new data identified a thrombosis rate of 1 of 46 patients (2.2%; 95% CI, 0.4%-11.3%) in patients treated with rivaroxaban during acute HIT (group A, n = 25; group B, n = 21); major hemorrhage was seen in 0 of 46 patients. Similar outcomes in smaller numbers of patients were observed with apixaban (n = 12) and dabigatran (n = 11). DOACs offer simplified management of selected patients, as illustrated by a case of persisting (autoimmune) HIT (>2-month platelet recovery with inversely parallel waning of serum-induced heparin-independent serotonin release) with successful outpatient rivaroxaban management of HIT-associated thrombosis. Evidence supporting efficacy and safety of DOACs for acute HIT is increasing, with the most experience reported for rivaroxaban. © 2017 by The American Society of Hematology.

Evaluation of a new nanoparticle-based lateral-flow immunoassay for the exclusion of heparin-induced thrombocytopenia (HIT).

PubMed

Sachs, Ulrich J; von Hesberg, Jakob; Santoso, Sentot; Bein, Gregor; Bakchoul, Tamam

2011-12-01

Heparin-induced thrombocytopenia (HIT) is an adverse complication of heparin caused by HIT antibodies (abs) that recognise platelet factor 4-heparin (PF4/hep) complexes. Several laboratory tests are available for the confirmation and/or refutation of HIT. A reliable and rapid single-sample test is still pending. It was the objective of this study to evaluate a new lateral-flow immunoassay based on nanoparticle technology. A cohort of 452 surgical and medical patients suspected of having HIT was evaluated. All samples were tested in two IgG-specific ELISAs, in a particle gel immunoassay (PaGIA) and in a newly developed lateral-flow immunoassay (LFI-HIT) as well as in a functional test (HIPA). Clinical pre-test probability was determined using 4T's score. Platelet-activating antibodies were present in 34/452 patients, all of whom had intermediate to high clinical probability. PF4/hep abs were detected in 79, 87, 86, and 63 sera using the four different immunoassays. The negative predictive values (NPV) were 100% for both ELISA tests and LFI-HIT but only 99.2% for PaGIA. There were less false positives (n=29) in the LFI-HIT compared to any other test. Additionally, significantly less time was required to perform LFI-HIT than to perform the other immunoassays. In conclusion, a newly developed lateral-flow assay, LFI-HIT, was capable of identifying all HIT patients in a cohort in a short period of time. Beside an NPV of 100%, the rate of false-positive signals is significantly lower with LFI-HIT than with other immunoassay(s). These performance characteristics suggest a high potency in reducing the risk and costs in patients suspected of having HIT.

Design, Synthesis and Evaluation of Novel 2,5,6-Trisubstituted Benzimidazoles Targeting FtsZ as Antitubercular Agents

PubMed Central

Park, Bora; Awasthi, Divya; Chowdhury, Soumya R.; Melief, Eduard H.; Kumar, Kunal; Knudson, Susan E.; Slayden, Richard A.; Ojima, Iwao

2014-01-01

Filamenting temperature-sensitive protein Z (FtsZ), an essential cell division protein, is a promising target for the drug discovery of new-generation antibacterial agents against various bacterial pathogens. As a part of SAR studies on benzimidazoles, we have synthesized a library of 376 novel 2,5,6-trisubstituted benzimidazoles, bearing ether or thioether linkage at the 6-position. In a preliminary HTP screening against Mtb H37Rv, 108 compounds were identified as hits at a cut off concentration of 5 μg/mL. Among those hits, 10 compounds exhibited MIC values in the range of 0.63–12.5 μg/mL. Light scattering assay and TEM analysis with the most potent compound 5a clearly indicate that its molecular target is Mtb-FtsZ. Also, the Kd of 5a with Mtb-FtsZ was determined to be 1.32 μM. PMID:24726304

Developing structure-activity relationships from an HTS hit for inhibition of the Cks1-Skp2 protein-protein interaction.

PubMed

Singh, Rajinder; Sran, Arvinder; Carroll, David C; Huang, Jianing; Tsvetkov, Lyuben; Zhou, Xiulan; Sheung, Julie; McLaughlin, John; Issakani, Sarkiz D; Payan, Donald G; Shaw, Simon J

2015-11-15

Structure-activity relationships have been developed around 5-bromo-8-toluylsulfonamidoquinoline 1 a hit compound in an assay for the interaction of the E3 ligase Skp2 with Cks1, part of the SCF ligase complex. Disruption of this protein-protein interaction results in higher levels of CDK inhibitor p27, which can act as a tumor suppressor. The results of the SAR developed highlight the relationship between the sulfonamide and quinoline nitrogen, while also suggesting that an aryl substituent at the 5-position of the quinoline ring contributes to the potency in the interaction assay. Compounds showing potency in the interaction assay result in greater levels of p27 and have been shown to inhibit cell growth of two p27 sensitive tumor cell lines. Copyright © 2015 Elsevier Ltd. All rights reserved.

A multi-substrate approach for functional metagenomics-based screening for (hemi)cellulases in two wheat straw-degrading microbial consortia unveils novel thermoalkaliphilic enzymes.

PubMed

Maruthamuthu, Mukil; Jiménez, Diego Javier; Stevens, Patricia; van Elsas, Jan Dirk

2016-01-28

Functional metagenomics is a promising strategy for the exploration of the biocatalytic potential of microbiomes in order to uncover novel enzymes for industrial processes (e.g. biorefining or bleaching pulp). Most current methodologies used to screen for enzymes involved in plant biomass degradation are based on the use of single substrates. Moreover, highly diverse environments are used as metagenomic sources. However, such methods suffer from low hit rates of positive clones and hence the discovery of novel enzymatic activities from metagenomes has been hampered. Here, we constructed fosmid libraries from two wheat straw-degrading microbial consortia, denoted RWS (bred on untreated wheat straw) and TWS (bred on heat-treated wheat straw). Approximately 22,000 clones from each library were screened for (hemi)cellulose-degrading enzymes using a multi-chromogenic substrate approach. The screens yielded 71 positive clones for both libraries, giving hit rates of 1:440 and 1:1,047 for RWS and TWS, respectively. Seven clones (NT2-2, T5-5, NT18-17, T4-1, 10BT, NT18-21 and T17-2) were selected for sequence analyses. Their inserts revealed the presence of 18 genes encoding enzymes belonging to twelve different glycosyl hydrolase families (GH2, GH3, GH13, GH17, GH20, GH27, GH32, GH39, GH53, GH58, GH65 and GH109). These encompassed several carbohydrate-active gene clusters traceable mainly to Klebsiella related species. Detailed functional analyses showed that clone NT2-2 (containing a beta-galactosidase of ~116 kDa) had highest enzymatic activity at 55 °C and pH 9.0. Additionally, clone T5-5 (containing a beta-xylosidase of ~86 kDa) showed > 90% of enzymatic activity at 55 °C and pH 10.0. This study employed a high-throughput method for rapid screening of fosmid metagenomic libraries for (hemi)cellulose-degrading enzymes. The approach, consisting of screens on multi-substrates coupled to further analyses, revealed high hit rates, as compared with recent other studies. Two clones, 10BT and T4-1, required the presence of multiple substrates for detectable activity, indicating a new avenue in library activity screening. Finally, clones NT2-2, T5-5 and NT18-17 were found to encode putative novel thermo-alkaline enzymes, which could represent a starting point for further biotechnological applications.

Current insights into the laboratory diagnosis of HIT.

PubMed

Bakchoul, T; Zöllner, H; Greinacher, A

2014-06-01

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction and prothrombotic disorder caused by immunization against platelet factor 4 (PF4) after complex formation with heparin or other polyanions. After antibody binding to PF4/heparin complexes, HIT antibodies are capable of intravascular platelet activation by cross-linking Fc gamma receptor IIa (FcγRIIa) on the platelet surface leading to a platelet count decrease and/or thrombosis. In contrast to most other immune-mediated disorders, the currently available laboratory tests for anti-PF4/heparin antibodies show a high sensitivity also for clinically irrelevant antibodies. This makes the diagnosis of HIT challenging and bears the risk to substantially overdiagnose HIT. The strength of the antigen assays for HIT is in ruling out HIT when the test is negative. Functional assays have a higher specificity for clinically relevant antibodies, but they are restricted to specialized laboratories. Currently, a Bayesian approach combining the clinical likelihood estimation for HIT with laboratory tests is the most appropriate approach to diagnose HIT. In this review, we give an overview on currently available diagnostic procedures and discuss their limitations. © 2014 John Wiley & Sons Ltd.

Nedley Depression Hit Hypothesis: Identifying Depression and Its Causes.

PubMed

Nedley, Neil; Ramirez, Francisco E

2016-11-01

Depression is often diagnosed using the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria. We propose how certain lifestyle choices and non-modifiable factors can predict the development of depression. We identified 10 cause categories (hits or "blows" to the brain) and theorize that four or more active hits could trigger a depression episode. Methods. A sample of 4271 participants from our community-based program (70% female; ages 17-94 years) was assessed at baseline and at the eighth week of the program using a custom test. Ten cause categories were examined as predictors of depression are (1) Genetic, (2)Developmental, (3)Lifestyle, (4)Circadian Rhythm, (5)Addiction, (6)Nutrition, (7)Toxic, (8)Social/Complicated Grief, (9)Medical Condition, and (10)Frontal Lobe. Results. The relationship between the DSM-5 score and a person having four hits categories in the first program week showed a sensitivity of 89.98 % (95% CI: 89.20 % - 90.73%), specificity 48.84% (CI 45.94-51.75) and Matthew Correlation Coefficient (MCC) .41 . For the eight-week test, the results showed a sensitivity 83.6% (CI 81.9-85.5), specificity 53.7% (CI 51.7-55.6) and MCC .38. Overall, the hits that improved the most from baseline after the eighth week were: Nutrition (47%), Frontal lobe (36%), Addiction (24%), Circadian rhythm (24%), Lifestyle (20%), Social (12%) and Medical (10%). Conclusions. The Nedley four-hit hypothesis seems to predict a depressive episode and correlates well with the DSM-5 criteria with good sensitivity and MCC but less specificity. Identifying these factors and applying lifestyle therapies could play an important role in the treatment of depressed individuals.

Positional Differences in External On-Field Load During Specific Drill Classifications Over a Professional Rugby League Preseason.

PubMed

Cummins, Cloe; McLean, Blake; Halaki, Mark; Orr, Rhonda

2017-07-01

To quantify the external training loads of positional groups in preseason training drills. Thirty-three elite rugby league players were categorized into 1 of 4 positional groups: outside backs (n = 9), adjustables (n = 9), wide-running forwards (n = 9), and hit-up forwards (n = 6). Data for 8 preseason weeks were collected using microtechnology devices. Training drills were classified based on drill focus: speed and agility, conditioning, and generic and positional skills. Total, high-speed, and very-high-speed distance decreased across the preseason in speed and agility (moderate, small, and small, respectively), conditioning (large, large, and small) and generic skills (large, large, and large). The duration of speed and generic skills also decreased (77% and 48%, respectively). This was matched by a concomitant increase in total distance (small), high-speed running (small), very-high-speed running (moderate), and 2-dimensional (2D) BodyLoad (small) demands in positional skills. In positional skills, hit-up forwards (1240 ± 386 m) completed less very-high-speed running than outside backs (2570 ± 1331 m) and adjustables (2121 ± 1163 m). Hit-up forwards (674 ± 253 AU) experienced greater 2D BodyLoad demands than outside backs (432 ± 230 AU, P = .034). In positional drills, hit-up forwards experienced greater relative 2D BodyLoad demands than outside backs (P = .015). Conversely, outside backs experienced greater relative high- (P = .007) and very-high-speed-running (P < .001) demands than hit-up forwards. Significant differences were observed in training loads between positional groups during positional skills but not in speed and agility, conditioning, and generic skills. This work also highlights the importance of different external-load parameters to adequately quantify workload across different positional groups.

Analysis of impact noise induced by hitting of titanium head golf driver.

PubMed

Kim, Young Ho; Kim, Young Chul; Lee, Jun Hee; An, Yong-Hwi; Park, Kyung Tae; Kang, Kyung Min; Kang, Yeon June

2014-11-01

The hitting of titanium head golf driver against golf ball creates a short duration, high frequency impact noise. We analyzed the spectra of these impact noises and evaluated the auditory hazards from exposure to the noises. Noises made by 10 titanium head golf drivers with five maximum hits were collected, and the spectra of the pure impact sounds were studied using a noise analysis program. The noise was measured at 1.7 m (position A) and 3.4 m (position B) from the hitting point in front of the hitter and at 3.4 m (position C) behind the hitting point. Average time duration was measured and auditory risk units (ARUs) at position A were calculated using the Auditory Hazard Assessment Algorithm for Humans. The average peak levels at position A were 119.9 dBA at the sound pressure level (SPL) peak and 100.0 dBA at the overall octave level. The average peak levels (SPL and overall octave level) at position B were 111.6 and 96.5 dBA, respectively, and at position C were 111.5 and 96.7 dBA, respectively. The average time duration and ARUs measured at position A were 120.6 ms and 194.9 units, respectively. Although impact noises made by titanium head golf drivers showed relatively low ARUs, individuals enjoying golf frequently may be susceptible to hearing loss due to the repeated exposure of this intense impact noise with short duration and high frequency. Unprotected exposure to impact noises should be limited to prevent cochleovestibular disorders.

False-Positive Head-Impulse Test in Cerebellar Ataxia

PubMed Central

Kremmyda, Olympia; Kirchner, Hanni; Glasauer, Stefan; Brandt, Thomas; Jahn, Klaus; Strupp, Michael

2012-01-01

The objective of this study was to compare the findings of the bedside head-impulse test (HIT), passive head rotation gain, and caloric irrigation in patients with cerebellar ataxia (CA). In 16 patients with CA and bilaterally pathological bedside HIT, vestibuloocular reflex (VOR) gains were measured during HIT and passive head rotation by scleral search coil technique. Eight of the patients had pathologically reduced caloric responsiveness, while the other eight had normal caloric responses. Those with normal calorics showed a slightly reduced HIT gain (mean ± SD: 0.73 ± 0.15). In those with pathological calorics, gains 80 and 100 ms after the HIT as well as the passive rotation VOR gains were significantly lower. The corrective saccade after head turn occurred earlier in patients with pathological calorics (111 ± 62 ms after onset of the HIT) than in those with normal calorics (191 ± 17 ms, p = 0.0064). We identified two groups of patients with CA: those with an isolated moderate HIT deficit only, probably due to floccular dysfunction, and those with combined HIT, passive rotation, and caloric deficit, probably due to a peripheral vestibular deficit. From a clinical point of view, these results show that the bedside HIT alone can be false-positive for establishing a diagnosis of a bilateral peripheral vestibular deficit in patients with CA. PMID:23162531

Predictive properties of the video head impulse test: measures of caloric symmetry and self-report dizziness handicap.

PubMed

McCaslin, Devin L; Jacobson, Gary P; Bennett, Marc L; Gruenwald, Jill M; Green, Andrea P

2014-01-01

The purpose of this investigation was to determine whether a predictable relationship existed between self-reported dizziness handicap and video Head Impulse Test (vHIT) results in a large sample of patients reporting to a dizziness clinic. Secondary objectives included describing the characteristics of the vHIT ipsilesional and contralesional vestibulo-ocular reflex slow-phase velocity in patients with varying levels of canal paresis. Finally, the authors calculated the sensitivity and specificity of the vHIT for detecting horizontal semicircular canal impairment using the caloric test as the "gold standard." Participants were 115 adults presenting to a tertiary medical care center with symptoms of dizziness. Participants were administered a measure of self-report dizziness handicap (i.e., Dizziness Handicap Inventory) and underwent caloric testing and vHIT at the same appointment. Results showed that (1) there were no significant group differences (i.e., vHIT normal versus vHIT abnormal) in the Dizziness Handicap Inventory total score, (2) both ipsilesional and contralateral velocity gain decreased with increases in caloric paresis, and (3) a caloric asymmetry of 39.5% was determined to be the cutoff that maximized discrimination of vHIT outcome. The level of self-reported dizziness handicap is not predicted by the outcome of the vHIT, which is consistent with the majority of published reports describing the poor relationship between quantitative tests of vestibular function and dizziness handicap. Further, the study findings have demonstrated that vHIT and caloric data are not redundant, and each test provides unique information regarding the functional integrity of the horizontal semicircular canal at different points on the frequency spectrum. The vHIT does offer some advantages over caloric testing, but at the expense of sensitivity. The vHIT can be completed in less time, is not noxious to the patient, and requires very little laboratory space. However, the study data show that a caloric asymmetry of 39.5% is required to optimize discrimination between an abnormal and normal vHIT. It is the authors' contention that the vHIT is a complementary test to the balance function examination and should viewed as such rather than as a replacement for caloric testing.

Microbeam mapping of single event latchups and single event upsets in CMOS SRAMs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barak, J.; Adler, E.; Fischer, B.E.

1998-06-01

The first simultaneous microbeam mapping of single event upset (SEU) and latchup (SEL) in the CMOS RAM HM65162 is presented. The authors found that the shapes of the sensitive areas depend on V{sub DD}, on the ions being used and on the site on the chip being hit by the ion. In particular, they found SEL sensitive sites close to the main power supply lines between the memory-bit-arrays by detecting the accompanying current surge. All these SELs were also accompanied by bit-flips elsewhere in the memory (which they call indirect SEUs in contrast to the well known SEUs induced inmore » the hit memory cell only). When identical SEL sensitive sites were hit farther away from the supply lines only indirect SEL sensitive sites could be detected. They interpret these events as latent latchups in contrast to the classical ones detected by their induced current surge. These latent SELs were probably decoupled from the main supply lines by the high resistivity of the local supply lines.« less

Random Photon Absorption Model Elucidates How Early Gain Control in Fly Photoreceptors Arises from Quantal Sampling

PubMed Central

Song, Zhuoyi; Zhou, Yu; Juusola, Mikko

2016-01-01

Many diurnal photoreceptors encode vast real-world light changes effectively, but how this performance originates from photon sampling is unclear. A 4-module biophysically-realistic fly photoreceptor model, in which information capture is limited by the number of its sampling units (microvilli) and their photon-hit recovery time (refractoriness), can accurately simulate real recordings and their information content. However, sublinear summation in quantum bump production (quantum-gain-nonlinearity) may also cause adaptation by reducing the bump/photon gain when multiple photons hit the same microvillus simultaneously. Here, we use a Random Photon Absorption Model (RandPAM), which is the 1st module of the 4-module fly photoreceptor model, to quantify the contribution of quantum-gain-nonlinearity in light adaptation. We show how quantum-gain-nonlinearity already results from photon sampling alone. In the extreme case, when two or more simultaneous photon-hits reduce to a single sublinear value, quantum-gain-nonlinearity is preset before the phototransduction reactions adapt the quantum bump waveform. However, the contribution of quantum-gain-nonlinearity in light adaptation depends upon the likelihood of multi-photon-hits, which is strictly determined by the number of microvilli and light intensity. Specifically, its contribution to light-adaptation is marginal (≤ 1%) in fly photoreceptors with many thousands of microvilli, because the probability of simultaneous multi-photon-hits on any one microvillus is low even during daylight conditions. However, in cells with fewer sampling units, the impact of quantum-gain-nonlinearity increases with brightening light. PMID:27445779

An Integrated In Silico Method to Discover Novel Rock1 Inhibitors: Multi- Complex-Based Pharmacophore, Molecular Dynamics Simulation and Hybrid Protocol Virtual Screening.

PubMed

Chen, Haining; Li, Sijia; Hu, Yajiao; Chen, Guo; Jiang, Qinglin; Tong, Rongsheng; Zang, Zhihe; Cai, Lulu

2016-01-01

Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) is an important regulator of focal adhesion, actomyosin contraction and cell motility. In this manuscript, a combination of the multi-complex-based pharmacophore (MCBP), molecular dynamics simulation and a hybrid protocol of a virtual screening method, comprised of multipharmacophore- based virtual screening (PBVS) and ensemble docking-based virtual screening (DBVS) methods were used for retrieving novel ROCK1 inhibitors from the natural products database embedded in the ZINC database. Ten hit compounds were selected from the hit compounds, and five compounds were tested experimentally. Thus, these results may provide valuable information for further discovery of more novel ROCK1 inhibitors.

HIT or miss: the application of health care information technology to managing uncertainty in clinical decision making.

PubMed

Kazandjian, Vahé A; Lipitz-Snyderman, Allison

2011-12-01

To discuss the usefulness of health care information technology (HIT) in assisting care providers minimize uncertainty while simultaneously increasing efficiency of the care provided. An ongoing study of HIT, performance measurement (clinical and production efficiency) and their implications to the payment for care represents the design of this study. Since 2006, all Maryland hospitals have embarked on a multi-faceted study of performance measures and HIT adoption surveys, which will shape the health care payment model in Maryland, the last of the all-payor states, in 2011. This paper focuses on the HIT component of the Maryland care payment initiative. While the payment model is still under review and discussion, 'appropriateness' of care has been discussed as an important dimension of measurement. Within this dimension, the 'uncertainty' concept has been identified as associated with variation in care practices. Hence, the methods of this paper define how HIT can assist care providers in addressing the concept of uncertainty, and then provides findings from the first HIT survey in Maryland to infer the readiness of Maryland hospital in addressing uncertainty of care in part through the use of HIT. Maryland hospitals show noteworthy variation in their adoption and use of HIT. While computerized, electronic patient records are not commonly used among and across Maryland hospitals, many of the uses of HIT internally in each hospital could significantly assist in better communication about better practices to minimize uncertainty of care and enhance the efficiency of its production. © 2010 Blackwell Publishing Ltd.

Evaluation of heparin-induced thrombocytopenia (HIT) laboratory testing and the 4Ts scoring system in the intensive care unit.

PubMed

Pierce, Wesly; Mazur, Joseph; Greenberg, Charles; Mueller, Joan; Foster, Joyce; Lazarchick, John

2013-01-01

Over-diagnosis of heparin-induced thrombocytopenia (HIT) results in costly and unnecessary laboratory screening and treatment with direct thrombin inhibitors. Our aim was to evaluate the utility of the 4Ts scoring system to predict HIT in multiple ICU settings and to characterize our treatment of these cases. Eighty-two patients from multiple ICU settings who underwent laboratory testing for HIT were classified as low-, intermediate-, or high-risk patients based on retrospectively adjudicated 4Ts scores. These results were compared with platelet-factor 4 enzyme-linked immunosorbent assays (PF4 ELISAs), optical density (OD) values, and serotonin-release assays (SRAs) to assess the utility of the 4Ts score to rule out ICU-related HIT and reduce laboratory and drug expenditures. Of the 82 patients reviewed, only 12 (11.4%) were PF4-positive and only 1 (1.2%) was SRA-positive for HIT. Heparin was discontinued in only 63.4% of patients suspected to have HIT. There were no significant differences in mean day of platelet fall, mean platelet nadir, and mean percent fall in platelet count between PF4-positive and negative patients (all p > 0.2). There was, however, a significantly higher proportion of patients with an intermediate to high 4Ts score in the PF4-positive group than in the PF4-negative group (66% vs. 30%, respectively; p = 0.02). The mean PF4 OD value in patients with intermediate to high 4Ts scores was significantly higher than in patients with low 4Ts scores (0.658 vs. 0.258, respectively; p < 0.001). The negative predictive values of the 4Ts score relative to the PF4 and SRA were 92% and 100%, respectively. The estimated laboratory and pharmacologic cost avoidance potential of the scoring system in this cohort was $21,450. Our modified 4Ts scoring system appears to be an effective tool for predicting HIT in the ICU and could avoid significant drug and laboratory expenditures if implemented prospectively. The clinical management of patients suspected of HIT is highly variable at our institution. Clinical protocols and education encouraging the proper identification and treatment of suspected HIT need to be established.

The costs of heparin-induced thrombocytopenia: a patient-based cost of illness analysis.

PubMed

Wilke, T; Tesch, S; Scholz, A; Kohlmann, T; Greinacher, A

2009-05-01

SUMMARY BACKGROUND AND OBJECTIVES: Due to the complexity of heparin-induced thrombocytopenia (HIT), currently available cost analyses are rough estimates. The objectives of this study were quantification of costs involved in HIT and identification of main cost drivers based on a patient-oriented approach. Patients diagnosed with HIT (1995-2004, University-hospital Greifswald, Germany) based on a positive functional assay (HIPA test) were retrieved from the laboratory records and scored (4T-score) by two medical experts using the patient file. For cost of illness analysis, predefined HIT-relevant cost parameters (medication costs, prolonged in-hospital stay, diagnostic and therapeutic interventions, laboratory tests, blood transfusions) were retrieved from the patient files. The data were analysed by linear regression estimates with the log of costs and a gamma regression model. Mean length of stay data of non-HIT patients were obtained from the German Federal Statistical Office, adjusted for patient characteristics, comorbidities and year of treatment. Hospital costs were provided by the controlling department. One hundred and thirty HIT cases with a 4T-score >or=4 and a positive HIPA test were analyzed. Mean additional costs of a HIT case were 9008 euro. The main cost drivers were prolonged in-hospital stay (70.3%) and costs of alternative anticoagulants (19.7%). HIT was more costly in surgical patients compared with medical patients and in patients with thrombosis. Early start of alternative anticoagulation did not increase HIT costs despite the high medication costs indicating prevention of costly complications. An HIT cost calculator is provided, allowing online calculation of HIT costs based on local cost structures and different currencies.

Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead

PubMed Central

Williams, Richard; Niswender, Colleen M.; Luo, Qingwei; Le, Uyen; Conn, P. Jeffrey; Lindsley, Craig W.

2013-01-01

This Letter describes the synthesis and SAR of two mGluR4 positive allosteric modulator leads, 6 and 7. VU001171 (6) represents the most potent (EC50 = 650 nM), efficacious (141% Glu Max) and largest fold shift (36-fold) of any mGluR4 PAM reported to date. However, this work highlights the challenges in hit-to-lead for mGluR4 PAMs, with multiple confirmed HTS hits displaying little or no tractable SAR. PMID:19097893

Health Information Technology Risks, Errors, External Threats, and Human Complacency.

PubMed

Felkey, Bill G; Fox, Brent I

2015-06-01

It may seem that our position is one of unwavering support for all things health information technology (HIT). However, we like to believe that we are cautious and deliberate in our evaluation of HIT. This month, we explore some of the common overt and covert challenges to optimal use of HIT.

Syndromic surveillance for health information system failures: a feasibility study.

PubMed

Ong, Mei-Sing; Magrabi, Farah; Coiera, Enrico

2013-05-01

To explore the applicability of a syndromic surveillance method to the early detection of health information technology (HIT) system failures. A syndromic surveillance system was developed to monitor a laboratory information system at a tertiary hospital. Four indices were monitored: (1) total laboratory records being created; (2) total records with missing results; (3) average serum potassium results; and (4) total duplicated tests on a patient. The goal was to detect HIT system failures causing: data loss at the record level; data loss at the field level; erroneous data; and unintended duplication of data. Time-series models of the indices were constructed, and statistical process control charts were used to detect unexpected behaviors. The ability of the models to detect HIT system failures was evaluated using simulated failures, each lasting for 24 h, with error rates ranging from 1% to 35%. In detecting data loss at the record level, the model achieved a sensitivity of 0.26 when the simulated error rate was 1%, while maintaining a specificity of 0.98. Detection performance improved with increasing error rates, achieving a perfect sensitivity when the error rate was 35%. In the detection of missing results, erroneous serum potassium results and unintended repetition of tests, perfect sensitivity was attained when the error rate was as small as 5%. Decreasing the error rate to 1% resulted in a drop in sensitivity to 0.65-0.85. Syndromic surveillance methods can potentially be applied to monitor HIT systems, to facilitate the early detection of failures.

Multi-Frame Object Detection

DTIC Science & Technology

2012-09-01

ensures that the trainer will produce a cascade that achieves a 0.9044 hit rate (= 0.9910) or better, or it will fail trying. The Viola-Jones...by the user. Thus, a final cascade cannot be produced, and the trainer has failed at the specific hit and FA rate requirements. 19 THIS PAGE...International Journal of Computer Vision, vol. 63, no. 2, pp. 153–161, July 2005. [3] L. Lee, “ Gait dynamics for recognition and classification,” in AI Memo

Antimicrobial combinations: Bliss independence and Loewe additivity derived from mechanistic multi-hit models

PubMed Central

Yu, Guozhi; Hozé, Nathanaël; Rolff, Jens

2016-01-01

Antimicrobial peptides (AMPs) and antibiotics reduce the net growth rate of bacterial populations they target. It is relevant to understand if effects of multiple antimicrobials are synergistic or antagonistic, in particular for AMP responses, because naturally occurring responses involve multiple AMPs. There are several competing proposals describing how multiple types of antimicrobials add up when applied in combination, such as Loewe additivity or Bliss independence. These additivity terms are defined ad hoc from abstract principles explaining the supposed interaction between the antimicrobials. Here, we link these ad hoc combination terms to a mathematical model that represents the dynamics of antimicrobial molecules hitting targets on bacterial cells. In this multi-hit model, bacteria are killed when a certain number of targets are hit by antimicrobials. Using this bottom-up approach reveals that Bliss independence should be the model of choice if no interaction between antimicrobial molecules is expected. Loewe additivity, on the other hand, describes scenarios in which antimicrobials affect the same components of the cell, i.e. are not acting independently. While our approach idealizes the dynamics of antimicrobials, it provides a conceptual underpinning of the additivity terms. The choice of the additivity term is essential to determine synergy or antagonism of antimicrobials. This article is part of the themed issue ‘Evolutionary ecology of arthropod antimicrobial peptides’. PMID:27160596

Hit Dexter: A Machine-Learning Model for the Prediction of Frequent Hitters.

PubMed

Stork, Conrad; Wagner, Johannes; Friedrich, Nils-Ole; de Bruyn Kops, Christina; Šícho, Martin; Kirchmair, Johannes

2018-03-20

False-positive assay readouts caused by badly behaving compounds-frequent hitters, pan-assay interference compounds (PAINS), aggregators, and others-continue to pose a major challenge to experimental screening. There are only a few in silico methods that allow the prediction of such problematic compounds. We report the development of Hit Dexter, two extremely randomized trees classifiers for the prediction of compounds likely to trigger positive assay readouts either by true promiscuity or by assay interference. The models were trained on a well-prepared dataset extracted from the PubChem Bioassay database, consisting of approximately 311 000 compounds tested for activity on at least 50 proteins. Hit Dexter reached MCC and AUC values of up to 0.67 and 0.96 on an independent test set, respectively. The models are expected to be of high value, in particular to medicinal chemists and biochemists who can use Hit Dexter to identify compounds for which extra caution should be exercised with positive assay readouts. Hit Dexter is available as a free web service at http://hitdexter.zbh. uni-hamburg.de. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

C2D8: An eight channel CCD readout electronics dedicated to low energy neutron detection

NASA Astrophysics Data System (ADS)

Bourrion, O.; Clement, B.; Tourres, D.; Pignol, G.; Xi, Y.; Rebreyend, D.; Nesvizhevsky, V. V.

2018-02-01

Position-sensitive detectors for cold and ultra-cold neutrons (UCN) are in use in fundamental research. In particular, measuring the properties of the quantum states of bouncing neutrons requires micro-metric spatial resolution. To this end, a Charge Coupled Device (CCD) coated with a thin conversion layer that allows a real time detection of neutron hits is under development at LPSC. In this paper, we present the design and performance of a dedicated electronic board designed to read-out eight CCDs simultaneously and operating under vacuum.

Video head impulse test: a review of the literature.

PubMed

Alhabib, Salman F; Saliba, Issam

2017-03-01

Video head impulse test (vHIT) is a new testing which able to identify the overt and covert saccades and study the gain of vestibulo-ocular reflex (VOR) of each semicircular canal. The aim of this study is to review the clinical use of vHIT in patients with vestibular disorders in different diseases. PubMed and Cochrane databases were searched for all articles that defined vHIT, compared vHIT with another clinical test, and studied the efficacy of vHIT as diagnostic tools with vestibular disease. 37 articles about vHIT were reviewed. All articles studied the vHIT in English and French languages up to May 2015 were included in the review. Editorial articles or short comments, conference abstracts, animal studies, and language restriction were excluded from the review. Four systems were used in the literature to do the vHIT. vHIT is physiological quick test, which studied the VOR at high frequency of each semicircular canal by calculating the duration ratio between the head impulse and gaze deviation. vHIT is more sensitive than clinical head impulse test (cHIT), especially in patient with isolated covert saccades. vHIT test is diagnostic of vestibular weakness by gain reduction and the appearance of overt and covert saccades. If the vHIT is normal, then caloric test is mandatory to rule out a peripheral origin of vertigo. It is recommended to test each semicircular canal, as isolated vertical canal weakness was identified in the literature. More investigation would be required to determine the evolution of the VOR gain with the progression of the vestibular disease.

Φ-score: A cell-to-cell phenotypic scoring method for sensitive and selective hit discovery in cell-based assays.

PubMed

Guyon, Laurent; Lajaunie, Christian; Fer, Frédéric; Bhajun, Ricky; Sulpice, Eric; Pinna, Guillaume; Campalans, Anna; Radicella, J Pablo; Rouillier, Philippe; Mary, Mélissa; Combe, Stéphanie; Obeid, Patricia; Vert, Jean-Philippe; Gidrol, Xavier

2015-09-18

Phenotypic screening monitors phenotypic changes induced by perturbations, including those generated by drugs or RNA interference. Currently-used methods for scoring screen hits have proven to be problematic, particularly when applied to physiologically relevant conditions such as low cell numbers or inefficient transfection. Here, we describe the Φ-score, which is a novel scoring method for the identification of phenotypic modifiers or hits in cell-based screens. Φ-score performance was assessed with simulations, a validation experiment and its application to gene identification in a large-scale RNAi screen. Using robust statistics and a variance model, we demonstrated that the Φ-score showed better sensitivity, selectivity and reproducibility compared to classical approaches. The improved performance of the Φ-score paves the way for cell-based screening of primary cells, which are often difficult to obtain from patients in sufficient numbers. We also describe a dedicated merging procedure to pool scores from small interfering RNAs targeting the same gene so as to provide improved visualization and hit selection.

Φ-score: A cell-to-cell phenotypic scoring method for sensitive and selective hit discovery in cell-based assays

PubMed Central

Guyon, Laurent; Lajaunie, Christian; fer, Frédéric; bhajun, Ricky; sulpice, Eric; pinna, Guillaume; campalans, Anna; radicella, J. Pablo; rouillier, Philippe; mary, Mélissa; combe, Stéphanie; obeid, Patricia; vert, Jean-Philippe; gidrol, Xavier

2015-01-01

Phenotypic screening monitors phenotypic changes induced by perturbations, including those generated by drugs or RNA interference. Currently-used methods for scoring screen hits have proven to be problematic, particularly when applied to physiologically relevant conditions such as low cell numbers or inefficient transfection. Here, we describe the Φ-score, which is a novel scoring method for the identification of phenotypic modifiers or hits in cell-based screens. Φ-score performance was assessed with simulations, a validation experiment and its application to gene identification in a large-scale RNAi screen. Using robust statistics and a variance model, we demonstrated that the Φ-score showed better sensitivity, selectivity and reproducibility compared to classical approaches. The improved performance of the Φ-score paves the way for cell-based screening of primary cells, which are often difficult to obtain from patients in sufficient numbers. We also describe a dedicated merging procedure to pool scores from small interfering RNAs targeting the same gene so as to provide improved visualization and hit selection. PMID:26382112

Hit-and-run, hit-and-stay, and commensal bacteria present different peptide content when viewed from the perspective of the T cell.

PubMed

He, Lu; De Groot, Anne S; Bailey-Kellogg, Chris

2015-11-27

Different types of bacteria face different pressures from the immune system, with those that persist ("hit-and-stay") potentially having to adapt more in order to escape than those prone to short-lived infection ("hit-and-run"), and with commensal bacteria potentially different from both due to additional physical mechanisms for avoiding immune detection. The Janus Immunogenicity Score (JIS) was recently developed to assess the likelihood of T cell recognition of an antigen, using an analysis that considers both binding of a peptide within the antigen by major histocompatability complex (MHC) and recognition of the peptide:MHC complex by cognate T cell receptor (TCR). This score was shown to be predictive of T effector vs. T regulatory or null responses in experimental data, as well as to distinguish viruses representative of the hit-and-stay vs. hit-and-run phenotypes. Here, JIS-based analyses were conducted in order to characterize the extent to which the pressure to avoid T cell recognition is manifested in genomic differences among representative hit-and-run, hit-and-stay, and commensal bacteria. Overall, extracellular proteins were found to have different JIS profiles from cytoplasmic ones. Contrasting the bacterial groups, extracellular proteins were shown to be quite different across the groups, much more so than intracellular proteins. The differences were evident even at the level of corresponding peptides in homologous protein pairs from hit-and-run and hit-and-stay bacteria. The multi-level analysis of patterns of immunogenicity across different groups of bacteria provides a new way to approach questions of bacterial immune camouflage or escape, as well as to approach the selection and optimization of candidates for vaccine design. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Chemogenomic Screen Reveals Novel Snf1p/AMPK Independent Regulators of Acetyl-CoA Carboxylase.

PubMed

Bozaquel-Morais, Bruno L; Madeira, Juliana B; Venâncio, Thiago M; Pacheco-Rosa, Thiago; Masuda, Claudio A; Montero-Lomeli, Monica

2017-01-01

Acetyl-CoA carboxylase (Acc1p) is a key enzyme in fatty acid biosynthesis and is essential for cell viability. To discover new regulators of its activity, we screened a Saccharomyces cerevisiae deletion library for increased sensitivity to soraphen A, a potent Acc1p inhibitor. The hits identified in the screen (118 hits) were filtered using a chemical-phenotype map to exclude those associated with pleiotropic drug resistance. This enabled the identification of 82 ORFs that are genetic interactors of Acc1p. The main functional clusters represented by these hits were "transcriptional regulation", "protein post-translational modifications" and "lipid metabolism". Further investigation of the "transcriptional regulation" cluster revealed that soraphen A sensitivity is poorly correlated with ACC1 transcript levels. We also studied the three top unknown ORFs that affected soraphen A sensitivity: SOR1 (YDL129W), SOR2 (YIL092W) and SOR3 (YJR039W). Since the C18/C16 ratio of lipid acyl lengths reflects Acc1p activity levels, we evaluated this ratio in the three mutants. Deletion of SOR2 and SOR3 led to reduced acyl lengths, suggesting that Acc1p is indeed down-regulated in these strains. Also, these mutants showed no differences in Snf1p/AMPK activation status and deletion of SNF1 in these backgrounds did not revert soraphen A sensitivity completely. Furthermore, plasmid maintenance was reduced in sor2Δ strain and this trait was shared with 18 other soraphen A sensitive hits. In summary, our screen uncovered novel Acc1p Snf1p/AMPK-independent regulators.

The impact of the heparin-induced thrombocytopenia (HIT) computerized alert on provider behaviors and patient outcomes.

PubMed

Austrian, Jonathan S; Adelman, Jason S; Reissman, Stan H; Cohen, Hillel W; Billett, Henny H

2011-01-01

The aim of this study was to measure the effect of an electronic heparin-induced thrombocytopenia (HIT) alert on provider ordering behaviors and on patient outcomes. A pop-up alert was created for providers when an individual's platelet values had decreased by 50% or to <100,000/mm(3) in the setting of recent heparin exposure. The authors retrospectively compared inpatients admitted between January 24, 2008 and August 24, 2008 to a control group admitted 1 year prior to the HIT alert. The primary outcome was a change in HIT antibody testing. Secondary outcomes included an assessment of incidence of HIT antibody positivity, percentage of patients started on a direct thrombin inhibitor (DTI), length of stay and overall mortality. There were 1006 and 1081 patients in the control and intervention groups, respectively. There was a 33% relative increase in HIT antibody test orders (p=0.01), and 33% more of these tests were ordered the first day after the criteria were met when a pop-up alert was given (p=0.03). Heparin was discontinued in 25% more patients in the alerted group (p=0.01), and more direct thrombin inhibitors were ordered for them (p=0.03). The number who tested HIT antibody-positive did not differ, however, between the two groups (p=0.99). The length of stay and mortality were similar in both groups. The HIT alert significantly impacted provider behaviors. However, the alert did not result in more cases of HIT being detected or an improvement in overall mortality. Our findings do not support implementation of a computerized HIT alert.

False Recognition in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease-Disinhibition or Amnesia?

PubMed

Flanagan, Emma C; Wong, Stephanie; Dutt, Aparna; Tu, Sicong; Bertoux, Maxime; Irish, Muireann; Piguet, Olivier; Rao, Sulakshana; Hodges, John R; Ghosh, Amitabha; Hornberger, Michael

2016-01-01

Episodic memory recall processes in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) can be similarly impaired, whereas recognition performance is more variable. A potential reason for this variability could be false-positive errors made on recognition trials and whether these errors are due to amnesia per se or a general over-endorsement of recognition items regardless of memory. The current study addressed this issue by analysing recognition performance on the Rey Auditory Verbal Learning Test (RAVLT) in 39 bvFTD, 77 AD and 61 control participants from two centers (India, Australia), as well as disinhibition assessed using the Hayling test. Whereas both AD and bvFTD patients were comparably impaired on delayed recall, bvFTD patients showed intact recognition performance in terms of the number of correct hits. However, both patient groups endorsed significantly more false-positives than controls, and bvFTD and AD patients scored equally poorly on a sensitivity index (correct hits-false-positives). Furthermore, measures of disinhibition were significantly associated with false positives in both groups, with a stronger relationship with false-positives in bvFTD. Voxel-based morphometry analyses revealed similar neural correlates of false positive endorsement across bvFTD and AD, with both patient groups showing involvement of prefrontal and Papez circuitry regions, such as medial temporal and thalamic regions, and a DTI analysis detected an emerging but non-significant trend between false positives and decreased fornix integrity in bvFTD only. These findings suggest that false-positive errors on recognition tests relate to similar mechanisms in bvFTD and AD, reflecting deficits in episodic memory processes and disinhibition. These findings highlight that current memory tests are not sufficient to accurately distinguish between bvFTD and AD patients.

Rationale and Study Protocol for a Multi-component Health Information Technology (HIT) Screening Tool for Depression and Post-traumatic Stress Disorder in the Primary Care Setting

PubMed Central

Biegler, Kelly; Mollica, Richard; Sim, Susan Elliott; Nicholas, Elisa; Chandler, Maria; Ngo-Metzger, Quyen; Paigne, Kittya; Paigne, Sompia; Nguyen, Danh V.; Sorkin, Dara H.

2016-01-01

The prevalence rate of depression in primary care is high. Primary care providers serve as the initial point of contact for the majority of patients with depression, yet, approximately 50% of cases remain unrecognized. The under-diagnosis of depression may be further exacerbated in limited English-language proficient (LEP) populations. Language barriers may result in less discussion of patients’ mental health needs and fewer referrals to mental health services, particularly given competing priorities of other medical conditions and providers’ time pressures. Recent advances in Health Information Technology (HIT) may facilitate novel ways to screen for depression in LEP populations. The purpose of this paper is to describe the rationale and protocol of a clustered-randomized controlled trial that will test the effectiveness of an HIT intervention that provides a multi-component approach to delivering culturally competent, mental health care in the primary care setting. The HIT intervention has four components: 1) web-based provider training, 2) multimedia electronic screening of depression and PTSD in the patients’ primary language, 3) Computer generated risk assessment scores delivered directly to the provider, and 4) clinical decision support. The outcomes of the study include assessing the potential of the HIT intervention to improve screening rates, clinical detection, provider initiation of treatment, and patient outcomes for depression and PTSD among LEP Cambodian refugees who experienced war atrocities and trauma during the Khmer Rouge. This technology has the potential to be adapted to any LEP population in order to facilitate mental health screening and treatment in the primary care setting. PMID:27394385

Rationale and study protocol for a multi-component Health Information Technology (HIT) screening tool for depression and post-traumatic stress disorder in the primary care setting.

PubMed

Biegler, Kelly; Mollica, Richard; Sim, Susan Elliott; Nicholas, Elisa; Chandler, Maria; Ngo-Metzger, Quyen; Paigne, Kittya; Paigne, Sompia; Nguyen, Danh V; Sorkin, Dara H

2016-09-01

The prevalence rate of depression in primary care is high. Primary care providers serve as the initial point of contact for the majority of patients with depression, yet, approximately 50% of cases remain unrecognized. The under-diagnosis of depression may be further exacerbated in limited English-language proficient (LEP) populations. Language barriers may result in less discussion of patients' mental health needs and fewer referrals to mental health services, particularly given competing priorities of other medical conditions and providers' time pressures. Recent advances in Health Information Technology (HIT) may facilitate novel ways to screen for depression and other mental health disorders in LEP populations. The purpose of this paper is to describe the rationale and protocol of a clustered randomized controlled trial that will test the effectiveness of an HIT intervention that provides a multi-component approach to delivering culturally competent, mental health care in the primary care setting. The HIT intervention has four components: 1) web-based provider training, 2) multimedia electronic screening of depression and PTSD in the patients' primary language, 3) Computer generated risk assessment scores delivered directly to the provider, and 4) clinical decision support. The outcomes of the study include assessing the potential of the HIT intervention to improve screening rates, clinical detection, provider initiation of treatment, and patient outcomes for depression and post-traumatic stress disorder (PTSD) among LEP Cambodian refugees who experienced war atrocities and trauma during the Khmer Rouge. This technology has the potential to be adapted to any LEP population in order to facilitate mental health screening and treatment in the primary care setting. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of two new automated chemiluminescent assays (HemosIL® AcuStar HIT-IgG and HemosIL® AcuStar HIT-Ab) for the detection of heparin-induced antibodies in the diagnosis of heparin-induced thrombocytopenia.

PubMed

Van Hoecke, F; Devreese, K

2012-08-01

Recently, two new, fully automated quantitative chemiluminescent immunoassays, the HemosIL(®) AcuStar HIT-IgG (PF4-H), specific for IgG anti-PF4/H antibodies, and the HemosIL(®) AcuStar HIT-Ab(PF4-H), detecting IgG, IgM and IgA anti-PF4/H antibodies, were introduced into the market. In this study, their performance was compared mutually and with the Zymutest HIA IgG and HIA IgGAM ELISA. Citrated plasmas from 87 patients with clinical suspicion of heparin-induced thrombocytopenia (HIT) were analyzed with all four assays and with a functional confirmation assay. Apart from the manufacturer's cutoffs, optimalized cutoffs were evaluated as well. Sensitivities of all assays were 100%. The Acustar HIT-IgG assay showed a higher specificity compared with the HIT-Ab assay (85%vs. 73%), using the manufacturer's cutoffs. Specificities of all assays, except for the AcuStar HIT-IgG, could be significantly improved when altering the cutoff. Titers were significantly higher for the HIT-Ab assay compared with the HIT-IgG assay (P = 0.0001). This was also the case for the patients with confirmed HIT (P = 0.0495), indicating that the one cutoff (1.0 OD) for both Acustar assays, as proposed by the manufacturer, can be adapted for the AcuStar Hit-Ab assay resulting in an increased specificity. Performance characteristics of the Acustar HIT-IgG and HIT-Ab assay are comparable to the Zymutest HIA IgG and HIA IgGAM. © 2012 Blackwell Publishing Ltd.

Combination of suberoylanilide hydroxamic acid with heavy ion therapy shows promising effects in infantile sarcoma cell lines

PubMed Central

2011-01-01

Introduction The pan-HDAC inhibitor (HDACI) suberoylanilide hydroxamic acid (SAHA) has previously shown to be a radio-sensitizer to conventional photon radiotherapy (XRT) in pediatric sarcoma cell lines. Here, we investigate its effect on the response of two sarcoma cell lines and a normal tissue cell line to heavy ion irradiation (HIT). Materials and methods Clonogenic assays after different doses of heavy ions were performed. DNA damage and repair were evaluated by measuring γH2AX via flow-cytometry. Apoptosis and cell cycle analysis were also measured via flow cytometry. Protein expression of repair proteins, p53 and p21 were measured using immunoblot analysis. Changes of nuclear architecture after treatment with SAHA and HIT were observed in one of the sarcoma cell lines via light microscopy after staining towards chromatin and γH2AX. Results Corresponding with previously reported photon data, SAHA lead to an increase of sensitivity to heavy ions along with an increase of DSB and apoptosis in the two sarcoma cell lines. In contrast, in the osteoblast cell line (hFOB 1.19), the combination of SAHA and HIT showed a significant radio-protective effect. Laser scanning microscopy revealed no significant morphologic changes after HIT compared to the combined treatment with SAHA. Immunoblot analysis revealed no significant up or down regulation of p53. However, p21 was significantly increased by SAHA and combination treatment as compared to HIT only in the two sarcoma cell lines - again in contrast to the osteoblast cell line. Changes in the repair kinetics of DSB p53-independent apoptosis with p21 involvement may be part of the underlying mechanisms for radio-sensitization by SAHA. Conclusion Our in vitro data suggest an increase of the therapeutic ratio by the combination of SAHA with HIT in infantile sarcoma cell lines. PMID:21933400

Heparin-induced thrombocytopenia in the critically ill: interpreting the 4Ts test in a randomized trial.

PubMed

Crowther, Mark; Cook, Deborah; Guyatt, Gordon; Zytaruk, Nicole; McDonald, Ellen; Williamson, David; Albert, Martin; Dodek, Peter; Finfer, Simon; Vallance, Shirley; Heels-Ansdell, Diane; McIntyre, Lauralyn; Mehta, Sangeeta; Lamontagne, Francois; Muscedere, John; Jacka, Michael; Lesur, Olivier; Kutsiogiannis, Jim; Friedrich, Jan; Klinger, James R; Qushmaq, Ismael; Burry, Lisa; Khwaja, Kosar; Sheppard, Jo-Ann; Warkentin, Theodore E

2014-06-01

Thrombocytopenia occurs in 20% to 45% of critically ill medical-surgical patients. The 4Ts heparin-induced thrombocytopenia (HIT) score (with 4 domains: Thrombocytopenia, Timing of thrombocytopenia, Thrombosis and oTher reason[s] for thrombocytopenia) might reliably identify patients at low risk for HIT. Interobserver agreement on 4Ts scoring is uncertain in this setting. To evaluate whether a published clinical prediction rule (the "4Ts score") reliably rules out HIT in "low-risk" intensive care unit (ICU) patients as assessed by research coordinators (who prospectively scored) and 2 adjudicators (who scored retrospectively) during an international heparin thromboprophylaxis trial (PROTECT, NCT00182143). Of 3746 medical-surgical ICU patients in PROTECT, 794 met the enrollment criteria for this HIT substudy. Enrollment was predicated on one of the following occurring in ICU: platelets less than 50×10(9)/L, platelets decreased to 50% of ICU admission value (if admission value<100×10(9)/L), any venous thrombosis, or if HIT was otherwise clinically suspected. Independently, 4Ts scores were completed in real time by research coordinators blinded to study drug and laboratory HIT results, and retrospectively by 2 adjudicators blinded to study drug, laboratory HIT results, and research coordinators' scores; the adjudicators arrived at consensus in all cases. Of the 763 patients, 474 had a central or local laboratory HIT test performed and had 4Ts scoring by adjudicators; 432 were scored by trained research coordinators. Heparin-induced thrombocytopenia was defined by a centrally performed positive serotonin release assay (SRA). Of the 474 patients with central adjudication, 407 (85.9%) had a 4Ts score of 3 or lower, conferring a low pretest probability (PTP) of HIT; of these, 6 (1.5% [95% confidence interval, 0.7%-3.2%) had a positive SRA. Fifty-nine (12.4%) had a moderate PTP (4Ts score of 4-5); of these, 4 (6.8%) had a positive SRA. Eight patients had a high PTP (4Ts score of ≥6); of these, 1 (12.5%) had a positive SRA. Raw agreement between research coordinators and central adjudication on each domain of the 4Ts score and low, intermediate, and high PTP was good. However, chance-corrected agreement was variable between adjudicators (weighted κ values of 0.31-0.93) and between the adjudicator consensus and research coordinators (weighted κ values of 0.13 and 0.78). Post hoc review of the 6 SRA-positive cases with an adjudicated low PTP demonstrated that their scores would have been increased if the adjudicators had had additional information on heparin exposure prior to ICU admission. In general, the fourth domain of 4Ts (oTher causes of thrombocytopenia) generated the most disagreement. Real-time 4Ts scoring by research coordinators at the time of testing for HIT was not consistent with 4Ts scores obtained by central adjudicators. The results of this comprehensive HIT testing highlight the need for further research to improve the assessment of PTP scoring of HIT for critically ill patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Positioning system for single or multi-axis sensitive instrument calibration and calibration system for use therewith

NASA Technical Reports Server (NTRS)

Finley, Tom D. (Inventor); Parker, Peter A. (Inventor)

2008-01-01

A positioning and calibration system are provided for use in calibrating a single or multi axis sensitive instrument, such as an inclinometer. The positioning system includes a positioner that defines six planes of tangential contact. A mounting region within the six planes is adapted to have an inclinometer coupled thereto. The positioning system also includes means for defining first and second flat surfaces that are approximately perpendicular to one another with the first surface adapted to be oriented relative to a local or induced reference field of interest to the instrument being calibrated, such as a gravitational vector. The positioner is positioned such that one of its six planes tangentially rests on the first flat surface and another of its six planes tangentially contacts the second flat surface. A calibration system is formed when the positioning system is used with a data collector and processor.

Design, synthesis and evaluation of novel 2,5,6-trisubstituted benzimidazoles targeting FtsZ as antitubercular agents.

PubMed

Park, Bora; Awasthi, Divya; Chowdhury, Soumya R; Melief, Eduard H; Kumar, Kunal; Knudson, Susan E; Slayden, Richard A; Ojima, Iwao

2014-05-01

Filamenting temperature-sensitive protein Z (FtsZ), an essential cell division protein, is a promising target for the drug discovery of new-generation antibacterial agents against various bacterial pathogens. As a part of SAR studies on benzimidazoles, we have synthesized a library of 376 novel 2,5,6-trisubstituted benzimidazoles, bearing ether or thioether linkage at the 6-position. In a preliminary HTP screening against Mtb H37Rv, 108 compounds were identified as hits at a cut off concentration of 5 μg/mL. Among those hits, 10 compounds exhibited MIC values in the range of 0.63-12.5 μg/mL. Light scattering assay and TEM analysis with the most potent compound 5a clearly indicate that its molecular target is Mtb-FtsZ. Also, the Kd of 5a with Mtb-FtsZ was determined to be 1.32 μM. Copyright © 2014 Elsevier Ltd. All rights reserved.

Probing glaucoma visual damage by rarebit perimetry.

PubMed

Brusini, P; Salvetat, M L; Parisi, L; Zeppieri, M

2005-02-01

To compare rarebit perimetry (RBP) with standard achromatic perimetry (SAP) in detecting early glaucomatous functional damage. 43 patients with ocular hypertension (OH), 39 with early primary open angle glaucoma (POAG), and 41 controls were considered. Visual fields were assessed using the Humphrey field analyser (HFA) 30-2 and RBP tests. Differences among the groups were evaluated using Student-Newman-Keuls and chi(2) tests. Correlation between HFA and RBP parameters was assessed using the Pearson's correlation coefficients and regression analysis. Sensitivity and specificity of RBP in detecting early glaucomatous visual damage were calculated with different algorithms. RBP-mean hit rate (MHR) was respectively 88.6% (SD 4.8%) in controls; 79.1% (10.9%) in the OH group; 64.3% (13.8%) in the POAG group (differences statistically significant). Good correlation in the POAG group was found between HFA-mean deviation and RBP-MHR. Largest AROC (0.95) and optimal sensitivity (97.4%) were obtained when an abnormal RBP test was defined as having (at least 1): MHR <80%; >15 areas with a non-hit rate of >10%; > or =2 areas with a non-hit rate of >50%; at least one area with a non-hit rate of > or =70%. The RBP appeared to be a rapid, comfortable, and easily available perimetric test (requiring only a PC device), showing a high sensitivity and specificity in detecting early glaucomatous visual field defects.

Syndromic surveillance for health information system failures: a feasibility study

PubMed Central

Ong, Mei-Sing; Magrabi, Farah; Coiera, Enrico

2013-01-01

Objective To explore the applicability of a syndromic surveillance method to the early detection of health information technology (HIT) system failures. Methods A syndromic surveillance system was developed to monitor a laboratory information system at a tertiary hospital. Four indices were monitored: (1) total laboratory records being created; (2) total records with missing results; (3) average serum potassium results; and (4) total duplicated tests on a patient. The goal was to detect HIT system failures causing: data loss at the record level; data loss at the field level; erroneous data; and unintended duplication of data. Time-series models of the indices were constructed, and statistical process control charts were used to detect unexpected behaviors. The ability of the models to detect HIT system failures was evaluated using simulated failures, each lasting for 24 h, with error rates ranging from 1% to 35%. Results In detecting data loss at the record level, the model achieved a sensitivity of 0.26 when the simulated error rate was 1%, while maintaining a specificity of 0.98. Detection performance improved with increasing error rates, achieving a perfect sensitivity when the error rate was 35%. In the detection of missing results, erroneous serum potassium results and unintended repetition of tests, perfect sensitivity was attained when the error rate was as small as 5%. Decreasing the error rate to 1% resulted in a drop in sensitivity to 0.65–0.85. Conclusions Syndromic surveillance methods can potentially be applied to monitor HIT systems, to facilitate the early detection of failures. PMID:23184193

Obstacles in the diagnostics and therapy of heparin-induced thrombocytopenia.

PubMed

Antonijević, Nebojsa M; Radovanović, Nebojsa; Obradović, Slobodan; Vucelić, Dragica; Stojanović, Bojan; Miković, Danijela; Kovac, Mirjana; Kocica, Tina; Tadić, Svetlana; Antonijević, Irina; Drasković, Snezana; Djordjević, Valentina; Calija, Branko; Perunicić, Jovan; Vasiljević, Zorana

2010-01-01

An immune-mediated, severe, acquired prothrombotic disorder, heparin-induced thrombocytopenia type II (HIT II) occurs in 0.5-5% of patients exposed to unfractionated heparin longer than 5-7 days. Arterial and venous thromboses are induced by HIT II in about 35-50% of patients. Typical death rate for HIT is about 29%, while 21% of HIT patients result in amputation of a limb. The trend towards the occurrence of HIT due to the administration of low molecular weight heparins (LMWH) taking ever conspicuous place in the standard venous thromboembolism (VTE) prophylaxis has been more frequently observed recently. It is considered that LMWH may cause HIT II in about 0.25-1%. The need for further modification of HIPA assays with LMWH has been imposed in the HIT laboratory diagnostics, heretofore overburdened with complexity. There are several constantly opposing problems arising in HIT laboratory diagnostics, one of which is that in a certain number of patients immunologic assays detect nonpathogenic antibodies (mainly IgM or IgA heparin-PF4 antibodies) while, on the other hand, the occurrence of HIT pathogenetically mediated by minor antigens (neutrophil-activating peptide 2 or interleukin 8) may be neglected in certain cases. The following factors play an important role in the interpretation of each laboratory HIT assays performed: 1. correlation with HIT clinical probability test, the best known of which is 4T'score, 2. the interpretation of the laboratory findings dependent on the time of the thrombocytopenia onset, as well as 3. the sensitivity and specificity of each test respectively. The HIT diagnostics in the presence of other comorbid states which may also induce thrombocytopenia, more precisely known as pseudo HIT (cancer, sepsis, disseminated intravascular coagulation, pulmonary embolism, antiphospholipid syndrome, etc), represents a specific clinical problem.

Clinical effectiveness of a Bayesian algorithm for the diagnosis and management of heparin-induced thrombocytopenia.

PubMed

Raschke, R A; Gallo, T; Curry, S C; Whiting, T; Padilla-Jones, A; Warkentin, T E; Puri, A

2017-08-01

Essentials We previously published a diagnostic algorithm for heparin-induced thrombocytopenia (HIT). In this study, we validated the algorithm in an independent large healthcare system. The accuracy was 98%, sensitivity 82% and specificity 99%. The algorithm has potential to improve accuracy and efficiency in the diagnosis of HIT. Background Heparin-induced thrombocytopenia (HIT) is a life-threatening drug reaction caused by antiplatelet factor 4/heparin (anti-PF4/H) antibodies. Commercial tests to detect these antibodies have suboptimal operating characteristics. We previously developed a diagnostic algorithm for HIT that incorporated 'four Ts' (4Ts) scoring and a stratified interpretation of an anti-PF4/H enzyme-linked immunosorbent assay (ELISA) and yielded a discriminant accuracy of 0.97 (95% confidence interval [CI], 0.93-1.00). Objectives The purpose of this study was to validate the algorithm in an independent patient population and quantitate effects that algorithm adherence could have on clinical care. Methods A retrospective cohort comprised patients who had undergone anti-PF4/H ELISA and serotonin release assay (SRA) testing in our healthcare system from 2010 to 2014. We determined the algorithm recommendation for each patient, compared recommendations with the clinical care received, and enumerated consequences of discrepancies. Operating characteristics were calculated for algorithm recommendations using SRA as the reference standard. Results Analysis was performed on 181 patients, 10 of whom were ruled in for HIT. The algorithm accurately stratified 98% of patients (95% CI, 95-99%), ruling out HIT in 158, ruling in HIT in 10 and recommending an SRA in 13 patients. Algorithm adherence would have obviated 165 SRAs and prevented 30 courses of unnecessary antithrombotic therapy for HIT. Diagnostic sensitivity was 0.82 (95% CI, 0.48-0.98), specificity 0.99 (95% CI, 0.97-1.00), PPV 0.90 (95% CI, 0.56-0.99) and NPV 0.99 (95% CI, 0.96-1.00). Conclusions An algorithm incorporating 4Ts scoring and a stratified interpretation of the anti-PF4/H ELISA has good operating characteristics and the potential to improve management of suspected HIT patients. © 2017 International Society on Thrombosis and Haemostasis.

Methods for increasing the sensitivity of gamma-ray imagers

DOEpatents

Mihailescu, Lucian [Pleasanton, CA; Vetter, Kai M [Alameda, CA; Chivers, Daniel H [Fremont, CA

2012-02-07

Methods are presented that increase the position resolution and granularity of double sided segmented semiconductor detectors. These methods increase the imaging resolution capability of such detectors, either used as Compton cameras, or as position sensitive radiation detectors in imagers such as SPECT, PET, coded apertures, multi-pinhole imagers, or other spatial or temporal modulated imagers.

Systems for increasing the sensitivity of gamma-ray imagers

DOEpatents

Mihailescu, Lucian; Vetter, Kai M.; Chivers, Daniel H.

2012-12-11

Systems that increase the position resolution and granularity of double sided segmented semiconductor detectors are provided. These systems increase the imaging resolution capability of such detectors, either used as Compton cameras, or as position sensitive radiation detectors in imagers such as SPECT, PET, coded apertures, multi-pinhole imagers, or other spatial or temporal modulated imagers.

The effect of health information technology implementation in Veterans Health Administration hospitals on patient outcomes.

PubMed

Spetz, Joanne; Burgess, James F; Phibbs, Ciaran S

2014-03-01

The impact of health information technology (HIT) in hospitals is dependent in large part on how it is used by nurses. This study examines the impact of HIT on the quality of care in hospitals in the Veterans Health Administration (VA), focusing on nurse-sensitive outcomes from 1995 to 2005. Data were obtained from VA databases and original data collection. Fixed-effects Poisson regression was used, with the dependent variables measured using the Agency for Healthcare Research and Quality Inpatient Quality Indicators and Patient Safety Indicators software. Dummy variables indicated when each facility began and completed implementation of each type of HIT. Other explanatory variables included hospital volume, patient characteristics, nurse characteristics, and a quadratic time trend. The start of computerized patient record implementation was associated with significantly lower mortality for two diagnoses but significantly higher pressure ulcer rates, and full implementation was associated with significantly more hospital-acquired infections. The start of bar-code medication administration implementation was linked to significantly lower mortality for one diagnosis, but full implementation was not linked to any change in patient outcomes. The commencement of HIT implementation had mixed effects on patient outcomes, and the completion of implementation had little or no effect on outcomes. This longitudinal study provides little support for the perception of VA staff and leaders that HIT has improved mortality rates or nurse-sensitive patient outcomes. Future research should examine patient outcomes associated with specific care processes affected by HIT. Copyright © 2014 Elsevier Inc. All rights reserved.

Combinatorial support vector machines approach for virtual screening of selective multi-target serotonin reuptake inhibitors from large compound libraries.

PubMed

Shi, Z; Ma, X H; Qin, C; Jia, J; Jiang, Y Y; Tan, C Y; Chen, Y Z

2012-02-01

Selective multi-target serotonin reuptake inhibitors enhance antidepressant efficacy. Their discovery can be facilitated by multiple methods, including in silico ones. In this study, we developed and tested an in silico method, combinatorial support vector machines (COMBI-SVMs), for virtual screening (VS) multi-target serotonin reuptake inhibitors of seven target pairs (serotonin transporter paired with noradrenaline transporter, H(3) receptor, 5-HT(1A) receptor, 5-HT(1B) receptor, 5-HT(2C) receptor, melanocortin 4 receptor and neurokinin 1 receptor respectively) from large compound libraries. COMBI-SVMs trained with 917-1951 individual target inhibitors correctly identified 22-83.3% (majority >31.1%) of the 6-216 dual inhibitors collected from literature as independent testing sets. COMBI-SVMs showed moderate to good target selectivity in misclassifying as dual inhibitors 2.2-29.8% (majority <15.4%) of the individual target inhibitors of the same target pair and 0.58-7.1% of the other 6 targets outside the target pair. COMBI-SVMs showed low dual inhibitor false hit rates (0.006-0.056%, 0.042-0.21%, 0.2-4%) in screening 17 million PubChem compounds, 168,000 MDDR compounds, and 7-8181 MDDR compounds similar to the dual inhibitors. Compared with similarity searching, k-NN and PNN methods, COMBI-SVM produced comparable dual inhibitor yields, similar target selectivity, and lower false hit rate in screening 168,000 MDDR compounds. The annotated classes of many COMBI-SVMs identified MDDR virtual hits correlate with the reported effects of their predicted targets. COMBI-SVM is potentially useful for searching selective multi-target agents without explicit knowledge of these agents. Copyright © 2011 Elsevier Inc. All rights reserved.

Health services research evaluation principles. Broadening a general framework for evaluating health information technology.

PubMed

Sockolow, P S; Crawford, P R; Lehmann, H P

2012-01-01

Our forthcoming national experiment in increased health information technology (HIT) adoption funded by the American Recovery and Reinvestment Act of 2009 will require a comprehensive approach to evaluating HIT. The quality of evaluation studies of HIT to date reveals a need for broader evaluation frameworks that limits the generalizability of findings and the depth of lessons learned. Develop an informatics evaluation framework for health information technology (HIT) integrating components of health services research (HSR) evaluation and informatics evaluation to address identified shortcomings in available HIT evaluation frameworks. A systematic literature review updated and expanded the exhaustive review by Ammenwerth and deKeizer (AdK). From retained studies, criteria were elicited and organized into classes within a framework. The resulting Health Information Technology Research-based Evaluation Framework (HITREF) was used to guide clinician satisfaction survey construction, multi-dimensional analysis of data, and interpretation of findings in an evaluation of a vanguard community health care EHR. The updated review identified 128 electronic health record (EHR) evaluation studies and seven evaluation criteria not in AdK: EHR Selection/Development/Training; Patient Privacy Concerns; Unintended Consequences/ Benefits; Functionality; Patient Satisfaction with EHR; Barriers/Facilitators to Adoption; and Patient Satisfaction with Care. HITREF was used productively and was a complete evaluation framework which included all themes that emerged. We can recommend to future EHR evaluators that they consider adding a complete, research-based HIT evaluation framework, such as HITREF, to their evaluation tools suite to monitor HIT challenges as the federal government strives to increase HIT adoption.

Non-linear relationship of cell hit and transformation probabilities in a low dose of inhaled radon progenies.

PubMed

Balásházy, Imre; Farkas, Arpád; Madas, Balázs Gergely; Hofmann, Werner

2009-06-01

Cellular hit probabilities of alpha particles emitted by inhaled radon progenies in sensitive bronchial epithelial cell nuclei were simulated at low exposure levels to obtain useful data for the rejection or support of the linear-non-threshold (LNT) hypothesis. In this study, local distributions of deposited inhaled radon progenies in airway bifurcation models were computed at exposure conditions characteristic of homes and uranium mines. Then, maximum local deposition enhancement factors at bronchial airway bifurcations, expressed as the ratio of local to average deposition densities, were determined to characterise the inhomogeneity of deposition and to elucidate their effect on resulting hit probabilities. The results obtained suggest that in the vicinity of the carinal regions of the central airways the probability of multiple hits can be quite high, even at low average doses. Assuming a uniform distribution of activity there are practically no multiple hits and the hit probability as a function of dose exhibits a linear shape in the low dose range. The results are quite the opposite in the case of hot spots revealed by realistic deposition calculations, where practically all cells receive multiple hits and the hit probability as a function of dose is non-linear in the average dose range of 10-100 mGy.

Patient safety goals for the proposed Federal Health Information Technology Safety Center.

PubMed

Sittig, Dean F; Classen, David C; Singh, Hardeep

2015-03-01

The Office of the National Coordinator for Health Information Technology is expected to oversee creation of a Health Information Technology (HIT) Safety Center. While its functions are still being defined, the center is envisioned as a public-private entity focusing on promotion of HIT related patient safety. We propose that the HIT Safety Center leverages its unique position to work with key administrative and policy stakeholders, healthcare organizations (HCOs), and HIT vendors to achieve four goals: (1) facilitate creation of a nationwide 'post-marketing' surveillance system to monitor HIT related safety events; (2) develop methods and governance structures to support investigation of major HIT related safety events; (3) create the infrastructure and methods needed to carry out random assessments of HIT related safety in complex HCOs; and (4) advocate for HIT safety with government and private entities. The convening ability of a federally supported HIT Safety Center could be critically important to our transformation to a safe and effective HIT enabled healthcare system. © The Author 2014. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Histamine, histamine intoxication and intolerance.

PubMed

Kovacova-Hanuskova, E; Buday, T; Gavliakova, S; Plevkova, J

2015-01-01

Excessive accumulation of histamine in the body leads to miscellaneous symptoms mediated by its bond to corresponding receptors (H1-H4). Increased concentration of histamine in blood can occur in healthy individuals after ingestion of foods with high contents of histamine, leading to histamine intoxication. In individuals with histamine intolerance (HIT) ingestion of food with normal contents of histamine causes histamine-mediated symptoms. HIT is a pathological process, in which the enzymatic activity of histamine-degrading enzymes is decreased or inhibited and they are insufficient to inactivate histamine from food and to prevent its passage to blood-stream. Diagnosis of HIT is difficult. Multi-faced, non-specific clinical symptoms provoked by certain kinds of foods, beverages and drugs are often attributed to different diseases, such as allergy and food intolerance, mastocytosis, psychosomatic diseases, anorexia nervosa or adverse drug reactions. Correct diagnosis of HIT followed by therapy based on histamine-free diet and supplementation of diamine oxidase can improve patient's quality of life. Copyright © 2015 SEICAP. Published by Elsevier Espana. All rights reserved.

Biostack: A study of the biological effects on HZE galactic cosmic radiation

NASA Technical Reports Server (NTRS)

Buecker, H.

1975-01-01

The Biostack experiment designed to study the effect of individual heavy nucleii of the cosmic radiation environment upon biological systems during actual space flight is described. In each Biostack, several thousand biological objects were hit by an HZE particle. The response of the biological objects was studied. Results are discussed in terms of sensitivity to the hit.

Interpretation of mutation induction by accelerated heavy ions in bacteria

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kozubek, S.; Ryznar, L.; Horneck, G.

In this report, a quantitative interpretation of mutation induction cross sections by heavy charged particles in bacterial cells is presented. The approach is based on the calculation of the fraction of energy deposited by indirect hits in the sensitive structure. In these events the particle does not pass through the sensitive volume, but this region is hit by {delta} rays. Four track structure models, developed by Katz, Chatterjee et al, Kiefer and Straaten and Kudryashov et al., respectively, were used for the calculations. With the latter two models, very good agreement of the calculations with experimental results on mutagenesis inmore » bacteria was obtained. Depending on the linear energy transfer (LET{infinity}) of the particles, two different modes of mutagenic action of heavy ions are distinguished: {open_quotes}{delta}-ray mutagenesis,{close_quotes} which is related to those radiation qualities that preferentially kill the cells in direct hits (LET{infinity} {ge} 100 keV/{mu}m), and {open_quotes}track core mutagenesis,{close_quotes} which arises from direct hits and is observed for lighter ions or ions with high energy (LET{infinity} {le} 100 keV/{mu}m). 37 refs., 6 figs., 1 tab.« less

An automated single ion hit at JAERI heavy ion microbeam to observe individual radiation damage

NASA Astrophysics Data System (ADS)

Kamiya, Tomihiro; Sakai, Takuro; Naitoh, Yutaka; Hamano, Tsuyoshi; Hirao, Toshio

1999-10-01

Microbeam scanning and a single ion hit technique have been combined to establish an automated beam positioning and single ion hit system at the JAERI Takasaki heavy ion microbeam system. Single ion irradiation on preset points of a sample in various patterns can be performed automatically in a short period. The reliability of the system was demonstrated using CR-39 nuclear track detectors. Single ion hit patterns were achieved with a positioning accuracy of 2 μm or less. In measurement of single event transient current using this system, the reduction of the pulse height by accumulation of radiation damages was observed by single ion injection to the same local areas. This technique showed a possibility to get some quantitative information about the lateral displacement of an individual radiation effect in silicon PIN photodiodes. This paper will give details of the irradiation system and present results from several experiments.

"I Feel like I'm Being Hit from All Directions": Enduring the Bombardment as a Mature-Age Learner Returning to Formal Learning

ERIC Educational Resources Information Center

Willans, Julie; Seary, Karen

2011-01-01

The mature-age learner's re-engagement with a formal learning environment may be somewhat akin to the novice Paintball player who, unless well positioned and attuned to the rules of the combative game, is bombarded and worn down by constant "hits". For the mature-age learner, such "hits" may come in the form of tensions…

Patterns of Sensitivity to Parenting and Peer Environments: Early Temperament and Adolescent Externalizing Behavior.

PubMed

Tung, Irene; Noroña, Amanda N; Morgan, Julia E; Caplan, Barbara; Lee, Steve S; Baker, Bruce L

2018-03-14

Although parenting behavior and friendship quality predict adolescent externalizing behaviors (EBs), individual differences in temperament may differentially affect susceptibility to these factors over time. In a multi-method and multi-informant study of 141 children followed prospectively from toddlerhood to adolescence, we tested the independent and interactive associations of age 3 reactive temperament (e.g., negative emotionality) and age 13 observed parenting (i.e., positive and negative behavior) and friendship (i.e., conflict and warmth), with multi-informant ratings of age 15 aggression and rule-breaking behavior. Negative parenting predicted growth in parent-rated EB, but only for adolescents with early reactive temperament. Temperament did not affect sensitivity to positive parenting or friendship. Results are discussed in the context of differential susceptibility theory and intervention implications for adolescents. © 2018 Society for Research on Adolescence.

Enhanced HTS hit selection via a local hit rate analysis.

PubMed

Posner, Bruce A; Xi, Hualin; Mills, James E J

2009-10-01

The postprocessing of high-throughput screening (HTS) results is complicated by the occurrence of false positives (inactive compounds misidentified as active by the primary screen) and false negatives (active compounds misidentified as inactive by the primary screen). An activity cutoff is frequently used to select "active" compounds from HTS data; however, this approach is insensitive to both false positives and false negatives. An alternative method that can minimize the occurrence of these artifacts will increase the efficiency of hit selection and therefore lead discovery. In this work, rather than merely using the activity of a given compound, we look at the presence and absence of activity among all compounds in its "chemical space neighborhood" to give a degree of confidence in its activity. We demonstrate that this local hit rate (LHR) analysis method outperforms hit selection based on ranking by primary screen activity values across ten diverse high throughput screens, spanning both cell-based and biochemical assay formats of varying biology and robustness. On average, the local hit rate analysis method was approximately 2.3-fold and approximately 1.3-fold more effective in identifying active compounds and active chemical series, respectively, than selection based on primary activity alone. Moreover, when applied to finding false negatives, this method was 2.3-fold better than ranking by primary activity alone. In most cases, novel hit series were identified that would have otherwise been missed. Additional uses of and observations regarding this HTS analysis approach are also discussed.

A zero dead-time multi-particle time and position sensitive detector based on correlation between brightness and amplitude

DOE Office of Scientific and Technical Information (OSTI.GOV)

Urbain, X., E-mail: xavier.urbain@uclouvain.be; Bech, D.; Van Roy, J.-P.

A new multi-particle time and position sensitive detector using only a set of microchannel plates, a waveform digitizer, a phosphor screen, and a CMOS camera is described. The assignment of the timing information, as taken from the microchannel plates by fast digitizing, to the positions, as recorded by the camera, is based on the COrrelation between the BRightness of the phosphor screen spots, defined as their integrated intensity and the Amplitude of the electrical signals (COBRA). Tests performed by observing the dissociation of HeH, the fragmentation of H{sub 3} into two or three fragments, and the photo-double-ionization of Xenon atomsmore » are presented, which illustrate the performances of the COBRA detection scheme.« less

Atomic features of an autoantigen in heparin-induced thrombocytopenia (HIT).

PubMed

Cai, Zheng; Zhu, Zhiqiang; Greene, Mark I; Cines, Douglas B

2016-07-01

Autoantigen development is poorly understood at the atomic level. Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by antibodies to an antigen composed of platelet factor 4 (PF4) and heparin or cellular glycosaminoglycans (GAGs). In solution, PF4 exists as an equilibrium among monomers, dimers and tetramers. Structural studies of these interacting components helped delineate a multi-step process involved in the pathogenesis of HIT. First, heparin binds to the 'closed' end of the PF4 tetramer and stabilizes its conformation; exposing the 'open' end. Second, PF4 arrays along heparin/GAG chains, which approximate tetramers, form large antigenic complexes that enhance antibody avidity. Third, pathogenic HIT antibodies bind to the 'open' end of stabilized PF4 tetramers to form an IgG/PF4/heparin ternary immune complex and also to propagate the formation of 'ultralarge immune complexes' (ULCs) that contain multiple IgG antibodies. Fourth, ULCs signal through FcγRIIA receptors, activating platelets and monocytes directly and generating thrombin, which transactivates hematopoietic and endothelial cells. A non-pathogenic anti-PF4 antibody prevents tetramer formation, binding of pathogenic antibody, platelet activation and thrombosis, providing a new approach to manage HIT. An improved understanding of the pathogenesis of HIT may lead to novel diagnostics and therapeutics for this autoimmune disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Forms of non-suicidal self-injury as a function of trait aggression.

PubMed

Kleiman, Evan M; Ammerman, Brooke A; Kulper, Daniel A; Uyeji, Lauren L; Jenkins, Abigail L; McCloskey, Michael S

2015-05-01

To date, the considerable body of research on predictors of non-suicidal self-injury (NSSI) has conceptualized NSSI as a unitary construct despite the fact that NSSI can exist in many forms (e.g., hitting, cutting, burning). The goal of the present study is to examine differential prediction of forms of NSSI. Specifically, we examined trait aggression as a predictor of more aggressive forms of NSSI (i.e., hitting). We hypothesized that higher trait aggression would differentiate those who engaged in hitting forms of NSSI from those who did not, whereas other factors (i.e., emotion regulation and trait anger) would serve as a non-specific predictor of NSSI. We also hypothesized that higher trait aggression would be related to lifetime frequency of hitting NSSI, but not other forms of NSSI, whereas emotion regulation and anger would act as predictors of other forms of NSSI. To test these hypotheses, a large sample of young adults completed measures of trait aggression, trait anger, emotion regulation, and NSSI behaviors. Results were generally in line with our hypotheses. Higher levels of trait aggression differentiated those who engaged in hitting NSSI from those who did not and was also associated with greater frequency of hitting NSSI. These results imply that different factors predict different forms of NSSI and that NSSI may be best examined as a multi-faceted construct. Copyright © 2015 Elsevier Inc. All rights reserved.

A multi-method pilot evaluation of an online diabetes exercise system.

PubMed

Schaarup, Clara; Hejlesen, Ole K

2015-01-01

The American Diabetes Association and The European Association of The Study of Diabetes recommend people with Type 2 diabetes to do moderate to vigorous aerobic exercise for 150 min per week to avoid late diabetic complications. However, most people with diabetes do not follow the recommendation. Consumer health information technology (CHIT) might play a role in supporting behavior changes that promote health and well-being. A CHIT prototype of an online diabetes exercise system, which contained the newest research of low volume high-intensity interval training (HIT), was developed. To test the system we used a multi-method pilot evaluation that includes; interviews, paper prototyping, heuristic evaluation, and test with patients. The patients expressed satisfaction with HIT and appreciated that the system was web-based. The findings from this pilot study inspire to further development and evaluation of online CHIT systems to diabetics.

Representing Misalignments of the STAR Geometry Model using AgML

NASA Astrophysics Data System (ADS)

Webb, Jason C.; Lauret, Jérôme; Perevotchikov, Victor; Smirnov, Dmitri; Van Buren, Gene

2017-10-01

The STAR Heavy Flavor Tracker (HFT) was designed to provide high-precision tracking for the identification of charmed hadron decays in heavy-ion collisions at RHIC. It consists of three independently mounted subsystems, providing four precision measurements along the track trajectory, with the goal of pointing decay daughters back to vertices displaced by less than 100 microns from the primary event vertex. The ultimate efficiency and resolution of the physics analysis will be driven by the quality of the simulation and reconstruction of events in heavy-ion collisions. In particular, it is important that the geometry model properly accounts for the relative misalignments of the HFT subsystems, along with the alignment of the HFT relative to STARs primary tracking detector, the Time Projection Chamber (TPC). The Abstract Geometry Modeling Language (AgML) provides a single description of the STAR geometry, generating both our simulation (GEANT 3) and reconstruction geometries (ROOT). AgML implements an ideal detector model, while misalignments are stored separately in database tables. These have historically been applied at the hit level. Simulated detector hits are projected from their ideal position along the track’s trajectory, until they intersect the misaligned detector volume, where the struck detector element is calculated for hit digitization. This scheme has worked well as hit errors have been negligible compared with the size of sensitive volumes. The precision and complexity of the HFT detector require us to apply misalignments to the detector volumes themselves. In this paper we summarize the extension of the AgML language and support libraries to enable the static misalignment of our reconstruction and simulation geometries, discussing the design goals, limitations and path to full misalignment support in ROOT/VMC-based simulation.

Acute intraoperative heparin-induced thrombocytopenia (HIT) and thrombosis during coronary artery bypass grafting: Two case reports providing evidence for the role of preoperative LMWH in triggering sensitization.

PubMed

Khoury, M; Pitsis, A; Poumpouridou-Kioura, H; Soufla, G; Kanthou, C; Matoula, N; Angelidis, A; Melissari, E

2016-10-01

Systemic anticoagulation is necessary during cardiac surgery. To date, the only well established anticoagulation protocol involves the use of heparin. However, heparin can cause heparin-induced thrombocytopenia (HIT) a potentially life threatening immune-mediated thromboembolic syndrome. Until now, devastating consequences of HIT syndrome in patients undergoing heart surgery have been described, but only postoperatively. Here we report the development of HIT syndrome during cardiac revascularization by intra-operative heparin administration in two patients previously exposed to LMWH. We report on two patients who developed rapid and profound intravascular coagulation with severe thrombocytopenia (platelet count decreased from ≥250×10 9 /L to 50×10 9 /L) due to HIT development caused by heparin administration during coronary artery bypass graft surgery. In addition we report that fondaparinux, given intra-operatively in association with antithrombin, may be a suitable alternative anticoagulant for successfully preventing the devastating consequences of intra-operative HIT development. To our knowledge, this is the first report describing the development of acute intra-operative HIT, secondary to high-dose UFH administered for coronary revascularization, in which the unexpected presence of platelet-activating anti-PF4/heparin antibodies at surgery was explained by preoperative administration of a one-week course of LMWH but without any preoperative evidence for HIT. Copyright © 2016 Elsevier Ltd. All rights reserved.

Using ProHits to store, annotate and analyze affinity purification - mass spectrometry (AP-MS) data

PubMed Central

Liu, Guomin; Zhang, Jianping; Choi, Hyungwon; Lambert, Jean-Philippe; Srikumar, Tharan; Larsen, Brett; Nesvizhskii, Alexey I.; Raught, Brian; Tyers, Mike; Gingras, Anne-Claude

2012-01-01

Affinity purification coupled with mass spectrometry (AP-MS) is a robust technique used to identify protein-protein interactions. With recent improvements in sample preparation, and dramatic advances in MS instrumentation speed and sensitivity, this technique is becoming more widely used throughout the scientific community. To meet the needs of research groups both large and small, we have developed software solutions for tracking, scoring and analyzing AP-MS data. Here, we provide details for the installation and utilization of ProHits, a Laboratory Information Management System designed specifically for AP-MS interaction proteomics. This protocol explains: (i) how to install the complete ProHits system, including modules for the management of mass spectrometry files and the analysis of interaction data, and (ii) alternative options for the use of pre-existing search results in simpler versions of ProHits, including a virtual machine implementation of our ProHits Lite software. We also describe how to use the main features of the software to analyze AP-MS data. PMID:22948730

Isolated orbital mass as the primary presentation of a triple-hit lymphoma transformed from a systemic follicular lymphoma.

PubMed

Zhou, Xiao Yi; Lu, Xinyan; Raparia, Kirtee; Chen, Yi-Hua

2018-06-01

Triple-hit lymphoma is a highly aggressive B-cell lymphoma. We report a case of triple-hit lymphoma transformed from systemic follicular lymphoma (FL) after 9-year remission and presented primarily as an isolated orbital mass without systemic symptoms or lymphadenopathy. A 58-year-old female presented with intermittent vertical binocular diplopia, left upper eyelid swelling and pain and was found to have a 2.9 cm orbital mass. Histological section revealed a CD10-positive large B-cell lymphoma, consistent with transformation of FL. Fluorescent in situ hybridization (FISH) analysis demonstrated rearrangements involving C-MYC, BCL-2 and BCL-6 genes, indicating a high grade, triple-hit lymphoma. Triple-hit lymphoma transformed from a low-grade lymphoma may initially present as an isolated orbital mass without systemic evidence of transformation. Early recognition of double or triple-hit lymphomas is important since these patients require aggressive chemotherapy.

Advanced X-ray Imaging Crystal Spectrometer for Magnetic Fusion Tokamak Devices

NASA Astrophysics Data System (ADS)

Lee, S. G.; Bak, J. G.; Bog, M. G.; Nam, U. W.; Moon, M. K.; Cheon, J. K.

2008-03-01

An advanced X-ray imaging crystal spectrometer is currently under development using a segmented position sensitive detector and time-to-digital converter (TDC) based delay-line readout electronics for burning plasma diagnostics. The proposed advanced XICS utilizes an eight-segmented position sensitive multi-wire proportional counter and supporting electronics to increase the spectrometer performance includes the photon count-rate capability and spatial resolution.

Health information technology and physicians' perceptions of healthcare quality.

PubMed

Fang, Hai; Peifer, Karen L; Chen, Jie; Rizzo, John A

2011-03-01

To investigate the relationship between the use of health information technology (HIT) and physician perceptions of providing high-quality care and to determine whether this relationship has changed over time. We used 2 waves of longitudinal data from the Community Tracking Study Physician Surveys, 2000-2001 and 2004-2005. Three measures of HIT were examined: a binary variable measuring the use of at least 1 type of HIT, a continuous variable measuring the total number of HIT types, and a binary variable measuring use of all 5 HIT types related to "meaningful use" of HIT as defined by Centers for Medicare and Medicaid Services. Three multivariate models were estimated to study the effect of each HIT measure on physicians' perception of providing high-quality care. Individual fixed-effects estimation also was used to control for individual time-invariant factors. Using at least 1 type of HIT significantly enhanced physicians' perception of providing high-quality care in 2000-2001, but not in 2004-2005. The marginal effect of adding 1 extra HIT type was positive and statistically significant in both periods. The association between using all 5 HIT types related to meaningful use and perceived quality was statistically significant in 2000-2001, but not in 2004-2005. Health information technology has become a multifunctional system and appears to have enhanced physicians' perception of providing high-quality care. Physicians' perceptions of medical care quality improved as the number of HIT types used increased. This study supports more extensive use of HIT in physician practices.

Tanzania Health Information Technology (T-HIT) System: Pilot Test of a Tablet-Based System to Improve Prevention of Mother-to-Child Transmission of HIV.

PubMed

Bull, Sheana; Thomas, Deborah Sk; Nyanza, Elias C; Ngallaba, Sospatro E

2018-01-15

The prevention of mother-to-child transmission (PMTCT) of HIV requires innovative solutions. Although routine monitoring is effective in some areas, standardized and easy-to-scale solutions to identify and monitor pregnant women, test them for HIV, and treat them and their children is still lacking. Mobile health (mHealth) offers opportunities for surveillance and reporting in rural areas of low- and middle-income countries. The aim of this study was to document the preliminary impacts of the Tanzania Health Information Technology (T-HIT) system mHealth intervention aimed at health workers for PMTCT care delivery and capacity building in a rural area of Tanzania. We developed T-HIT as a tablet-based system for an electronic data collection system designed to capture and report PMTCT data during antenatal, delivery, and postnatal visits in Misungwi, Tanzania. T-HIT was tested by health workers in a pilot randomized trial comparing seven sites using T-HIT assigned at random to seven control sites; all sites maintained standard paper record-keeping during the pilot intervention period. We compared numbers of antenatal visits, number of HIV tests administered, and women testing positive across all sites. Health workers recorded data from antenatal visits for 1530 women; of these, 695 (45.42%) were tested for HIV and 3.59% (55/1530) tested positive. Health workers were unable to conduct an HIV test for 103 women (6.73%, 103/1530) because of lack of reagent, which is not captured on paper logs. There was no difference in the activity level for testing when comparing sites T-HIT to non-T-HIT sites. We observed a significant postintervention increase in the numbers of women testing positive for HIV compared with the preintervention period (P=.04), but this was likely not attributable to the T-HIT system. T-HIT had a high degree of acceptability and feasibility and is perceived as useful by health workers, who documented more antenatal visits during the pilot intervention compared with a traditional system of paper logs, suggesting potential for improvements in antenatal care for women at risk for HIV. ©Sheana Bull, Deborah SK Thomas, Elias C Nyanza, Sospatro E Ngallaba. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 15.01.2018.

Tanzania Health Information Technology (T-HIT) System: Pilot Test of a Tablet-Based System to Improve Prevention of Mother-to-Child Transmission of HIV

PubMed Central

Bull, Sheana; Nyanza, Elias C; Ngallaba, Sospatro E

2018-01-01

Background The prevention of mother-to-child transmission (PMTCT) of HIV requires innovative solutions. Although routine monitoring is effective in some areas, standardized and easy-to-scale solutions to identify and monitor pregnant women, test them for HIV, and treat them and their children is still lacking. Mobile health (mHealth) offers opportunities for surveillance and reporting in rural areas of low- and middle-income countries. Objective The aim of this study was to document the preliminary impacts of the Tanzania Health Information Technology (T-HIT) system mHealth intervention aimed at health workers for PMTCT care delivery and capacity building in a rural area of Tanzania. Methods We developed T-HIT as a tablet-based system for an electronic data collection system designed to capture and report PMTCT data during antenatal, delivery, and postnatal visits in Misungwi, Tanzania. T-HIT was tested by health workers in a pilot randomized trial comparing seven sites using T-HIT assigned at random to seven control sites; all sites maintained standard paper record-keeping during the pilot intervention period. We compared numbers of antenatal visits, number of HIV tests administered, and women testing positive across all sites. Results Health workers recorded data from antenatal visits for 1530 women; of these, 695 (45.42%) were tested for HIV and 3.59% (55/1530) tested positive. Health workers were unable to conduct an HIV test for 103 women (6.73%, 103/1530) because of lack of reagent, which is not captured on paper logs. There was no difference in the activity level for testing when comparing sites T-HIT to non-T-HIT sites. We observed a significant postintervention increase in the numbers of women testing positive for HIV compared with the preintervention period (P=.04), but this was likely not attributable to the T-HIT system. Conclusions T-HIT had a high degree of acceptability and feasibility and is perceived as useful by health workers, who documented more antenatal visits during the pilot intervention compared with a traditional system of paper logs, suggesting potential for improvements in antenatal care for women at risk for HIV. PMID:29335236

Sepsis Patients with First and Second-Hit Infections Show Different Outcomes Depending on the Causative Organism

PubMed Central

Morgan, Matt P.; Szakmany, Tamas; Power, Sarah G.; Olaniyi, Patrick; Hall, Judith E.; Rowan, Kathy; Eberl, Matthias

2016-01-01

Objective: With improving rates of initial survival in severe sepsis, second-hit infections that occur following resolution of the primary insult carry an increasing burden of morbidity. However, despite the clinical relevance of these infections, no data are available on differential outcomes in patients with first and second-hit infections depending on the nature of the causative organism. This study aims to explore any differences in these subgroups. Design: In a retrospective, observational cohort study, the United Kingdom Intensive Care National Audit & Research Centre (ICNARC) database was used to explore the outcomes of patient with first-hit infections leading to sepsis, and sepsis patients with second-hit infections grouped according to the Gram status of the causative organism. Setting: General critical care units in England, Wales, and Northern Ireland participating in the ICNARC programme between 1 January, 2007 and 30 June, 2012. Patients: Patient groups analyzed included 2119 patients with and 1319 patients without sepsis who developed an intensive care unit acquired infection in blood. Subgroups included patients with trauma, emergency neurosurgery, elective surgery, and cardiogenic shock. Measurements and main results: Gram-negative organisms were associated with poorer outcomes in first-hit infections. The 90-day mortality of patients who developed a Gram-negative infection was 43.6% following elective surgery and 27.9% following trauma. This compared with a mortality of 25.6 and 20.6%, respectively, in Gram-positive infections. Unexpectedly, an inverse relationship between Gram status and mortality was observed in second-hit infections. Patients with an initial diagnosis of sepsis who developed secondary infections caused by Gram-negative organisms had a 90-day mortality of 40.4%, compared with 43.6% in Gram-positive infections. Conclusions: Our study identifies a fundamental difference in patient outcomes between first-hit and second-hit bacterial infections, which may be due to genetic, microbiological, immunological, and environmental factors. This finding has direct implications for risk stratification and defines future research priorities. PMID:26955367

Sepsis Patients with First and Second-Hit Infections Show Different Outcomes Depending on the Causative Organism.

PubMed

Morgan, Matt P; Szakmany, Tamas; Power, Sarah G; Olaniyi, Patrick; Hall, Judith E; Rowan, Kathy; Eberl, Matthias

2016-01-01

With improving rates of initial survival in severe sepsis, second-hit infections that occur following resolution of the primary insult carry an increasing burden of morbidity. However, despite the clinical relevance of these infections, no data are available on differential outcomes in patients with first and second-hit infections depending on the nature of the causative organism. This study aims to explore any differences in these subgroups. In a retrospective, observational cohort study, the United Kingdom Intensive Care National Audit & Research Centre (ICNARC) database was used to explore the outcomes of patient with first-hit infections leading to sepsis, and sepsis patients with second-hit infections grouped according to the Gram status of the causative organism. General critical care units in England, Wales, and Northern Ireland participating in the ICNARC programme between 1 January, 2007 and 30 June, 2012. Patient groups analyzed included 2119 patients with and 1319 patients without sepsis who developed an intensive care unit acquired infection in blood. Subgroups included patients with trauma, emergency neurosurgery, elective surgery, and cardiogenic shock. Gram-negative organisms were associated with poorer outcomes in first-hit infections. The 90-day mortality of patients who developed a Gram-negative infection was 43.6% following elective surgery and 27.9% following trauma. This compared with a mortality of 25.6 and 20.6%, respectively, in Gram-positive infections. Unexpectedly, an inverse relationship between Gram status and mortality was observed in second-hit infections. PATIENTS with an initial diagnosis of sepsis who developed secondary infections caused by Gram-negative organisms had a 90-day mortality of 40.4%, compared with 43.6% in Gram-positive infections. Our study identifies a fundamental difference in patient outcomes between first-hit and second-hit bacterial infections, which may be due to genetic, microbiological, immunological, and environmental factors. This finding has direct implications for risk stratification and defines future research priorities.

Functional high intensity exercise training ameliorates insulin resistance and cardiometabolic risk factors in type 2 diabetes.

PubMed

Fealy, Ciarán E; Nieuwoudt, Stephan; Foucher, Julie A; Scelsi, Amanda R; Malin, Steve K; Pagadala, Mangesh; Cruz, Lauren A; Li, Miranda; Rocco, Michael; Burguera, Bartolome; Kirwan, John P

2018-05-15

Functional high intensity training (F-HIT) is a novel fitness paradigm that integrates simultaneous aerobic and resistance training in sets of constantly varied movements, based on real-world situational exercises, performed at high intensity in workouts that range from ∼8-20 min/session. We hypothesized that F-HIT would be an effective exercise mode for reducing insulin resistance in type 2 diabetes (T2D). We recruited 13 overweight/obese adults (5 males, 8 females; 53 ± 7 years; BMI 34.5 ± 3.6 kg•m -2 , Mean ± SD) with T2D to participate in a 6 week (3d/wk) supervised F-HIT program. An oral glucose tolerance test was used to derive measures of insulin sensitivity. F-HIT significantly reduced fat mass (43.8 ± 83.8 vs 41.6 ± 7.9 kg; P < 0.01), diastolic blood pressure (80.2 ± 7.1 vs 74.5 ± 5.8; P < 0.01), blood lipids (triglyceride and VLDL, both P < 0.05) and metabolic syndrome z-score (6.4 ± 4.5 vs -0.2 ± 5.2 AU; P < 0.001), and increased basal fat oxidation (FOX: 0.08 ± 0.03 vs 0.10 ± 0.04 g•min -1 ; P = 0.05), and HMW adiponectin (214.4 ± 88.9 vs 288.8 ± 127.4 ng•mL -1 ; P < 0.01). Importantly, F-HIT also increased insulin sensitivity (0.037 ± 0.010 vs 0.042 ± 0.010 AU; P < 0.05). Increases in HMW adiponectin and FOX correlated with the change in insulin sensitivity (rho: 0.75; P < 0.05, rho: 0.81; P < 0.01, respectively). Compliance with the training program was > 95% and no injuries or adverse events were reported. These data suggest that F-HIT may be an effective exercise mode for managing T2D. The increase in insulin sensitivity addresses a key defect in T2D and is consistent with improvements observed after more traditional aerobic exercise programs in overweight/obese adults with T2D. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Progress on FIR interferometry and Thomson Scattering measurements on HIT-SI3

NASA Astrophysics Data System (ADS)

Everson, Christopher; Jarboe, Thomas; Morgan, Kyle

2017-10-01

Spatially resolved measurements of the electron temperature (Te) and density (ne) will be fundamental in assessing the degree to which HIT-SI3 demonstrates closed magnetic flux and energy confinement. Further, electron temperature measurements have not yet been made on an inductively-driven spheromak. Far infrared (FIR) interferometer and Thomson Scattering (TS) systems have been installed on the HIT-SI3 spheromak. The TS system currently implemented on HIT-SI3 was originally designed for other magnetic confinement experiments, and progress continues toward modifying and optimizing for HIT-SI3 plasmas. Initial results suggest that the electron temperature is of order 10 eV. Plans to modify the TS system to provide more sensitivity and accuracy at low temperatures are presented. The line-integrated ne is measured on one chord by the FIR interferometer, with densities near 5x1019 m-3. Four cylindrical volumes have been added to the HIT-SI3 apparatus to enhance passive pumping. It is hoped that this will allow for more control of the density during the 2 ms discharges. Density measurements from before and after the installation of the passive pumping volumes are presented for comparison.

Comparison of Video Head Impulse Test (vHIT) Gains Between Two Commercially Available Devices and by Different Gain Analytical Methods.

PubMed

Lee, Sang Hun; Yoo, Myung Hoon; Park, Jun Woo; Kang, Byung Chul; Yang, Chan Joo; Kang, Woo Suk; Ahn, Joong Ho; Chung, Jong Woo; Park, Hong Ju

2018-06-01

To evaluate whether video head impulse test (vHIT) gains are dependent on the measuring device and method of analysis. Prospective study. vHIT was performed in 25 healthy subjects using two devices simultaneously. vHIT gains were compared between these instruments and using five different methods of comparing position and velocity gains during head movement intervals. The two devices produced different vHIT gain results with the same method of analysis. There were also significant differences in the vHIT gains measured using different analytical methods. The gain analytic method that compares the areas under the velocity curve (AUC) of the head and eye movements during head movements showed lower vHIT gains than a method that compared the peak velocities of the head and eye movements. The former method produced the vHIT gain with the smallest standard deviation among the five procedures tested in this study. vHIT gains differ in normal subjects depending on the device and method of analysis used, suggesting that it is advisable for each device to have its own normal values. Gain calculations that compare the AUC of the head and eye movements during the head movements show the smallest variance.

Documenting the location of systematic transrectal ultrasound-guided prostate biopsies: correlation with multi-parametric MRI.

PubMed

Turkbey, Baris; Xu, Sheng; Kruecker, Jochen; Locklin, Julia; Pang, Yuxi; Shah, Vijay; Bernardo, Marcelino; Baccala, Angelo; Rastinehad, Ardeshir; Benjamin, Compton; Merino, Maria J; Wood, Bradford J; Choyke, Peter L; Pinto, Peter A

2011-03-29

During transrectal ultrasound (TRUS)-guided prostate biopsies, the actual location of the biopsy site is rarely documented. Here, we demonstrate the capability of TRUS-magnetic resonance imaging (MRI) image fusion to document the biopsy site and correlate biopsy results with multi-parametric MRI findings. Fifty consecutive patients (median age 61 years) with a median prostate-specific antigen (PSA) level of 5.8 ng/ml underwent 12-core TRUS-guided biopsy of the prostate. Pre-procedural T2-weighted magnetic resonance images were fused to TRUS. A disposable needle guide with miniature tracking sensors was attached to the TRUS probe to enable fusion with MRI. Real-time TRUS images during biopsy and the corresponding tracking information were recorded. Each biopsy site was superimposed onto the MRI. Each biopsy site was classified as positive or negative for cancer based on the results of each MRI sequence. Sensitivity, specificity, and receiver operating curve (ROC) area under the curve (AUC) values were calculated for multi-parametric MRI. Gleason scores for each multi-parametric MRI pattern were also evaluated. Six hundred and 5 systemic biopsy cores were analyzed in 50 patients, of whom 20 patients had 56 positive cores. MRI identified 34 of 56 positive cores. Overall, sensitivity, specificity, and ROC area values for multi-parametric MRI were 0.607, 0.727, 0.667, respectively. TRUS-MRI fusion after biopsy can be used to document the location of each biopsy site, which can then be correlated with MRI findings. Based on correlation with tracked biopsies, T2-weighted MRI and apparent diffusion coefficient maps derived from diffusion-weighted MRI are the most sensitive sequences, whereas the addition of delayed contrast enhancement MRI and three-dimensional magnetic resonance spectroscopy demonstrated higher specificity consistent with results obtained using radical prostatectomy specimens.

High-performance gas sensors with temperature measurement

PubMed Central

Zhang, Yong; Li, Shengtao; Zhang, Jingyuan; Pan, Zhigang; Min, Daomin; Li, Xin; Song, Xiaoping; Liu, Junhua

2013-01-01

There are a number of gas ionization sensors using carbon nanotubes as cathode or anode. Unfortunately, their applications are greatly limited by their multi-valued sensitivity, one output value corresponding to several measured concentration values. Here we describe a triple-electrode structure featuring two electric fields with opposite directions, which enable us to overcome the multi-valued sensitivity problem at 1 atm in a wide range of gas concentrations. We used a carbon nanotube array as the first electrode, and the two electric fields between the upper and the lower interelectrode gaps were designed to extract positive ions generated in the upper gap, hence significantly reduced positive ion bombardment on the nanotube electrode, which allowed us to maintain a high electric field near the nanotube tips, leading to a single-valued sensitivity and a long nanotube life. We have demonstrated detection of various gases and simultaneously monitoring temperature, and a potential for applications. PMID:23405281

Leveraging health information technology to achieve the “triple aim” of healthcare reform

PubMed Central

Sood, Harpreet S; Bates, David W

2015-01-01

Objective To investigate experiences with leveraging health information technology (HIT) to improve patient care and population health, and reduce healthcare expenditures. Materials and methods In-depth qualitative interviews with federal government employees, health policy, HIT and medico-legal experts, health providers, physicians, purchasers, payers, patient advocates, and vendors from across the United States. Results The authors undertook 47 interviews. There was a widely shared belief that Health Information Technology for Economic and Clinical Health (HITECH) had catalyzed the creation of a digital infrastructure, which was being used in innovative ways to improve quality of care and curtail costs. There were however major concerns about the poor usability of electronic health records (EHRs), their limited ability to support multi-disciplinary care, and major difficulties with health information exchange, which undermined efforts to deliver integrated patient-centered care. Proposed strategies for enhancing the benefits of HIT included federal stimulation of competition by mandating vendors to open-up their application program interfaces, incenting development of low-cost consumer informatics tools, and promoting Congressional review of the The Health Insurance Portability and Accountability Act (HIPPA) to optimize the balance between data privacy and reuse. Many underscored the need to “kick the legs from underneath the fee-for-service model” and replace it with a data-driven reimbursement system that rewards high quality care. Conclusions The HITECH Act has stimulated unprecedented, multi-stakeholder interest in HIT. Early experiences indicate that the resulting digital infrastructure is being used to improve quality of care and curtail costs. Reform efforts are however severely limited by problems with usability, limited interoperability and the persistence of the fee-for-service paradigm—addressing these issues therefore needs to be the federal government’s main policy target. PMID:25882032

Diagnostic and prognostic utility of an inexpensive rapid on site malaria diagnostic test (ParaHIT f) among ethnic tribal population in areas of high, low and no transmission in central India.

PubMed

Singh, Neeru; Mishra, A K; Shukla, M M; Chand, S K; Bharti, Praveen Kumar

2005-06-21

Malaria presents a diagnostic challenge in most tropical countries. Rapid detection of the malaria parasite and early treatment of infection still remain the most important goals of disease management. Therefore, performance characteristics of the new indigenous ParaHIT f test (Span diagnostic Ltd, Surat, India) was determined among ethnic tribal population in four districts of different transmission potential in central India to assess whether this rapid diagnostic test (RDT) could be widely applied as a diagnostic tool to control malaria. Beyond diagnosis, the logical utilization of RDTs is to monitor treatment outcome. A finger prick blood sample was collected from each clinically suspected case of malaria to prepare blood smear and for testing with the RDT after taking informed consent. The blood smears were read by an experienced technician blinded to the RDT results and clinical status of the subjects. The figures for specificity, sensitivity, accuracy and predictive values were calculated using microscopy as gold standard. The prevalence of malaria infection estimated by RDT in parallel with microscopy provide evidence of the type of high, low or no transmission in the study area. Analysis revealed (pooled data of all four epidemiological settings) that overall sensitivity, specificity and accuracy of the RDT were >90% in areas of different endemicity. While, RDT is useful to confirm the diagnosis of new symptomatic cases of suspected P. falciparum infection, the persistence of parasite antigen leading to false positives even after clearance of asexual parasitaemia has limited its utility as a prognostic tool. The study showed that the ParaHIT f test was easy to use, reliable and cheap. Thus this RDT is an appropriate test for the use in the field by paramedical staff when laboratory facilities are not available and thus likely to contribute greatly to an effective control of malaria in resource poor countries.

A strategy for comprehensive identification of sequential constituents using ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometer, application study on chlorogenic acids in Flos Lonicerae Japonicae.

PubMed

Zhang, Jia-yu; Wang, Zi-jian; Li, Yun; Liu, Ying; Cai, Wei; Li, Chen; Lu, Jian-qiu; Qiao, Yan-jiang

2016-01-15

The analytical methodologies for evaluation of multi-component system in traditional Chinese medicines (TCMs) have been inadequate or unacceptable. As a result, the unclarity of multi-component hinders the sufficient interpretation of their bioactivities. In this paper, an ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap (UPLC-LTQ-Orbitrap)-based strategy focused on the comprehensive identification of TCM sequential constituents was developed. The strategy was characterized by molecular design, multiple ion monitoring (MIM), targeted database hits and mass spectral trees similarity filter (MTSF), and even more isomerism discrimination. It was successfully applied in the HRMS data-acquisition and processing of chlorogenic acids (CGAs) in Flos Lonicerae Japonicae (FLJ), and a total of 115 chromatographic peaks attributed to 18 categories were characterized, allowing a comprehensive revelation of CGAs in FLJ for the first time. This demonstrated that MIM based on molecular design could improve the efficiency to trigger MS/MS fragmentation reactions. Targeted database hits and MTSF searching greatly facilitated the processing of extremely large information data. Besides, the introduction of diagnostic product ions (DPIs) discrimination, ClogP analysis, and molecular simulation, raised the efficiency and accuracy to characterize sequential constituents especially position and geometric isomers. In conclusion, the results expanded our understanding on CGAs in FLJ, and the strategy could be exemplary for future research on the comprehensive identification of sequential constituents in TCMs. Meanwhile, it may propose a novel idea for analyzing sequential constituents, and is promising for quality control and evaluation of TCMs. Copyright © 2015 Elsevier B.V. All rights reserved.

Flat Field Anomalies in an X-ray CCD Camera Measured Using a Manson X-ray Source

DOE Office of Scientific and Technical Information (OSTI.GOV)

M. J. Haugh and M. B. Schneider

2008-10-31

The Static X-ray Imager (SXI) is a diagnostic used at the National Ignition Facility (NIF) to measure the position of the X-rays produced by lasers hitting a gold foil target. The intensity distribution taken by the SXI camera during a NIF shot is used to determine how accurately NIF can aim laser beams. This is critical to proper NIF operation. Imagers are located at the top and the bottom of the NIF target chamber. The CCD chip is an X-ray sensitive silicon sensor, with a large format array (2k x 2k), 24 μm square pixels, and 15 μm thick. Amore » multi-anode Manson X-ray source, operating up to 10kV and 10W, was used to characterize and calibrate the imagers. The output beam is heavily filtered to narrow the spectral beam width, giving a typical resolution E/ΔE≈10. The X-ray beam intensity was measured using an absolute photodiode that has accuracy better than 1% up to the Si K edge and better than 5% at higher energies. The X-ray beam provides full CCD illumination and is flat, within ±1% maximum to minimum. The spectral efficiency was measured at 10 energy bands ranging from 930 eV to 8470 eV. We observed an energy dependent pixel sensitivity variation that showed continuous change over a large portion of the CCD. The maximum sensitivity variation occurred at 8470 eV. The geometric pattern did not change at lower energies, but the maximum contrast decreased and was not observable below 4 keV. We were also able to observe debris, damage, and surface defects on the CCD chip. The Manson source is a powerful tool for characterizing the imaging errors of an X-ray CCD imager. These errors are quite different from those found in a visible CCD imager.« less

The Marble-Hand Illusion

PubMed Central

Senna, Irene; Maravita, Angelo; Bolognini, Nadia; Parise, Cesare V.

2014-01-01

Our body is made of flesh and bones. We know it, and in our daily lives all the senses constantly provide converging information about this simple, factual truth. But is this always the case? Here we report a surprising bodily illusion demonstrating that humans rapidly update their assumptions about the material qualities of their body, based on their recent multisensory perceptual experience. To induce a misperception of the material properties of the hand, we repeatedly gently hit participants' hand with a small hammer, while progressively replacing the natural sound of the hammer against the skin with the sound of a hammer hitting a piece of marble. After five minutes, the hand started feeling stiffer, heavier, harder, less sensitive, unnatural, and showed enhanced Galvanic skin response (GSR) to threatening stimuli. Notably, such a change in skin conductivity positively correlated with changes in perceived hand stiffness. Conversely, when hammer hits and impact sounds were temporally uncorrelated, participants did not spontaneously report any changes in the perceived properties of the hand, nor did they show any modulation in GSR. In two further experiments, we ruled out that mere audio-tactile synchrony is the causal factor triggering the illusion, further demonstrating the key role of material information conveyed by impact sounds in modulating the perceived material properties of the hand. This novel bodily illusion, the ‘Marble-Hand Illusion', demonstrates that the perceived material of our body, surely the most stable attribute of our bodily self, can be quickly updated through multisensory integration. PMID:24621793

Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual hit hypothesis of neurodegeneration

PubMed Central

Heinemann, Scott D.; Posimo, Jessica M.; Mason, Daniel M.; Hutchison, Daniel F.; Leak, Rehana K.

2016-01-01

The dual hit hypothesis of neurodegeneration states that severe stress sensitizes vulnerable cells to subsequent challenges so that the two hits are synergistic in their toxic effects. Although the hippocampus is vulnerable to a number of neurodegenerative disorders, there are no models of synergistic cell death in hippocampal neurons in response to combined proteotoxic and oxidative stressors, the two major characteristics of these diseases. Therefore, we developed a relatively high-throughput dual hit model of stress synergy in primary hippocampal neurons. In order to increase the rigor of our study and strengthen our interpretations, we employed three independent, unbiased viability assays at multiple timepoints. Stress synergy was elicited when hippocampal neurons were treated with the proteasome inhibitor MG132 followed by exposure to the oxidative toxicant paraquat, but only after 48h. MG132 and paraquat only elicited additive effects 24h after the final hit and even loss of heat shock protein 70 activity and glutathione did not promote stress synergy at this early timepoint. Dual hits of MG132 elicited modest glutathione loss and slightly synergistic toxic effects 48h after the second hit, but only at some concentrations and only according to two viability assays (metabolic fitness and cytoskeletal integrity). The thiol N-acetyl cysteine protected hippocampal neurons against dual MG132/MG132 hits but not dual MG132/paraquat hits. Our findings support the view that proteotoxic and oxidative stress propel and propagate each other in hippocampal neurons, leading to synergistically toxic effects, but not as the default response and only after a delay. The neuronal stress synergy observed here lies in contrast to astrocytic responses to dual hits, because astrocytes that survive severe proteotoxic stress resist additional cell loss following second hits. In conclusion, we present a new model of hippocampal vulnerability in which to test therapies, because neuroprotective treatments that are effective against severe, synergistic stress are more likely to succeed in the clinic. PMID:26934478

Use and clinical efficacy of standard and health information technology fall risk assessment tools.

PubMed

Teh, Ruth C; Wilson, Anne; Ranasinghe, Damith; Visvanathan, Renuka

2017-12-01

To evaluate the health information technology (HIT) compared to Fall Risk for Older Persons (FROP) tool in fall risk screening. A HIT tool trial was conducted on the geriatric evaluation and management (GEM, n = 111) and acute medical units (AMU, n = 424). Health information technology and FROP scores were higher on GEM versus AMU, with no differences between people who fell and people who did not fall. Both score completion rates were similar, and their values correlated marginally (Spearman's correlation coefficient 0.33, P < 0.01). HIT and FROP scores demonstrated similar sensitivity (80 vs 82%) and specificity (32 vs 36%) for detecting hospital falls. Hospital fall rates trended towards reduction on AMU (4.20 vs 6.96, P = 0.15) and increase on GEM (10.98 vs 6.52, P = 0.54) with HIT tool implementation. Health information technology tool acceptability and scoring were comparable to FROP screening, with mixed effects on fall rate with HIT tool implementation. Clinician partnership remains key to effective tool development. © 2017 AJA Inc.

Molecular Dynamics Simulations of Novel Potential Inhibitors for Penicillin Binding Protein 2B of the Resistant 5204 Strain of Streptococcus Pneumoniae.

PubMed

Suvaithenamudhan, Suvaiyarasan; Parthasarathy, Subbiah

2017-01-01

Top five best hit compounds (ZINC59376795, ZINC60175365, ZINC36922620, ZINC39550705 and ZINC36953975) were obtained through our high throughput virtual screening (HTVS) analysis with resistant 5204-PBP2B (5204 Penicillin Binding Protein 2B) and sensitive R6-PBP2B (R6 Penicillin Binding Protein 2B) proteins of Streptococcus pneumoniae. To gain insight in molecular docking and dynamics simulations of these top five best hit compounds with both resistant 5204-PBP2B and sensitive R6-PBP2B targets. We have employed Glide XP docking and molecular dynamics simulations of these five best hit compounds with 5204-PBP2B and R6-PBP2B targets. The stability analysis has been carried out through DFT, prime-MM/GBSA binding free energy, RMSD, RMSF and Principal Component Analysis. The reference drug, penicillin G forms stable complex with sensitive R6-PBP2B protein. Similar stability is observed for the mutant resistant 5204-PBP2B with the top scoring compound ZINC592376795 which implies that this compound may act as an effective potential inhibitor. The compound ZINC59376795 forms a total of five hydrogen bonds with resistant 5204-PBP2B protein of which three are with mutated residues. Similarly, the other four compounds including penicillin G also form hydrogen bonds with mutated residue. The MD simulations and stability analysis of the complexes of wild and mutant forms are evaluated for a trajectory period of 16ns and further MD simulations of ZINC59376795 with resistant 5204-PBP2B and sensitive R6-PBP2B confirmed the stability for 50 ns. These results suggest that the top five best hit compounds are found to be a promising gateway for the further development of anti-pneumococcal therapeutics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Applications of Biophysics in High-Throughput Screening Hit Validation.

PubMed

Genick, Christine Clougherty; Barlier, Danielle; Monna, Dominique; Brunner, Reto; Bé, Céline; Scheufler, Clemens; Ottl, Johannes

2014-06-01

For approximately a decade, biophysical methods have been used to validate positive hits selected from high-throughput screening (HTS) campaigns with the goal to verify binding interactions using label-free assays. By applying label-free readouts, screen artifacts created by compound interference and fluorescence are discovered, enabling further characterization of the hits for their target specificity and selectivity. The use of several biophysical methods to extract this type of high-content information is required to prevent the promotion of false positives to the next level of hit validation and to select the best candidates for further chemical optimization. The typical technologies applied in this arena include dynamic light scattering, turbidometry, resonance waveguide, surface plasmon resonance, differential scanning fluorimetry, mass spectrometry, and others. Each technology can provide different types of information to enable the characterization of the binding interaction. Thus, these technologies can be incorporated in a hit-validation strategy not only according to the profile of chemical matter that is desired by the medicinal chemists, but also in a manner that is in agreement with the target protein's amenability to the screening format. Here, we present the results of screening strategies using biophysics with the objective to evaluate the approaches, discuss the advantages and challenges, and summarize the benefits in reference to lead discovery. In summary, the biophysics screens presented here demonstrated various hit rates from a list of ~2000 preselected, IC50-validated hits from HTS (an IC50 is the inhibitor concentration at which 50% inhibition of activity is observed). There are several lessons learned from these biophysical screens, which will be discussed in this article. © 2014 Society for Laboratory Automation and Screening.

The e-health implementation toolkit: qualitative evaluation across four European countries

PubMed Central

2011-01-01

Background Implementation researchers have attempted to overcome the research-practice gap in e-health by developing tools that summarize and synthesize research evidence of factors that impede or facilitate implementation of innovation in healthcare settings. The e-Health Implementation Toolkit (e-HIT) is an example of such a tool that was designed within the context of the United Kingdom National Health Service to promote implementation of e-health services. Its utility in international settings is unknown. Methods We conducted a qualitative evaluation of the e-HIT in use across four countries--Finland, Norway, Scotland, and Sweden. Data were generated using a combination of interview approaches (n = 22) to document e-HIT users' experiences of the tool to guide decision making about the selection of e-health pilot services and to monitor their progress over time. Results e-HIT users evaluated the tool positively in terms of its scope to organize and enhance their critical thinking about their implementation work and, importantly, to facilitate discussion between those involved in that work. It was easy to use in either its paper- or web-based format, and its visual elements were positively received. There were some minor criticisms of the e-HIT with some suggestions for content changes and comments about its design as a generic tool (rather than specific to sites and e-health services). However, overall, e-HIT users considered it to be a highly workable tool that they found useful, which they would use again, and which they would recommend to other e-health implementers. Conclusion The use of the e-HIT is feasible and acceptable in a range of international contexts by a range of professionals for a range of different e-health systems. PMID:22098945

The e-Health Implementation Toolkit: qualitative evaluation across four European countries.

PubMed

MacFarlane, Anne; Clerkin, Pauline; Murray, Elizabeth; Heaney, David J; Wakeling, Mary; Pesola, Ulla-Maija; Waterworth, Eva Lindh; Larsen, Frank; Makiniemi, Minna; Winblad, Ilkka

2011-11-19

Implementation researchers have attempted to overcome the research-practice gap in e-health by developing tools that summarize and synthesize research evidence of factors that impede or facilitate implementation of innovation in healthcare settings. The e-Health Implementation Toolkit (e-HIT) is an example of such a tool that was designed within the context of the United Kingdom National Health Service to promote implementation of e-health services. Its utility in international settings is unknown. We conducted a qualitative evaluation of the e-HIT in use across four countries--Finland, Norway, Scotland, and Sweden. Data were generated using a combination of interview approaches (n = 22) to document e-HIT users' experiences of the tool to guide decision making about the selection of e-health pilot services and to monitor their progress over time. e-HIT users evaluated the tool positively in terms of its scope to organize and enhance their critical thinking about their implementation work and, importantly, to facilitate discussion between those involved in that work. It was easy to use in either its paper- or web-based format, and its visual elements were positively received. There were some minor criticisms of the e-HIT with some suggestions for content changes and comments about its design as a generic tool (rather than specific to sites and e-health services). However, overall, e-HIT users considered it to be a highly workable tool that they found useful, which they would use again, and which they would recommend to other e-health implementers. The use of the e-HIT is feasible and acceptable in a range of international contexts by a range of professionals for a range of different e-health systems.

Informatics technology mimics ecology: dense, mutualistic collaboration networks are associated with higher publication rates.

PubMed

Sorani, Marco D

2012-01-01

Information technology (IT) adoption enables biomedical research. Publications are an accepted measure of research output, and network models can describe the collaborative nature of publication. In particular, ecological networks can serve as analogies for publication and technology adoption. We constructed network models of adoption of bioinformatics programming languages and health IT (HIT) from the literature.We selected seven programming languages and four types of HIT. We performed PubMed searches to identify publications since 2001. We calculated summary statistics and analyzed spatiotemporal relationships. Then, we assessed ecological models of specialization, cooperativity, competition, evolution, biodiversity, and stability associated with publications.Adoption of HIT has been variable, while scripting languages have experienced rapid adoption. Hospital systems had the largest HIT research corpus, while Perl had the largest language corpus. Scripting languages represented the largest connected network components. The relationship between edges and nodes was linear, though Bioconductor had more edges than expected and Perl had fewer. Spatiotemporal relationships were weak. Most languages shared a bioinformatics specialization and appeared mutualistic or competitive. HIT specializations varied. Specialization was highest for Bioconductor and radiology systems. Specialization and cooperativity were positively correlated among languages but negatively correlated among HIT. Rates of language evolution were similar. Biodiversity among languages grew in the first half of the decade and stabilized, while diversity among HIT was variable but flat. Compared with publications in 2001, correlation with publications one year later was positive while correlation after ten years was weak and negative.Adoption of new technologies can be unpredictable. Spatiotemporal relationships facilitate adoption but are not sufficient. As with ecosystems, dense, mutualistic, specialized co-habitation is associated with faster growth. There are rapidly changing trends in external technological and macroeconomic influences. We propose that a better understanding of how technologies are adopted can facilitate their development.

Prospective multicentre cohort study of heparin-induced thrombocytopenia in acute ischaemic stroke patients

PubMed Central

Kawano, Hiroyuki; Yamamoto, Haruko; Miyata, Shigeki; Izumi, Manabu; Hirano, Teruyuki; Toratani, Naomi; Kakutani, Isami; Sheppard, Jo-Ann I; Warkentin, Theodore E; Kada, Akiko; Sato, Shoichiro; Okamoto, Sadahisa; Nagatsuka, Kazuyuki; Naritomi, Hiroaki; Toyoda, Kazunori; Uchino, Makoto; Minematsu, Kazuo

2011-01-01

Acute ischaemic stroke patients sometimes receive heparin for treatment and/or prophylaxis of thromboembolic complications. This study was designed to elucidate the incidence and clinical features of heparin-induced thrombocytopenia (HIT) in acute stroke patients treated with heparin. We conducted a prospective multicentre cohort study of 267 patients who were admitted to three stroke centres within 7 d after stroke onset. We examined clinical data until discharge and collected blood samples on days 1 and 14 of hospitalization to test anti-platelet factor 4/heparin antibodies (anti-PF4/H Abs) using an enzyme-linked immunosorbent assay (ELISA); platelet-activating antibodies were identified by serotonin-release assay (SRA). Patients with a 4Ts score ≥4 points, positive-ELISA, and positive-SRA were diagnosed as definite HIT. Heparin was administered to 172 patients (64·4%: heparin group). Anti-PF4/H Abs were detected by ELISA in 22 cases (12·8%) in the heparin group. Seven patients had 4Ts ≥ 4 points. Among them, three patients (1·7% overall) were also positive by both ELISA and SRA. National Institutes of Health Stroke Scale score on admission was high (range, 16–23) and in-hospital mortality was very high (66·7%) in definite HIT patients. In this study, the incidence of definite HIT in acute ischaemic stroke patients treated with heparin was 1·7% (95% confidence interval: 0·4–5·0). The clinical severity and outcome of definite HIT were unfavourable. PMID:21671895

HITS-CLIP yields genome-wide insights into brain alternative RNA processing

NASA Astrophysics Data System (ADS)

Licatalosi, Donny D.; Mele, Aldo; Fak, John J.; Ule, Jernej; Kayikci, Melis; Chi, Sung Wook; Clark, Tyson A.; Schweitzer, Anthony C.; Blume, John E.; Wang, Xuning; Darnell, Jennifer C.; Darnell, Robert B.

2008-11-01

Protein-RNA interactions have critical roles in all aspects of gene expression. However, applying biochemical methods to understand such interactions in living tissues has been challenging. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova revealed extremely reproducible RNA-binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3' untranslated regions, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo.

Effects of electronic health information technology implementation on nursing home resident outcomes.

PubMed

Pillemer, Karl; Meador, Rhoda H; Teresi, Jeanne A; Chen, Emily K; Henderson, Charles R; Lachs, Mark S; Boratgis, Gabriel; Silver, Stephanie; Eimicke, Joseph P

2012-02-01

To examine the effects of electronic health information technology (HIT) on nursing home residents. The study evaluated the impact of implementing a comprehensive HIT system on resident clinical, functional, and quality of care outcome indicators as well as measures of resident awareness of and satisfaction with the technology. The study used a prospective, quasi-experimental design, directly assessing 761 nursing home residents in 10 urban and suburban nursing homes in the greater New York City area. No statistically significant impact of the introduction of HIT on residents was found on any outcomes, with the exception of a significant negative effect on behavioral symptoms. Residents' subjective assessment of the HIT intervention were generally positive. The absence of effects on most indicators is encouraging for the future development of HIT in nursing homes. The single negative finding suggests that further investigation is needed on possible impact on resident behavior. © The Author(s) 2012

The role of backward cell migration in two-hit mutants' production in the stem cell niche.

PubMed

Bollas, Audrey; Shahriyari, Leili

2017-01-01

It has been discovered that there are two stem cell groups in the intestinal crypts: central stem cells (CeSCs), which are at the very bottom of the crypt, and border stem cells (BSCs), which are located between CeSCs and transit amplifying cells (TAs). Moreover, backward cell migration from BSCs to CeSCs has been observed. Recently, a bi-compartmental stochastic model, which includes CeSCs and BSCs, has been developed to investigate the probability of two-hit mutant production in the stem cell niche. In this project, we improve this stochastic model by adding the probability of backward cell migration to the model. The model suggests that the probability of two-hit mutant production increases when the frequency of backward cell migration increases. Furthermore, a small non-zero probability of backward cell migration leads to the largest range of optimal values for the frequency of symmetric divisions and the portion of divisions at each stem cell compartment in terms of delaying 2-hit mutant production. Moreover, the probability of two-hit mutant production is more sensitive to the probability of symmetric divisions than to the rate of backward cell migrations. The highest probability of two-hit mutant production corresponds to the case when all stem cell's divisions are asymmetric.

The role of backward cell migration in two-hit mutants’ production in the stem cell niche

PubMed Central

Bollas, Audrey

2017-01-01

It has been discovered that there are two stem cell groups in the intestinal crypts: central stem cells (CeSCs), which are at the very bottom of the crypt, and border stem cells (BSCs), which are located between CeSCs and transit amplifying cells (TAs). Moreover, backward cell migration from BSCs to CeSCs has been observed. Recently, a bi-compartmental stochastic model, which includes CeSCs and BSCs, has been developed to investigate the probability of two-hit mutant production in the stem cell niche. In this project, we improve this stochastic model by adding the probability of backward cell migration to the model. The model suggests that the probability of two-hit mutant production increases when the frequency of backward cell migration increases. Furthermore, a small non-zero probability of backward cell migration leads to the largest range of optimal values for the frequency of symmetric divisions and the portion of divisions at each stem cell compartment in terms of delaying 2-hit mutant production. Moreover, the probability of two-hit mutant production is more sensitive to the probability of symmetric divisions than to the rate of backward cell migrations. The highest probability of two-hit mutant production corresponds to the case when all stem cell’s divisions are asymmetric. PMID:28931019

Two-fluid (plasma-neutral) Extended-MHD simulations of spheromak configurations in the HIT-SI experiment with PSI-Tet

NASA Astrophysics Data System (ADS)

Sutherland, D. A.; Hansen, C. J.; Jarboe, T. R.

2017-10-01

A self-consistent, two-fluid (plasma-neutral) dynamic neutral model has been implemented into the 3-D, Extended-MHD code PSI-Tet. A monatomic, hydrogenic neutral fluid reacts with a plasma fluid through elastic scattering collisions and three inelastic collision reactions: electron-impact ionization, radiative recombination, and resonant charge-exchange. Density, momentum, and energy are evolved for both the plasma and neutral species. The implemented plasma-neutral model in PSI-Tet is being used to simulate decaying spheromak configurations in the HIT-SI experimental geometry, which is being compare to two-photon absorption laser induced fluorescence measurements (TALIF) made on the HIT-SI3 experiment. TALIF is used to measure the absolute density and temperature of monatomic deuterium atoms. Neutral densities on the order of 1015 m-3 and neutral temperatures between 0.6-1.7 eV were measured towards the end of decay of spheromak configurations with initial toroidal currents between 10-12 kA. Validation results between TALIF measurements and PSI-Tet simulations with the implemented dynamic neutral model will be presented. Additionally, preliminary dynamic neutral simulations of the HIT-SI/HIT-SI3 spheromak plasmas sustained with inductive helicity injection will be presented. Lastly, potential benefits of an expansion of the two-fluid model into a multi-fluid model that includes multiple neutral species and tracking of charge states will be discussed.

Rare transformation to double hit lymphoma in Waldenstrom's macroglobulinemia.

PubMed

Okolo, Onyemaechi N; Johnson, Ariel C; Yun, Seongseok; Arnold, Stacy J; Anwer, Faiz

2017-08-01

Waldenström macroglobulinemia (WM) is a lymphoproliferative lymphoma that is characterized by monoclonal immunoglobulin M (IgM) protein and bone marrow infiltration. Its incidence is rare and rarer still is its ability to transform to a B-cell lymphoma, particularly the aggressive diffuse large B-cell lymphoma, which bodes a poor prognosis. When transformation includes mutations of MYC, BCL-2 and/or BCL-6, it is known as a 'double hit' or 'triple hit' lymphoma respectively. This paper presents a rare case of WM with mutations positive for MYC and BCL2, making it a case of double hit B-cell lymphoplasmacytic lymphoma with plasmatic differentiation without morphological transformation to aggressive histology like DLBCL. The paper also broadens to include discussions on current topics in the classification, diagnosis, possible causes of transformation, and treatment of WM, including transformation to double hit lymphoma. The significance of this case lies in that the presence of double hit lymphoma-like genetic mutations in WM have not been previously described in the literature and potentially such changes are harbinger of extra-nodal presentation, aggressive growth, and possibly poor prognosis, if data from other double-hit lymphoma are extrapolated.

The impact of Health Information Technology (I-HIT) Scale: the Australian results.

PubMed

Cook, Robyn; Foster, Joanne

2009-01-01

One of role of the nurse in the clinical setting is that of co-ordinating communication across the healthcare team. On a daily basis nurses interact with the person receiving care, their family members, and multiple care providers thus placing the nurse in the central position with access to a vast array of information on the person. Through this nurses have historically functioned as "information repositories". With the advent of Health Information Technology (HIT) tools there is a potential that HIT could impact interdisciplinary communication, practice efficiency and effectiveness, relationships and workflow in acute care settings [1][3]. In 2005, the HIMSS Nursing Informatics Community developed the I-HIT Scale to measure the impact of HIT on the nursing role and interdisciplinary communication in USA hospitals. In 2007, nursing informatics colleagues from Australia, Finland, Ireland, New Zealand, Scotland and the USA formed a research collaborative to validate the I-HIT in six additional countries. This paper will discuss the background, methodology, results and implications from the Australian I-HIT survey of over 1,100 nurses. The results are currently being analyzed and will be presented at the conference.

Validation of the Generalized Anxiety Disorder-7 (GAD-7) and GAD-2 in patients with migraine.

PubMed

Seo, Jong-Geun; Park, Sung-Pa

2015-01-01

Psychiatric problems have been commonly reported in patients with migraine. This study investigated the reliability and validity of the Generalized Anxiety Disorder-7 (GAD-7) and Generalized Anxiety Disorder-2 (GAD-2) in patients with migraine. Subjects were recruited from a headache clinic and a neuropsychologist examined their GAD using the Mini International Neuropsychiatric Interview-Plus Version 5.0.0 (MINI). Subjects completed several instruments, including the GAD-7, the Beck Anxiety Inventory (BAI), the Migraine Disability Assessment Scale (MIDAS), the Headache Impact Test-6 (HIT-6), and the Migraine-Specific Quality of Life (MSQoL). Among 146 participants, 32 patients (21.9 %) had GAD as determined by the MINI. Cronbach's α for the GAD-7 and GAD-2 were 0.915 and 0.820, respectively. At a cutoff score of 5, the GAD-7 had a sensitivity of 78.1 %, a specificity of 74.6 %, a positive predictive value (PPV) of 46.3 %, and a negative predictive value (NPV) of 92.4 %. At a cutoff score of 1, the GAD-2 had a sensitivity of 84.4 %, a specificity of 72.8 %, a PPV of 46.6 %, and a NPV of 94.3 %. The scores of the GAD-7 and GAD-2 well correlated with the BAI score, the MIDAS score, the HIT-6 score, and the MSQoL score. The GAD-7 and GAD-2 are both reliable and valid screening instruments for GAD in patients with migraine.

Multi-fingered haptic palpation utilizing granular jamming stiffness feedback actuators

NASA Astrophysics Data System (ADS)

Li, Min; Ranzani, Tommaso; Sareh, Sina; Seneviratne, Lakmal D.; Dasgupta, Prokar; Wurdemann, Helge A.; Althoefer, Kaspar

2014-09-01

This paper describes a multi-fingered haptic palpation method using stiffness feedback actuators for simulating tissue palpation procedures in traditional and in robot-assisted minimally invasive surgery. Soft tissue stiffness is simulated by changing the stiffness property of the actuator during palpation. For the first time, granular jamming and pneumatic air actuation are combined to realize stiffness modulation. The stiffness feedback actuator is validated by stiffness measurements in indentation tests and through stiffness discrimination based on a user study. According to the indentation test results, the introduction of a pneumatic chamber to granular jamming can amplify the stiffness variation range and reduce hysteresis of the actuator. The advantage of multi-fingered palpation using the proposed actuators is proven by the comparison of the results of the stiffness discrimination performance using two-fingered (sensitivity: 82.2%, specificity: 88.9%, positive predicative value: 80.0%, accuracy: 85.4%, time: 4.84 s) and single-fingered (sensitivity: 76.4%, specificity: 85.7%, positive predicative value: 75.3%, accuracy: 81.8%, time: 7.48 s) stiffness feedback.

Experimental design and statistical methods for improved hit detection in high-throughput screening.

PubMed

Malo, Nathalie; Hanley, James A; Carlile, Graeme; Liu, Jing; Pelletier, Jerry; Thomas, David; Nadon, Robert

2010-09-01

Identification of active compounds in high-throughput screening (HTS) contexts can be substantially improved by applying classical experimental design and statistical inference principles to all phases of HTS studies. The authors present both experimental and simulated data to illustrate how true-positive rates can be maximized without increasing false-positive rates by the following analytical process. First, the use of robust data preprocessing methods reduces unwanted variation by removing row, column, and plate biases. Second, replicate measurements allow estimation of the magnitude of the remaining random error and the use of formal statistical models to benchmark putative hits relative to what is expected by chance. Receiver Operating Characteristic (ROC) analyses revealed superior power for data preprocessed by a trimmed-mean polish method combined with the RVM t-test, particularly for small- to moderate-sized biological hits.

Increased Health Information Technology Adoption and Use Among Small Primary Care Physician Practices Over Time: A National Cohort Study.

PubMed

Rittenhouse, Diane R; Ramsay, Patricia P; Casalino, Lawrence P; McClellan, Sean; Kandel, Zosha K; Shortell, Stephen M

2017-01-01

Implementation and meaningful use of health information technology (HIT) has been shown to facilitate delivery system transformation, yet implementation is far from universal. This study examined correlates of greater HIT implementation over time among a national cohort of small primary care practices in the United States. We used data from a 40-minute telephone panel survey of 566 small primary care practices having 8 or fewer physicians to investigate adoption and use of HIT in 2007-2010 and 2012-2013. We used generalized estimating equations (GEE) to estimate the association of practice characteristics and external incentives with the adoption and use of HIT. We studied 18 measures of HIT functionalities, including record keeping, clinical decision support, patient communication, and health information exchange with hospitals and pharmacies. Overall, use of 16 HIT functionalities increased significantly over time, whereas use of 2 decreased significantly. On average, compared with physician-owned practices, hospital-owned practices used 1.48 (95% CI, 1.07-1.88; P <.001) more HIT processes. And relative to smaller practices, practices with 3 to 8 physicians used 2.49 (95% CI, 2.26-2.72; P <.001) more HIT processes. Participation in pay-for-performance programs, participation in public reporting of clinical quality data, and a larger proportion of revenue from Medicare were also associated with greater adoption and use of HIT. The new Medicare Access and CHIP Reauthorization Act (MACRA) will provide payment incentives and technical support to speed HIT adoption and use by small practices. We found that external incentives were, indeed, positively associated with greater adoption and use of HIT. Our findings also support a strategy of targeting assistance to smaller physician practices and those that are physician owned. © 2017 Annals of Family Medicine, Inc.

The use and role of open source software applications in public and not-for-profit hospitals in the United States.

PubMed

Vest, Joshua R; Stephens, James H

2013-01-01

The potential cost savings and customizability of open source software (OSS) may be particularly attractive for hospitals. However, numerous health-care-specific OSS applications exist, the adoption of OSS health information technology (HIT) applications is not widespread in the United States. This disconnect between the availability of promising software and low adoption raises the basic question: If OSS HIT is so advantageous, why are more health care organizations not using it? We interviewed the chief information officer, or equivalent position, at 17 not-for-profit and public hospitals across the United States. Through targeted recruitment, our sample included nine hospitals using OSS HIT and eight hospitals not using OSS HIT. The open-ended interview questions were guided by domains included in the fit-viability theory, an organizational-level innovation adoption framework, and those suggested by a review of the literature. Transcripts were analyzed using an inductive and comparative approach, which involved an open coding for relevant themes. Interviews described the state of OSS use in hospitals. Specifically, general OSS applications were widely used by IT professionals. In addition, hospitals using OSS HIT still relied heavily on vendor support. In terms of why decisions arose to use OSS HIT, several hospitals using OSS HIT noted the cost advantages. In contrast, hospitals avoiding OSS HIT were clear, OSS as a class did not fit with clinical work and posed too much risk. Perceptions of OSS HIT ranged from enthusiastic embracement to resigned adoption, to refusal, to abandonment. Some organizations were achieving success with their OSS HIT choices, but they still relied on vendors for significant support. The decision to adopt OSS HIT was not uniform but contingent upon views of the risk posed by the technology, economic factors, and the hospital's existing capabilities.

HIT-6 and MIDAS as measures of headache disability in a headache referral population.

PubMed

Sauro, Khara M; Rose, Marianne S; Becker, Werner J; Christie, Suzanne N; Giammarco, Rose; Mackie, Gordon F; Eloff, Arnoldas G; Gawel, Marek J

2010-03-01

The objective of this study was to compare the headache impact test (HIT-6) and the migraine disability assessment scale (MIDAS) as clinical measures of headache-related disability. The degree of headache-related disability is an important factor in treatment planning. Many quality of life and headache disability measures exist but it is unclear which of the available disability measures is the most helpful in planning and measuring headache management. We compared HIT-6 and MIDAS scores from 798 patients from the Canadian Headache Outpatient Registry and Database (CHORD). Correlation and regression analyses were used to examine the relationships between the HIT-6 and MIDAS total scores, headache frequency and intensity, and Beck Depression Inventory (BDI-II) scores. A positive correlation was found between HIT-6 and MIDAS scores (r = 0.52). The BDI-II scores correlated equally with the HIT-6 and the MIDAS (r = 0.42). There was a non-monotonic relationship between headache frequency and the MIDAS, and a non-linear monotonic relationship between headache frequency and the HIT-6 (r = 0.24). The correlation was higher between the intensity and the HIT-6 scores (r = 0.46), than MIDAS (r = 0.26) scores. Seventy-nine percent of patients fell into the most severe HIT-6 disability category, compared with the 57% of patients that fell into the most severe MIDAS disability category. Significantly more patients were placed in a more severe category with the HIT-6 than with the MIDAS (McNemar chi-square = 191 on 6 d.f., P < .0001). The HIT-6 and MIDAS appear to measure headache-related disability in a similar fashion. However, some important differences may exist. Headache intensity appears to influence HIT-6 score more than the MIDAS, whereas the MIDAS was influenced more by headache frequency. Using the HIT-6 and MIDAS together may give a more accurate assessment of a patient's headache-related disability.

Radiation microscope for SEE testing using GeV ions.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Doyle, Barney Lee; Knapp, James Arthur; Rossi, Paolo

2009-09-01

Radiation Effects Microscopy is an extremely useful technique in failure analysis of electronic parts used in radiation environment. It also provides much needed support for development of radiation hard components used in spacecraft and nuclear weapons. As the IC manufacturing technology progresses, more and more overlayers are used; therefore, the sensitive region of the part is getting farther and farther from the surface. The thickness of these overlayers is so large today that the traditional microbeams, which are used for REM are unable to reach the sensitive regions. As a result, higher ion beam energies have to be used (>more » GeV), which are available only at cyclotrons. Since it is extremely complicated to focus these GeV ion beams, a new method has to be developed to perform REM at cyclotrons. We developed a new technique, Ion Photon Emission Microscopy, where instead of focusing the ion beam we use secondary photons emitted from a fluorescence layer on top of the devices being tested to determine the position of the ion hit. By recording this position information in coincidence with an SEE signal we will be able to indentify radiation sensitive regions of modern electronic parts, which will increase the efficiency of radiation hard circuits.« less

Carrier transport and sensitivity issues in heterojunction with intrinsic thin layer solar cells on N-type crystalline silicon: A computer simulation study

NASA Astrophysics Data System (ADS)

Rahmouni, M.; Datta, A.; Chatterjee, P.; Damon-Lacoste, J.; Ballif, C.; Roca i Cabarrocas, P.

2010-03-01

Heterojunction with intrinsic thin layer or "HIT" solar cells are considered favorable for large-scale manufacturing of solar modules, as they combine the high efficiency of crystalline silicon (c-Si) solar cells, with the low cost of amorphous silicon technology. In this article, based on experimental data published by Sanyo, we simulate the performance of a series of HIT cells on N-type crystalline silicon substrates with hydrogenated amorphous silicon (a-Si:H) emitter layers, to gain insight into carrier transport and the general functioning of these devices. Both single and double HIT structures are modeled, beginning with the initial Sanyo cells having low open circuit voltages but high fill factors, right up to double HIT cells exhibiting record values for both parameters. The one-dimensional numerical modeling program "Amorphous Semiconductor Device Modeling Program" has been used for this purpose. We show that the simulations can correctly reproduce the electrical characteristics and temperature dependence for a set of devices with varying I-layer thickness. Under standard AM1.5 illumination, we show that the transport is dominated by the diffusion mechanism, similar to conventional P/N homojunction solar cells, and tunneling is not required to describe the performance of state-of-the art devices. Also modeling has been used to study the sensitivity of N-c-Si HIT solar cell performance to various parameters. We find that the solar cell output is particularly sensitive to the defect states on the surface of the c-Si wafer facing the emitter, to the indium tin oxide/P-a-Si:H front contact barrier height and to the band gap and activation energy of the P-a-Si:H emitter, while the I-a-Si:H layer is necessary to achieve both high Voc and fill factor, as it passivates the defects on the surface of the c-Si wafer. Finally, we describe in detail for most parameters how they affect current transport and cell properties.

Robust statistical methods for hit selection in RNA interference high-throughput screening experiments.

PubMed

Zhang, Xiaohua Douglas; Yang, Xiting Cindy; Chung, Namjin; Gates, Adam; Stec, Erica; Kunapuli, Priya; Holder, Dan J; Ferrer, Marc; Espeseth, Amy S

2006-04-01

RNA interference (RNAi) high-throughput screening (HTS) experiments carried out using large (>5000 short interfering [si]RNA) libraries generate a huge amount of data. In order to use these data to identify the most effective siRNAs tested, it is critical to adopt and develop appropriate statistical methods. To address the questions in hit selection of RNAi HTS, we proposed a quartile-based method which is robust to outliers, true hits and nonsymmetrical data. We compared it with the more traditional tests, mean +/- k standard deviation (SD) and median +/- 3 median of absolute deviation (MAD). The results suggested that the quartile-based method selected more hits than mean +/- k SD under the same preset error rate. The number of hits selected by median +/- k MAD was close to that by the quartile-based method. Further analysis suggested that the quartile-based method had the greatest power in detecting true hits, especially weak or moderate true hits. Our investigation also suggested that platewise analysis (determining effective siRNAs on a plate-by-plate basis) can adjust for systematic errors in different plates, while an experimentwise analysis, in which effective siRNAs are identified in an analysis of the entire experiment, cannot. However, experimentwise analysis may detect a cluster of true positive hits placed together in one or several plates, while platewise analysis may not. To display hit selection results, we designed a specific figure called a plate-well series plot. We thus suggest the following strategy for hit selection in RNAi HTS experiments. First, choose the quartile-based method, or median +/- k MAD, for identifying effective siRNAs. Second, perform the chosen method experimentwise on transformed/normalized data, such as percentage inhibition, to check the possibility of hit clusters. If a cluster of selected hits are observed, repeat the analysis based on untransformed data to determine whether the cluster is due to an artifact in the data. If no clusters of hits are observed, select hits by performing platewise analysis on transformed data. Third, adopt the plate-well series plot to visualize both the data and the hit selection results, as well as to check for artifacts.

Validation of concussion risk curves for collegiate football players derived from HITS data.

PubMed

Funk, James R; Rowson, Steven; Daniel, Ray W; Duma, Stefan M

2012-01-01

For several years, Virginia Tech and other schools have measured the frequency and severity of head impacts sustained by collegiate American football players in real time using the Head Impact Telemetry (HIT) System of helmet-mounted accelerometers. In this study, data from 37,128 head impacts collected at Virginia Tech during games from 2006 to 2010 were analyzed. Peak head acceleration exceeded 100 g in 516 impacts, and the Head Injury Criterion (HIC) exceeded 200 in 468 impacts. Four instrumented players in the dataset sustained a concussion. These data were used to develop risk curves for concussion as a function of peak head acceleration and HIC. The validity of this biomechanical approach was assessed using epidemiological data on concussion incidence from other sources. Two specific aspects of concussion incidence were addressed: the variation by player position, and the frequency of repeat concussions. The HIT System data indicated that linemen sustained the highest overall number of head impacts, while skill positions sustained a higher number of more severe head impacts (peak acceleration > 100 g or HIC > 200). When weighted using injury risk curves, the HIT System data predicted a higher incidence of concussion in skill positions compared to linemen at rates that were in strong agreement with the epidemiological literature (Pearson's r = 0.72-0.87). The predicted rates of repeat concussions (21-39% over one season and 33-50% over five seasons) were somewhat higher than the ranges reported in the epidemiological literature. These analyses demonstrate that simple biomechanical parameters that can be measured by the HIT System possess a high level of power for predicting concussion.

Cellular immune responses to platelet factor 4 and heparin complexes in patients with heparin-induced thrombocytopenia.

PubMed

Nazy, Ishac; Clare, Rumi; Staibano, Phillip; Warkentin, Theodore E; Larche, Mark; Moore, Jane C; Smith, James W; Whitlock, Richard P; Kelton, John G; Arnold, Donald M

2018-05-03

Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin characterized by thrombocytopenia and thrombotic complications. HIT is caused by pathogenic antibodies that bind to complexes of platelet factor 4 and heparin (PF4/heparin) leading to platelet activation and inducing a hypercoagulable state. Previous studies have shown immunity to PF4/heparin occurs early in life even before heparin exposure; however, the immunogenesis of HIT is not well characterized. The aim of this study was to investigate cellular proliferation in response to PF4/heparin complexes in patients with HIT. Peripheral blood mononuclear cells (PBMCs) from healthy controls (n = 30), postoperative cardiac surgery patients who underwent cardiopulmonary bypass (CPB, n = 17), and patients with confirmed HIT (n = 41) were cultured with PF4 and PF4/heparin. Cellular proliferation was assessed by 3 H-thymidine uptake and 5-ethynyl-2'-deoxyuridine (EdU) detection. PBMCs proliferated in the presence of PF4 and was enhanced by the addition of heparin in all study groups. CPB and HIT patients exhibited significantly higher proliferative responses compared to healthy controls. PBMC proliferation was antigen-specific, depended on the presence of platelets, and only CD14 + cells were identified as proliferating cells. Culture supernatants were tested for the levels of regulatory cytokines and both CPB and HIT patients produced significantly lower levels of IL-10 and TGF-β1 compared to healthy controls. These findings further demonstrate that cellular immune sensitization to PF4/heparin occurs before heparin exposure and suggests that immune dysregulation can contribute to the immunogenesis of HIT. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual-hit hypothesis of neurodegeneration.

PubMed

Heinemann, Scott D; Posimo, Jessica M; Mason, Daniel M; Hutchison, Daniel F; Leak, Rehana K

2016-08-01

The dual-hit hypothesis of neurodegeneration states that severe stress sensitizes vulnerable cells to subsequent challenges so that the two hits are synergistic in their toxic effects. Although the hippocampus is vulnerable to a number of neurodegenerative disorders, there are no models of synergistic cell death in hippocampal neurons in response to combined proteotoxic and oxidative stressors, the two major characteristics of these diseases. Therefore, a relatively high-throughput dual-hit model of stress synergy was developed in primary hippocampal neurons. In order to increase the rigor of the study and strengthen the interpretations, three independent, unbiased viability assays were employed at multiple timepoints. Stress synergy was elicited when hippocampal neurons were treated with the proteasome inhibitor MG132 followed by exposure to the oxidative toxicant paraquat, but only after 48 h. MG132 and paraquat only elicited additive effects 24 h after the final hit and even loss of heat shock protein 70 activity and glutathione did not promote stress synergy at this early timepoint. Dual hits of MG132 elicited modest glutathione loss and slightly synergistic toxic effects 48 h after the second hit, but only at some concentrations and only according to two viability assays (metabolic fitness and cytoskeletal integrity). The thiol N-acetyl cysteine protected hippocampal neurons against dual MG132/MG132 hits but not dual MG132/paraquat hits. These findings support the view that proteotoxic and oxidative stress propel and propagate each other in hippocampal neurons, leading to synergistically toxic effects, but not as the default response and only after a delay. The neuronal stress synergy observed here lies in contrast to astrocytic responses to dual hits, because astrocytes that survive severe proteotoxic stress resist additional cell loss following second hits. In conclusion, a new model of hippocampal vulnerability was developed for the testing of therapies, because neuroprotective treatments that are effective against severe, synergistic stress are more likely to succeed in the clinic. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

On hitting children: a review of corporal punishment in the United States.

PubMed

Knox, Michele

2010-01-01

Research has clearly demonstrated associations between corporal punishment of children and maladaptive behavior patterns such as aggression and delinquency. Hitting children is an act of violence and a clear violation of children's human rights. In this article, the position of the United States on corporal punishment of children is discussed. Professional and international progress on ending corporal punishment is explained, and the relationship between corporal punishment and child abuse is discussed. An appeal is made for prevention efforts such as parent education and removal of social sanctions for hitting children that may hold significant promise for preventing child maltreatment.

Building and Growing a Hospital Intranet: A Case Study

PubMed Central

Polkowski, Michelle; McLemore, Geoff; Greaker, Mark; Murray, Malcolm

2001-01-01

Background The Intranet is a rapidly evolving technology in large hospitals. In this paper, we describe the first phase of an Intranet project in a multi-hospital system in New York City. Objectives (1) To encourage the use of the Intranet among physicians, nurses, managers, and other associates in a multi-hospital system; and (2) to build the Intranet in a cost-effective manner using existing resources. Methods A WebTrends Log Analyzer assessed the Intranet use in terms of the number of accesses from each department. Results A broad range of features, including medical knowledge resources, clinical practice guidelines, directions, patient education, online forms, phone directory, and discussion forums were developed. Analysis of more than 890,000 hits revealed the departments with hits greater than 1,000 were the 'Library' (6,130), 'Physicians Gateway' (2,539), 'Marketing' (1,321), 'Information Systems' (1,241), and 'Nutrition' (1,221). Of 819 unique visitors, 74 per cent visited more than once. Conclusions It is possible to create and diffuse an Intranet in a multi-hospital system in a cost-effective manner. However, the key challenges were selling the potential of this new technology to opinion leaders and other stakeholders, and converting pre-existing printed content by obtaining word processed and image files from other departments or contracted print publishers. PMID:11720952

Building and growing a hospital intranet: a case study.

PubMed

Ong, K R; Polkowski, M; McLemore, G; Greaker, M; Murray, M

2001-01-01

The Intranet is a rapidly evolving technology in large hospitals. In this paper, we describe the first phase of an Intranet project in a multi-hospital system in New York City. (1) To encourage the use of the Intranet among physicians, nurses, managers, and other associates in a multi-hospital system; and (2) to build the Intranet in a cost-effective manner using existing resources. A WebTrends Log Analyzer assessed the Intranet use in terms of the number of accesses from each department. A broad range of features, including medical knowledge resources, clinical practice guidelines, directions, patient education, online forms, phone directory, and discussion forums were developed. Analysis of more than 890,000 hits revealed the departments with hits greater than 1,000 were the Library (6,130), Physicians Gateway (2,539), Marketing (1,321), Information Systems (1,241), and Nutrition (1,221). Of 819 unique visitors, 74 per cent visited more than once. It is possible to create and diffuse an Intranet in a multi-hospital system in a cost-effective manner. However, the key challenges were selling the potential of this new technology to opinion leaders and other stakeholders, and converting pre-existing printed content by obtaining word processed and image files from other departments or contracted print publishers.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Aiwu; Hohlmann, Marcus; Azmoun, Babak

Here, we study the position sensitivity of radial zigzag strips intended to read out large GEM detectors for tracking at future experiments. Zigzag strips can cover a readout area with fewer strips than regular straight strips while maintaining good spatial resolution. Consequently, they can reduce the number of required electronic channels and related cost for large-area GEM detector systems. A non-linear relation between incident particle position and hit position measured from charge sharing among zigzag strips was observed in a previous study. We significantly reduce this non-linearity by improving the interleaving of adjacent physical zigzag strips. Zigzag readout structures aremore » implemented on PCBs and on a flexible foil and are tested using a 10 cm × 10 cm triple-GEM detector scanned with a strongly collimated X-ray gun on a 2D motorized stage. Lastly, angular resolutions of 60–84 μrad are achieved with a 1.37 mrad angular strip pitch at a radius of 784 mm. On a linear scale this corresponds to resolutions below 100 μm.« less

Systematic Errors in Peptide and Protein Identification and Quantification by Modified Peptides*

PubMed Central

Bogdanow, Boris; Zauber, Henrik; Selbach, Matthias

2016-01-01

The principle of shotgun proteomics is to use peptide mass spectra in order to identify corresponding sequences in a protein database. The quality of peptide and protein identification and quantification critically depends on the sensitivity and specificity of this assignment process. Many peptides in proteomic samples carry biochemical modifications, and a large fraction of unassigned spectra arise from modified peptides. Spectra derived from modified peptides can erroneously be assigned to wrong amino acid sequences. However, the impact of this problem on proteomic data has not yet been investigated systematically. Here we use combinations of different database searches to show that modified peptides can be responsible for 20–50% of false positive identifications in deep proteomic data sets. These false positive hits are particularly problematic as they have significantly higher scores and higher intensities than other false positive matches. Furthermore, these wrong peptide assignments lead to hundreds of false protein identifications and systematic biases in protein quantification. We devise a “cleaned search” strategy to address this problem and show that this considerably improves the sensitivity and specificity of proteomic data. In summary, we show that modified peptides cause systematic errors in peptide and protein identification and quantification and should therefore be considered to further improve the quality of proteomic data annotation. PMID:27215553

Discovery and hit-to-lead optimization of 2,6-diaminopyrimidine inhibitors of interleukin-1 receptor-associated kinase 4

DOE Office of Scientific and Technical Information (OSTI.GOV)

McElroy, William T.; Michael Seganish, W.; Jason Herr, R.

2015-05-01

Interleukin receptor-associated kinase 4 (IRAK4) is a critical element of the Toll-like/interleukin-1 receptor inflammation signaling pathway. A screening campaign identified a novel diaminopyrimidine hit that exhibits weak IRAK4 inhibitory activity and a ligand efficiency of 0.25. Hit-to-lead activities were conducted through independent SAR studies of each of the four pyrimidine substituents. Optimal activity was observed upon removal of the pyrimidine C-4 chloro substituent. The intact C-6 carboribose is required for IRAK4 inhibition. Numerous heteroaryls were tolerated at the C-5 position, with azabenzothiazoles conferring the best activities. Aminoheteroaryls were preferred at the C-2 position. These studies led to the discovery ofmore » inhibitors 35, 36, and 38 that exhibit nanomolar inhibition of IRAK4, improved ligand efficiencies, and modest kinase selectivities.« less

Discovery and hit-to-lead optimization of 2,6-diaminopyrimidine inhibitors of interleukin-1 receptor-associated kinase 4.

PubMed

McElroy, William T; Michael Seganish, W; Jason Herr, R; Harding, James; Yang, Jinhai; Yet, Larry; Komanduri, Venukrishnan; Prakash, Koraboina Chandra; Lavey, Brian; Tulshian, Deen; Greenlee, William J; Sondey, Christopher; Fischmann, Thierry O; Niu, Xiaoda

2015-05-01

Interleukin receptor-associated kinase 4 (IRAK4) is a critical element of the Toll-like/interleukin-1 receptor inflammation signaling pathway. A screening campaign identified a novel diaminopyrimidine hit that exhibits weak IRAK4 inhibitory activity and a ligand efficiency of 0.25. Hit-to-lead activities were conducted through independent SAR studies of each of the four pyrimidine substituents. Optimal activity was observed upon removal of the pyrimidine C-4 chloro substituent. The intact C-6 carboribose is required for IRAK4 inhibition. Numerous heteroaryls were tolerated at the C-5 position, with azabenzothiazoles conferring the best activities. Aminoheteroaryls were preferred at the C-2 position. These studies led to the discovery of inhibitors 35, 36, and 38 that exhibit nanomolar inhibition of IRAK4, improved ligand efficiencies, and modest kinase selectivities. Copyright © 2015 Elsevier Ltd. All rights reserved.

Extracting Information from Narratives: An Application to Aviation Safety Reports

DOE Office of Scientific and Technical Information (OSTI.GOV)

Posse, Christian; Matzke, Brett D.; Anderson, Catherine M.

2005-05-12

Aviation safety reports are the best available source of information about why a flight incident happened. However, stream of consciousness permeates the narratives making difficult the automation of the information extraction task. We propose an approach and infrastructure based on a common pattern specification language to capture relevant information via normalized template expression matching in context. Template expression matching handles variants of multi-word expressions. Normalization improves the likelihood of correct hits by standardizing and cleaning the vocabulary used in narratives. Checking for the presence of negative modifiers in the proximity of a potential hit reduces the chance of false hits.more » We present the above approach in the context of a specific application, which is the extraction of human performance factors from NASA ASRS reports. While knowledge infusion from experts plays a critical role during the learning phase, early results show that in a production mode, the automated process provides information that is consistent with analyses by human subjects.« less

Mass spectrometry for fragment screening.

PubMed

Chan, Daniel Shiu-Hin; Whitehouse, Andrew J; Coyne, Anthony G; Abell, Chris

2017-11-08

Fragment-based approaches in chemical biology and drug discovery have been widely adopted worldwide in both academia and industry. Fragment hits tend to interact weakly with their targets, necessitating the use of sensitive biophysical techniques to detect their binding. Common fragment screening techniques include differential scanning fluorimetry (DSF) and ligand-observed NMR. Validation and characterization of hits is usually performed using a combination of protein-observed NMR, isothermal titration calorimetry (ITC) and X-ray crystallography. In this context, MS is a relatively underutilized technique in fragment screening for drug discovery. MS-based techniques have the advantage of high sensitivity, low sample consumption and being label-free. This review highlights recent examples of the emerging use of MS-based techniques in fragment screening. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Inhibitory control differentiates rare target search performance in children.

PubMed

Li, Hongting; Chan, John S Y; Cheung, Sui-Yin; Yan, Jin H

2012-02-01

Age-related differences in rare-target search are primarily explained by the speed-accuracy trade-off, primed responses, or decision making. The goal was to examine how motor inhibition influences visual search. Children pressed a key when a rare target was detected. On no-target trials, children withheld reactions. Response time (RT), hits, misses, correct rejection, and false alarms were measured. Tapping tests assessed motor control. Older children tapped faster, were more sensitive to rare targets (higher d'), and reacted more slowly than younger ones. Girls outperformed boys in search sensitivity but not in RT. Motor speed was closely associated with hit rate and RT. Results suggest that development of inhibitory control plays a key role in visual detection. The potential implications for cognitive-motor development and individual differences are discussed.

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons.

PubMed

Ali, Yousuf O; Bradley, Gillian; Lu, Hui-Chen

2017-03-07

Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer's, Huntington's, Parkinson's diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons.

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

PubMed Central

Ali, Yousuf O.; Bradley, Gillian; Lu, Hui-Chen

2017-01-01

Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer’s, Huntington’s, Parkinson’s diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons. PMID:28266613

The KLOE-2 high energy taggers

NASA Astrophysics Data System (ADS)

Curciarello, F.

2017-06-01

The precision measurement of the π0 → γγ width allows to gain insights into the low-energy QCD dynamics. A way to achieve the precision needed (1%) in order to test theory predictions is to study the π0 production through γγ fusion in the e+e- → e+e-γ*γ* → e+e-π0 reaction. The KLOE-2 experiment, currently running at the DAΦNE facility in Frascati, aims to perform this measurement. For this reason, new detectors, which allow to tag final state leptons, have been installed along the DAΦNE beam line in order to reduce the background coming from phi-meson decays. The High Energy Tagger (HET) detector measures the deviation of leptons from their main orbit by determining their position and timing. The HET detectors are placed in roman pots just at the exit of the DAΦNE dipole magnets, 11 m away from the IP, both on positron and electron sides. The HET sensitive area is made up of a set of 28 plastic scintillators. A dedicated DAQ electronic board, based on a Xilinx Virtex-5 FPGA, has been developed for this detector. It provides a MultiHit TDC with a time resolution of 550(1) ps and the possibility to clearly identify the correct bunch crossing (ΔTbunch ~ 2.7 ns). The most relevant features of the KLOE-2 tagging system operation as time performance, stability and the techniques used to determine the time overlap between the KLOE and HET asynchronous DAQs will be presented.

How I treat double-hit lymphoma.

PubMed

Friedberg, Jonathan W

2017-08-03

The 2016 revision of the World Health Organization (WHO) classification for lymphoma has included a new category of lymphoma, separate from diffuse large B-cell lymphoma, termed high-grade B-cell lymphoma with translocations involving myc and bcl-2 or bcl-6 . These lymphomas, which occur in <10% of cases of diffuse large B-cell lymphoma, have been referred to as double-hit lymphomas (or triple-hit lymphomas if all 3 rearrangements are present). It is important to differentiate these lymphomas from the larger group of double-expressor lymphomas, which have increased expression of MYC and BCL-2 and/or BCL-6 by immunohistochemistry, by using variable cutoff percentages to define positivity. Patients with double-hit lymphomas have a poor prognosis when treated with standard chemoimmunotherapy and have increased risk of central nervous system involvement and progression. Double-hit lymphomas may arise as a consequence of the transformation of the underlying indolent lymphoma. There are no published prospective trials in double-hit lymphoma, however retrospective studies strongly suggest that aggressive induction regimens may confer a superior outcome. In this article, I review my approach to the evaluation and treatment of double-hit lymphoma, with an eye toward future clinical trials incorporating rational targeted agents into the therapeutic armamentarium. © 2017 by The American Society of Hematology.

Fragment-based drug design.

PubMed

Feyfant, Eric; Cross, Jason B; Paris, Kevin; Tsao, Désirée H H

2011-01-01

Fragment-based drug design (FBDD), which is comprised of both fragment screening and the use of fragment hits to design leads, began more than 15 years ago and has been steadily gaining in popularity and utility. Its origin lies on the fact that the coverage of chemical space and the binding efficiency of hits are directly related to the size of the compounds screened. Nevertheless, FBDD still faces challenges, among them developing fragment screening libraries that ensure optimal coverage of chemical space, physical properties and chemical tractability. Fragment screening also requires sensitive assays, often biophysical in nature, to detect weak binders. In this chapter we will introduce the technologies used to address these challenges and outline the experimental advantages that make FBDD one of the most popular new hit-to-lead process.

Physical attractiveness stereotype and memory.

PubMed

Rohner, Jean-Christophe; Rasmussen, Anders

2011-08-01

Three experiments examined explicit and implicit memory for information that is congruent with the physical attractiveness stereotype (i.e. attractive-positive and unattractive-negative) and information that is incongruent with the physical attractiveness stereotype (i.e. attractive-negative and unattractive-positive). Measures of explicit recognition sensitivity and implicit discriminability revealed a memorial advantage for congruent compared to incongruent information, as evident from hit and false alarm rates and reaction times, respectively. Measures of explicit memory showed a recognition bias toward congruent compared to incongruent information, where participants tended to call congruent information old, independently of whether the information had been shown previously or not. This recognition bias was unrelated to reports of subjective confidence in retrieval. The present findings shed light on the cognitive mechanisms that might mediate discriminatory behavior towards physically attractive and physically unattractive individuals. © 2011 The Authors. Scandinavian Journal of Psychology © 2011 The Scandinavian Psychological Associations.

Computers in the clinical encounter: a scoping review and thematic analysis.

PubMed

Crampton, Noah H; Reis, Shmuel; Shachak, Aviv

2016-05-01

Patient-clinician communication has been associated with increased patient satisfaction, trust in the clinician, adherence to prescribed therapy, and various health outcomes. The impact of health information technology (HIT) on the clinical encounter in general and patient-clinician communication in particular is a growing concern. The purpose of this study was to review the current literature on HIT use during the clinical encounter to update best practices and inform the continuous development of HIT policies and educational interventions. We conducted a literature search of four databases. After removing duplicates, reviewing titles and abstracts, performing a full-text review, and snowballing from references and citations, 51 articles were included in the analysis. We employed a qualitative thematic analysis to compare and contrast the findings across studies. Our analysis revealed that the use of HIT affects consultations in complex ways, impacting eye contact and gaze, information sharing, building relationships, and pauses in the conversation. Whether these impacts are positive or negative largely depends on the combination of consultation room layout, patient and clinician styles of interaction with HIT as well as each other, and the strategies and techniques employed by clinicians to integrate HIT into consultations. The in-depth insights into the impact of HIT on the clinical encounter, especially the strategies and techniques employed by clinicians to adapt to using HIT in consultations, can inform policies, educational interventions, and research. In contrast to the common negative views of HIT, it affects the clinical encounter in multiple ways. By applying identified strategies and best practices, HIT can support patient-clinician interactions rather than interfering with them. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Perioperative use of iloprost in cardiac surgery patients diagnosed with heparin-induced thrombocytopenia-reactive antibodies or with true HIT (HIT-reactive antibodies plus thrombocytopenia): An 11-year experience.

PubMed

Palatianos, George; Michalis, Alkiviadis; Alivizatos, Petros; Lacoumenda, Stavroula; Geroulanos, Stefanos; Karabinis, Andreas; Iliopoulou, Eugenia; Soufla, Giannoula; Kanthou, Chryso; Khoury, Mazen; Sfyrakis, Petros; Stavridis, George; Astras, George; Vassili, Maria; Antzaka, Christina; Marathias, Katerina; Kriaras, Ioannis; Tasouli, Androniki; Papadopoulos, Kyrillos; Katafygioti, Marina; Matoula, Nikoletta; Angelidis, Antonios; Melissari, Euthemia

2015-07-01

Thrombocytopenia and thromboembolism(s) may develop in heparin immune-mediated thrombocytopenia (HIT) patients after reexposure to heparin. At the Onassis Cardiac Surgery Center, 530 out of 17,000 patients requiring heart surgery over an 11-year period underwent preoperative HIT assessment by ELISA and a three-point heparin-induced platelet aggregation assay (HIPAG). The screening identified 110 patients with HIT-reactive antibodies, out of which 46 were also thrombocytopenic (true HIT). Cardiac surgery was performed in HIT-positive patients under heparin anticoagulation and iloprost infusion. A control group of 118 HIT-negative patients received heparin but no iloprost during surgery. For the first 20 patients, the dose of iloprost diminishing the HIPAG test to ≤5% was determined prior to surgery by in vitro titration using the patients' own plasma and donor platelets. In parallel, the iloprost "target dose" was also established for each patient intraoperatively, but before heparin administration. Iloprost was infused initially at 3 ng/kg/mL and further adjusted intraoperatively, until ex vivo aggregation reached ≤5%. As a close correlation was observed between the "target dose" identified before surgery and that established intraoperatively, the remaining 90 patients were administered iloprost starting at the presurgery identified "target dose." This process significantly reduced the number of intraoperative HIPAG reassessments needed to determine the iloprost target dose, and reduced surgical time, while maintaining similar primary clinical outcomes to controls. Therefore, infusion of iloprost throughout surgery, under continuous titration, allows cardiac surgery to be undertaken safely using heparin, while avoiding life-threatening iloprost-induced hypotension in patients diagnosed with HIT-reactive antibodies or true HIT. © 2015 Wiley Periodicals, Inc.

"Hits" (Not "Discussion Posts") Predict Student Success in Online Courses: A Double Cross-Validation Study

ERIC Educational Resources Information Center

Ramos, Cheryl; Yudko, Errol

2008-01-01

The efficacy of individual components of an online course on positive course outcome was examined via stepwise multiple regression analysis. Outcome was measured as the student's total score on all exams given during the course. The predictors were page hits, discussion posts, and discussion reads. The vast majority of the variance of outcome was…

Informatics Technology Mimics Ecology: Dense, Mutualistic Collaboration Networks Are Associated with Higher Publication Rates

PubMed Central

Sorani, Marco D.

2012-01-01

Information technology (IT) adoption enables biomedical research. Publications are an accepted measure of research output, and network models can describe the collaborative nature of publication. In particular, ecological networks can serve as analogies for publication and technology adoption. We constructed network models of adoption of bioinformatics programming languages and health IT (HIT) from the literature. We selected seven programming languages and four types of HIT. We performed PubMed searches to identify publications since 2001. We calculated summary statistics and analyzed spatiotemporal relationships. Then, we assessed ecological models of specialization, cooperativity, competition, evolution, biodiversity, and stability associated with publications. Adoption of HIT has been variable, while scripting languages have experienced rapid adoption. Hospital systems had the largest HIT research corpus, while Perl had the largest language corpus. Scripting languages represented the largest connected network components. The relationship between edges and nodes was linear, though Bioconductor had more edges than expected and Perl had fewer. Spatiotemporal relationships were weak. Most languages shared a bioinformatics specialization and appeared mutualistic or competitive. HIT specializations varied. Specialization was highest for Bioconductor and radiology systems. Specialization and cooperativity were positively correlated among languages but negatively correlated among HIT. Rates of language evolution were similar. Biodiversity among languages grew in the first half of the decade and stabilized, while diversity among HIT was variable but flat. Compared with publications in 2001, correlation with publications one year later was positive while correlation after ten years was weak and negative. Adoption of new technologies can be unpredictable. Spatiotemporal relationships facilitate adoption but are not sufficient. As with ecosystems, dense, mutualistic, specialized co-habitation is associated with faster growth. There are rapidly changing trends in external technological and macroeconomic influences. We propose that a better understanding of how technologies are adopted can facilitate their development. PMID:22279593

Increasing Human Papillomavirus Vaccine Initiation among Publically-Insured Florida Adolescents

PubMed Central

Staras, Stephanie A. S.; Vadaparampil, Susan T.; Livingston, Melvin D.; Thompson, Lindsay A.; Sanders, Ashley H.; Shenkman, Elizabeth A.

2014-01-01

Purpose We evaluated the feasibility of a multi-level intervention to increase HPV vaccine initiation among adolescents. Methods We used a four-arm factorial quasi-experimental trial to assess feasibility and short-term, preliminary effectiveness of a health system-level, gender-specific postcard campaign and an in-clinic health information technology (HIT) system. Between August to November 2013, we tested the intervention among 11–17 year olds without prior HPV vaccine claims in Florida Medicaid or Children’s Health Insurance Program encounters (2773 girls and 3350 boys) who attended or were assigned to primary care clinics in North Central Florida. Results At least one postcard was deliverable to 95% of parents. Most parents (91% boys’ and 80% girls’) who participated in the process evaluation survey (n=162) reported seeking additional information about the vaccine after receiving the postcard. Only 8% (57 of the 1062) of adolescents assigned to a HIT provider with an office visit during the study used the HIT system. When compared with arms not containing that component, HPV vaccine initiation increased with the postcard campaign [girls Odds Ratio (OR) = 1.6, 95% Confidence Interval (CI) = 1.1–2.3 and boys = not significant], the HIT system (girls OR = 1.5, 95% CI =1.0–2.3 and boys OR = 1.4, 95% CI=1.0–2.0), and the combined HIT and postcard intervention (girls OR = 2.4, 95% CI =1.4–4.3 and boys OR = 1.6, 95% CI=1.0–2.5). Conclusions A system-level postcard campaign was feasible. Despite low recruitment to the inclinic HIT system, the intervention demonstrated short-term, preliminary effectiveness similar to prior HPV vaccine interventions. PMID:25863554

Assessing the level of healthcare information technology adoption in the United States: a snapshot

PubMed Central

Poon, Eric G; Jha, Ashish K; Christino, Melissa; Honour, Melissa M; Fernandopulle, Rushika; Middleton, Blackford; Newhouse, Joseph; Leape, Lucian; Bates, David W; Blumenthal, David; Kaushal, Rainu

2006-01-01

Background Comprehensive knowledge about the level of healthcare information technology (HIT) adoption in the United States remains limited. We therefore performed a baseline assessment to address this knowledge gap. Methods We segmented HIT into eight major stakeholder groups and identified major functionalities that should ideally exist for each, focusing on applications most likely to improve patient safety, quality of care and organizational efficiency. We then conducted a multi-site qualitative study in Boston and Denver by interviewing key informants from each stakeholder group. Interview transcripts were analyzed to assess the level of adoption and to document the major barriers to further adoption. Findings for Boston and Denver were then presented to an expert panel, which was then asked to estimate the national level of adoption using the modified Delphi approach. We measured adoption level in Boston and Denver was graded on Rogers' technology adoption curve by co-investigators. National estimates from our expert panel were expressed as percentages. Results Adoption of functionalities with financial benefits far exceeds adoption of those with safety and quality benefits. Despite growing interest to adopt HIT to improve safety and quality, adoption remains limited, especially in the area of ambulatory electronic health records and physician-patient communication. Organizations, particularly physicians' practices, face enormous financial challenges in adopting HIT, and concerns remain about its impact on productivity. Conclusion Adoption of HIT is limited and will likely remain slow unless significant financial resources are made available. Policy changes, such as financial incentivesto clinicians to use HIT or pay-for-performance reimbursement, may help health care providers defray upfront investment costs and initial productivity loss. PMID:16396679

Characterization of the Saccharomyces cerevisiae ATP-Interactome using the iTRAQ-SPROX Technique

NASA Astrophysics Data System (ADS)

Geer, M. Ariel; Fitzgerald, Michael C.

2016-02-01

The stability of proteins from rates of oxidation (SPROX) technique was used in combination with an isobaric mass tagging strategy to identify adenosine triphosphate (ATP) interacting proteins in the Saccharomyces cerevisiae proteome. The SPROX methodology utilized in this work enabled 373 proteins in a yeast cell lysate to be assayed for ATP interactions (both direct and indirect) using the non-hydrolyzable ATP analog, adenylyl imidodiphosphate (AMP-PNP). A total of 28 proteins were identified with AMP-PNP-induced thermodynamic stability changes. These protein hits included 14 proteins that were previously annotated as ATP-binding proteins in the Saccharomyces Genome Database (SGD). The 14 non-annotated ATP-binding proteins included nine proteins that were previously found to be ATP-sensitive in an earlier SPROX study using a stable isotope labeling with amino acids in cell culture (SILAC)-based approach. A bioinformatics analysis of the protein hits identified here and in the earlier SILAC-SPROX experiments revealed that many of the previously annotated ATP-binding protein hits were kinases, ligases, and chaperones. In contrast, many of the newly discovered ATP-sensitive proteins were not from these protein classes, but rather were hydrolases, oxidoreductases, and nucleic acid-binding proteins.

Choosing the right amount of healthcare information technologies investments.

PubMed

Meyer, Rodolphe; Degoulet, Patrice

2010-04-01

Choosing and justifying the right amount of investment in healthcare information technologies (HITECH or HIT) in hospitals is an ever increasing challenge. Our objectives are to assess the financial impact of HIT on hospital outcome, and propose decision-helping tools that could be used to rationalize the distribution of hospital finances. We used a production function and microeconomic tools on data of 21 Paris university hospitals recorded from 1998 to 2006 to compute the elasticity coefficients of HIT versus non-HIT capital and labor as regards to hospital financial outcome and optimize the distribution of investments according to the productivity associated with each input. HIT inputs and non-HIT inputs both have a positive and significant impact on hospital production (elasticity coefficients respectively of 0.106 and 0.893; R(2) of 0.92). We forecast 2006 results from the 1998 to 2005 dataset with an accuracy of +0.61%. With the model used, the best proportion of HIT investments was estimated to be 10.6% of total input and this was predicted to lead to a total saving of 388 million Euros for the 2006 dataset. Considering HIT investment from the point of view of a global portfolio and applying econometric and microeconomic tools allow the required confidence level to be attained for choosing the right amount of HIT investments. It could also allow hospitals using these tools to make substantial savings, and help them forecast their choices for the following year for better HITECH governance in the current stimulation context. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Effects of sweet flavorings and nicotine on the appeal and sensory properties of e-cigarettes among young adult vapers: Application of a novel methodology.

PubMed

Goldenson, Nicholas I; Kirkpatrick, Matthew G; Barrington-Trimis, Jessica L; Pang, Raina D; McBeth, Julia F; Pentz, Mary Ann; Samet, Jonathan M; Leventhal, Adam M

2016-11-01

Product characteristics that impact e-cigarette appeal by altering the sensory experience of vaping need to be identified to formulate evidence-based regulatory policies. While products that contain sweet flavorings and produce a "throat hit" (i.e., desirable airway irritation putatively caused by nicotine) are anecdotally cited as desirable reasons for vaping among young adults, experimental evidence of their impact on user appeal is lacking. This experiment applied a novel laboratory protocol to assess whether: (1) sweet flavorings and nicotine affect e-cigarette appeal; (2) sweet flavorings increase perceived sweetness; (3) nicotine increases throat hit; and (4) perceived sweetness and throat hit are associated with appeal. Young adult vapers (N=20; age 19-34) self-administered 20 standardized doses of aerosolized e-cigarette solutions varied according to a 3 flavor (sweet [e.g., cotton candy] vs. non-sweet [e.g., tobacco-flavored] vs. flavorless)×2 nicotine (6mg/mL nicotine vs. 0mg/mL [placebo]) double-blind, cross-over design. Participants rated appeal (liking, willingness to use again and perceived monetary value), perceived sweetness and throat hit strength after each administration. Sweet-flavored (vs. non-sweet and flavorless) solutions produced greater appeal and perceived sweetness ratings. Nicotine produced greater throat hit ratings than placebo, but did not significantly increase appeal nor interact with flavor effects on appeal. Controlling for flavor and nicotine, perceived sweetness was positively associated with appeal ratings; throat hit was not positively associated with appeal. Further identification of compounds in e-cigarette solutions that enhance sensory perceptions of sweetness, appeal, and utilization of e-cigarettes are warranted to inform evidence-based regulatory policies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Environmental factors and health information technology management strategy.

PubMed

Menachemi, Nir; Shin, Dong Yeong; Ford, Eric W; Yu, Feliciano

2011-01-01

: Previous studies have provided theoretical and empirical evidence that environmental forces influence hospital strategy. : Rooted in resource dependence theory and the information uncertainty perspective, this study examined the relationship between environmental market characteristics and hospitals' selection of a health information technology (HIT) management strategy. : A cross-sectional design is used to analyze secondary data from the American Hospital Association Annual Survey, the Healthcare Information and Management Systems Society Analytics Database, and the Area Resource File. Univariate and multinomial logistic regression analyses are used. : Overall, 3,221 hospitals were studied, of which 60.9% pursed a single-vendor HIT management strategy, 28.9% pursued a best-of-suite strategy, and 10.2% used a best-of-breed strategy. Multivariate analyses controlling for hospital characteristics found that measures of environmental factors representing munificence, dynamism, and/or complexity were systematically associated with various hospital HIT management strategy use. Specifically, the number of generalist physicians per capita was positively associated with the single-vendor strategy (B = -5.64, p = .10). Hospitals in urban markets were more likely to pursue the best-of-suite strategy (B = 0.622, p < .001). Dynamism, measured as the number of managed care contracts for a given hospital, was negatively associated with the single-vendor strategy (B = 0.004, p = .049). Lastly, complexity, measured as market competition, was positively associated with the best-of-breed strategy (B = 0.623, p = .042). : By and large, environmental factors are associated with hospital HIT management strategies in mostly theoretically supported ways. Hospital leaders and policy makers interested in influencing the adoption of hospital HIT should consider how market conditions influence HIT management decisions as part of programs to promote meaningful use.

Usability Methods for Ensuring Health Information Technology Safety: Evidence-Based Approaches. Contribution of the IMIA Working Group Health Informatics for Patient Safety.

PubMed

Borycki, E; Kushniruk, A; Nohr, C; Takeda, H; Kuwata, S; Carvalho, C; Bainbridge, M; Kannry, J

2013-01-01

Issues related to lack of system usability and potential safety hazards continue to be reported in the health information technology (HIT) literature. Usability engineering methods are increasingly used to ensure improved system usability and they are also beginning to be applied more widely for ensuring the safety of HIT applications. These methods are being used in the design and implementation of many HIT systems. In this paper we describe evidence-based approaches to applying usability engineering methods. A multi-phased approach to ensuring system usability and safety in healthcare is described. Usability inspection methods are first described including the development of evidence-based safety heuristics for HIT. Laboratory-based usability testing is then conducted under artificial conditions to test if a system has any base level usability problems that need to be corrected. Usability problems that are detected are corrected and then a new phase is initiated where the system is tested under more realistic conditions using clinical simulations. This phase may involve testing the system with simulated patients. Finally, an additional phase may be conducted, involving a naturalistic study of system use under real-world clinical conditions. The methods described have been employed in the analysis of the usability and safety of a wide range of HIT applications, including electronic health record systems, decision support systems and consumer health applications. It has been found that at least usability inspection and usability testing should be applied prior to the widespread release of HIT. However, wherever possible, additional layers of testing involving clinical simulations and a naturalistic evaluation will likely detect usability and safety issues that may not otherwise be detected prior to widespread system release. The framework presented in the paper can be applied in order to develop more usable and safer HIT, based on multiple layers of evidence.

PF4-HIT antibody (KKO) complexes activate broad innate immune and inflammatory responses.

PubMed

Haile, Lydia A; Rao, Roshni; Polumuri, Swamy K; Arepally, Gowthami M; Keire, David A; Verthelyi, Daniela; Sommers, Cynthia D

2017-11-01

Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication of heparin anticoagulation therapy resulting in thrombocytopenia frequently accompanied by thrombosis. Current evidence suggests that HIT is associated with antibodies developed in response to multi-molecular complexes formed by platelet factor 4 (PF4) bound to heparin or cell surface glycosaminoglycans. These antibody complexes activate platelets and monocytes typically through FcγRIIA receptors increasing the production of PF4, inflammatory mediators, tissue factor and thrombin. The influence of underlying events in HIT including complex-induced pro-inflammatory cell activation and structural determinants leading to local inflammatory responses are not fully understood. The stoichiometry and complex component requirements were determined by incubating fresh peripheral blood mononuclear cells (PBMC) with different concentrations of unfractionated heparin (H), low molecular weight heparin (LMWH), PF4- and anti-PF4-H complex antibodies (KKO). Cytokine mRNA or protein were measured by qRT-PCR or Meso Scale Discovery technology, respectively. Gene expression profile analysis for 594 genes was performed using Nanostring technology and analyzed using Ingenuity Pathway Analysis software. The data show that antibodies magnify immune responses induced in PBMCs by PF4 alone or in complex with heparin or LMWH. We propose that following induction of HIT antibodies by heparin-PF4 complexes, binding of the antibodies to PF4 is sufficient to induce a local pro-inflammatory response which may play a role in the progression of HIT. In vitro assays using PBMCs may be useful in characterizing local inflammatory and innate immune responses induced by HIT antibodies in the presence of PF4 and different sources of heparins. The findings and conclusions in this article are solely the responsibility of the authors and are not being formally disseminated by the Food and Drug Administration. Thus, they should not be construed to represent any Agency determination or policy. Published by Elsevier Ltd.

CMOS image sensor for detection of interferon gamma protein interaction as a point-of-care approach.

PubMed

Marimuthu, Mohana; Kandasamy, Karthikeyan; Ahn, Chang Geun; Sung, Gun Yong; Kim, Min-Gon; Kim, Sanghyo

2011-09-01

Complementary metal oxide semiconductor (CMOS)-based image sensors have received increased attention owing to the possibility of incorporating them into portable diagnostic devices. The present research examined the efficiency and sensitivity of a CMOS image sensor for the detection of antigen-antibody interactions involving interferon gamma protein without the aid of expensive instruments. The highest detection sensitivity of about 1 fg/ml primary antibody was achieved simply by a transmission mechanism. When photons are prevented from hitting the sensor surface, a reduction in digital output occurs in which the number of photons hitting the sensor surface is approximately proportional to the digital number. Nanoscale variation in substrate thickness after protein binding can be detected with high sensitivity by the CMOS image sensor. Therefore, this technique can be easily applied to smartphones or any clinical diagnostic devices for the detection of several biological entities, with high impact on the development of point-of-care applications.

Effective implementation of health information technologies in U.S. hospitals.

PubMed

Khatri, Naresh; Gupta, Vishal

2016-01-01

Two issues pertaining to the effective implementation of health information technologies (HITs) in U.S. hospitals are examined. First, which information technology (IT) system is better--a homegrown or an outsourced one? In the second issue, the critical role of in-house IT expertise/capabilities in the effective implementation of HITs is investigated. The data on type of HIT system and IT expertise/capabilities were collected from a national sample of senior executives of U.S. hospitals. The data on quality of patient care were gathered from the Hospital Compare Web site. The quality of patient care was significantly higher in hospitals deploying a homegrown HIT system than hospitals deploying an outsourced HIT system. Furthermore, the professional competence and compelling vision of the chief information officer was found to be a major driver of another key IT capability of hospitals-professionalism of IT staff. The positive relationship of professionalism of IT staff with quality of patient care was mediated by proactive employee behavior. A homegrown HIT system achieves better quality of patient care than an outsourced one. The chief information officer's IT vision and the professional expertise and professionalism of IT staff are important IT capabilities in U.S. hospitals.

Effects of autonomous motivational priming on motivation and affective responses towards high-intensity interval training.

PubMed

Brown, Denver M Y; Teseo, Amanda J; Bray, Steven R

2016-08-01

This study examined the effect of autonomous motivational priming on motivation, attitudes and intentions towards high-intensity interval training (HIT). Participants (N = 42) performed a graded exercise test to determine their peak aerobic power (WPEAK). At a subsequent testing session, participants were randomised to complete either an autonomous or neutral motivational priming task followed by a 10 × 1 HIT exercise protocol, alternating 1-min bouts of hard (70% WPEAK) and light (12.5% WPEAK) exercises for 20 min. Participants primed with autonomous motivation reported greater enjoyment, P = .009, ηp(2) = .16, and perceived competence, P = .005, ηp(2) = .18, post-exercise compared to those in the neutral priming condition. Participants in the autonomous motivational priming condition also reported more positive attitudes, P = .014, ηp(2) = .14, towards HIT; however, there was no difference between the conditions for task motivation during HIT or intentions, P = .53, ηp(2) = .01, to engage in HIT. These findings highlight autonomous motivational priming as a method of enhancing affective and motivational experiences regarding HIT.

Back-end and interface implementation of the STS-XYTER2 prototype ASIC for the CBM experiment

NASA Astrophysics Data System (ADS)

Kasinski, K.; Szczygiel, R.; Zabolotny, W.

2016-11-01

Each front-end readout ASIC for the High-Energy Physics experiments requires robust and effective hit data streaming and control mechanism. A new STS-XYTER2 full-size prototype chip for the Silicon Tracking System and Muon Chamber detectors in the Compressed Baryonic Matter experiment at Facility for Antiproton and Ion Research (FAIR, Germany) is a 128-channel time and amplitude measuring solution for silicon microstrip and gas detectors. It operates at 250 kHit/s/channel hit rate, each hit producing 27 bits of information (5-bit amplitude, 14-bit timestamp, position and diagnostics data). The chip back-end implements fast front-end channel read-out, timestamp-wise hit sorting, and data streaming via a scalable interface implementing the dedicated protocol (STS-HCTSP) for chip control and hit transfer with data bandwidth from 9.7 MHit/s up to 47 MHit/s. It also includes multiple options for link diagnostics, failure detection, and throttling features. The back-end is designed to operate with the data acquisition architecture based on the CERN GBTx transceivers. This paper presents the details of the back-end and interface design and its implementation in the UMC 180 nm CMOS process.

HIT: a new approach for hiding multimedia information in text

NASA Astrophysics Data System (ADS)

El-Kwae, Essam A.; Cheng, Li

2002-04-01

A new technique for hiding multimedia data in text, called the Hiding in Text (HIT) technique, is introduced. The HIT technique can transform any type of media represented by a long binary string into innocuous text that follows correct grammatical rules. This technique divides English words into types where each word can appear in any number of types. For each type, there is a dictionary, which maps words to binary codes. Marker types are special types whose words do not repeat in any other type. Each generated sentence must include at least one word from the marker type. In the hiding phase, a binary string is input to the HIT encoding algorithm, which then selects sentence templates at random. The output is a set of English sentences according to the selected templates and the dictionaries of types. In the retrieving phase, the HIT technique uses the position of the marker word to identify the template used to build each sentence. The proposed technique greatly improves the efficiency and the security features of previous solutions. Examples for hiding text and image information in a cover text are given to illustrate the HIT technique.

Leveraging health information technology to achieve the "triple aim" of healthcare reform.

PubMed

Sheikh, Aziz; Sood, Harpreet S; Bates, David W

2015-07-01

To investigate experiences with leveraging health information technology (HIT) to improve patient care and population health, and reduce healthcare expenditures. In-depth qualitative interviews with federal government employees, health policy, HIT and medico-legal experts, health providers, physicians, purchasers, payers, patient advocates, and vendors from across the United States. The authors undertook 47 interviews. There was a widely shared belief that Health Information Technology for Economic and Clinical Health (HITECH) had catalyzed the creation of a digital infrastructure, which was being used in innovative ways to improve quality of care and curtail costs. There were however major concerns about the poor usability of electronic health records (EHRs), their limited ability to support multi-disciplinary care, and major difficulties with health information exchange, which undermined efforts to deliver integrated patient-centered care. Proposed strategies for enhancing the benefits of HIT included federal stimulation of competition by mandating vendors to open-up their application program interfaces, incenting development of low-cost consumer informatics tools, and promoting Congressional review of the The Health Insurance Portability and Accountability Act (HIPPA) to optimize the balance between data privacy and reuse. Many underscored the need to "kick the legs from underneath the fee-for-service model" and replace it with a data-driven reimbursement system that rewards high quality care. The HITECH Act has stimulated unprecedented, multi-stakeholder interest in HIT. Early experiences indicate that the resulting digital infrastructure is being used to improve quality of care and curtail costs. Reform efforts are however severely limited by problems with usability, limited interoperability and the persistence of the fee-for-service paradigm-addressing these issues therefore needs to be the federal government's main policy target. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Bridging the Digital Divide in Diabetes: Family Support and Implications for Health Literacy

PubMed Central

Mayberry, Lindsay S.; Kripalani, Sunil; Rothman, Russell L.

2011-01-01

Abstract Background Patient web portals (PWPs) offer patients remote access to their medical record and communication with providers. Adults with health literacy limitations are less likely to access and use health information technology (HIT), including PWPs. In diabetes, PWP use has been associated with patient satisfaction, patient–provider communication, and glycemic control. Methods Using mixed methods, we explored the relationships between health literacy, numeracy, and computer literacy and the usage of a PWP and HIT. Participants (N=61 adults with type 2 diabetes) attended focus groups and completed surveys, including measures of health literacy, numeracy, and computer anxiety (an indicator of computer literacy) and frequency of PWP and HIT use. Results Computer literacy was positively associated with health literacy (r=0.41, P<0.001) and numeracy (r=0.35, P<0.001), but health literacy was not associated with numeracy. Participants with limited health literacy (23%), numeracy (43%), or computer literacy (25%) were no less likely to access PWPs or HIT, but lower health literacy was associated with less frequent use of a computer to research diabetes medications or treatments. In focus groups, participants spontaneously commented on family support when accessing and using PWPs or HIT for diabetes management. Conclusions Participants reported family members facilitated access and usage of HIT, taught them usage skills, and acted as online delegates. Participant statements suggest family members may bridge the HIT “digital divide” in diabetes by helping adults access a PWP or HIT for diabetes management. PMID:21718098

Acute hormonal responses before and after 2 weeks of HIT in well trained junior triathletes.

PubMed

Zinner, C; Wahl, P; Achtzehn, S; Reed, J L; Mester, J

2014-04-01

The aim was to compare the acute hormonal response to a single HIT session at the beginning and end of a HIT shock microcycle. 13 male junior triathletes (15.8±1.8 yrs.) performed 16 HIT sessions within a 2 week period. Venous blood samples were collected before and after the first and last HIT session. Significant increases in cortisol (first session +89.7%; last session +70.3%) and hGH (first session +435.1%; last session +314.6%) concentrations were observed after both training sessions (P<0.05). The acute responses of cortisol, hGH, T3, and fT3 were not different between the first and last HIT sessions (P=1.00). Although no acute changes in testosterone were detected after the training sessions, testosterone concentrations were significantly higher at all time points (62.6-80.1%) during the last compared to first training session (P≤0.001). Findings from the present study reveal that 16 sessions of HIT led to significant increases in baseline concentrations of serum testosterone. This might indicate a heightened anabolic state even in junior triathletes. Based on the hormonal data, we conclude that at the end of this 2 week microcycle no familiarization effect was evident and that the training stimulus produced by HIT was still great enough to "stress" the athletes and induce positive training adaptations. © Georg Thieme Verlag KG Stuttgart · New York.

Using state variables to model the response of tumour cells to radiation and heat: a novel multi-hit-repair approach.

PubMed

Scheidegger, Stephan; Fuchs, Hans U; Zaugg, Kathrin; Bodis, Stephan; Füchslin, Rudolf M

2013-01-01

In order to overcome the limitations of the linear-quadratic model and include synergistic effects of heat and radiation, a novel radiobiological model is proposed. The model is based on a chain of cell populations which are characterized by the number of radiation induced damages (hits). Cells can shift downward along the chain by collecting hits and upward by a repair process. The repair process is governed by a repair probability which depends upon state variables used for a simplistic description of the impact of heat and radiation upon repair proteins. Based on the parameters used, populations up to 4-5 hits are relevant for the calculation of the survival. The model describes intuitively the mathematical behaviour of apoptotic and nonapoptotic cell death. Linear-quadratic-linear behaviour of the logarithmic cell survival, fractionation, and (with one exception) the dose rate dependencies are described correctly. The model covers the time gap dependence of the synergistic cell killing due to combined application of heat and radiation, but further validation of the proposed approach based on experimental data is needed. However, the model offers a work bench for testing different biological concepts of damage induction, repair, and statistical approaches for calculating the variables of state.

Prediction of Potential Hit Song and Musical Genre Using Artificial Neural Networks

NASA Astrophysics Data System (ADS)

Monterola, Christopher; Abundo, Cheryl; Tugaff, Jeric; Venturina, Lorcel Ericka

Accurately quantifying the goodness of music based on the seemingly subjective taste of the public is a multi-million industry. Recording companies can make sound decisions on which songs or artists to prioritize if accurate forecasting is achieved. We extract 56 single-valued musical features (e.g. pitch and tempo) from 380 Original Pilipino Music (OPM) songs (190 are hit songs) released from 2004 to 2006. Based on an effect size criterion which measures a variable's discriminating power, the 20 highest ranked features are fed to a classifier tasked to predict hit songs. We show that regardless of musical genre, a trained feed-forward neural network (NN) can predict potential hit songs with an average accuracy of ΦNN = 81%. The accuracy is about +20% higher than those of standard classifiers such as linear discriminant analysis (LDA, ΦLDA = 61%) and classification and regression trees (CART, ΦCART = 57%). Both LDA and CART are above the proportional chance criterion (PCC, ΦPCC = 50%) but are slightly below the suggested acceptable classifier requirement of 1.25*ΦPCC = 63%. Utilizing a similar procedure, we demonstrate that different genres (ballad, alternative rock or rock) of OPM songs can be automatically classified with near perfect accuracy using LDA or NN but only around 77% using CART.

Affective Responses to Repeated Sessions of High-Intensity Interval Training.

PubMed

Saanijoki, Tiina; Nummenmaa, Lauri; Eskelinen, Jari-Joonas; Savolainen, Anna M; Vahlberg, Tero; Kalliokoski, Kari K; Hannukainen, Jarna C

2015-12-01

Vigorous exercise feels unpleasant, and negative emotions may discourage adherence to regular exercise. We quantified the subjective affective responses to short-term high-intensity interval training (HIT) in comparison with moderate-intensity continuous training (MIT). Twenty-six healthy middle-age (mean age, 47 ± 5 yr; mean VO2peak, 34.2 ± 4.1 mL·kg⁻¹·min⁻¹) sedentary men were randomized into HIT (n = 13, 4-6 × 30 s of all-out cycling efforts at approximately 180% of peak workload with 4-min recovery) or MIT (n = 13, 40- to 60-min continuous cycling at 60% of peak workload) groups, performing six sessions within two weeks. Perceived exertion, stress, and affective state were recorded before, during, and after each session. Perceived exertion and arousal were higher, and affective state, more negative during the HIT than that during MIT sessions (P < 0.001). HIT versus MIT exercise acutely increased the experience of stress, tension, and irritation and decreased positive affect (P < 0.05). In addition, satisfaction was lower and pain and negative affect were higher in the HIT than those in the MIT group (P < 0.05). However, perceived exertion and displeasure experienced during exercise alleviated similarly in response to HIT and MIT over the 6 d of training. Peak oxygen consumption increased (P < 0.001) after intervention (HIT, 34.7 ± 3.9 vs 36.7 ± 4.5; MIT, 33.9 ± 4.6 vs 35.0 ± 4.6) and was not different between HIT and MIT (P = 0.28 for group × training). Short-term HIT and MIT are equally effective in improving aerobic fitness, but HIT increases experience of negative emotions and exertion in sedentary middle-age men. This may limit the adherence to this time-effective training mode, even though displeasure lessens over time and suggests similar mental adaptations to both MIT and HIT.

Validation of the Patient Health Questionnaire-9 (PHQ-9) and PHQ-2 in patients with migraine.

PubMed

Seo, Jong-Geun; Park, Sung-Pa

2015-01-01

Psychiatric problems have been commonly reported in patients with migraine. This study investigated the reliability and validity of the Patient Health Questionnaire-9 (PHQ-9) and Patient Health Questionnaire-9 (PHQ-2) in patients with migraine. Patients with migraine (with or without aura) were consecutively recruited from our headache clinic. They completed several instruments, including the Mini International Neuropsychiatric Interview-Plus Version 5.0.0 (MINI), the PHQ-9, the Beck Depression Inventory-II (BDI-II), the Migraine Disability Assessment Scale (MIDAS), the Headache Impact Test-6 (HIT-6), and the Migraine-Specific Quality of Life (MSQoL). Among 132 participants, 39 patients (29.5%) had a major depressive disorder (MDD) as determined by the MINI. Cronbach's α coefficients for the PHQ-9 and PHQ-2 were 0.894 and 0.747, respectively. At a cutoff score of 7, the PHQ-9 had a sensitivity of 79.5%, a specificity of 81.7%, a positive predictive value (PPV) of 64.6%, and a negative predictive value (NPV) of 90.5%. At a cutoff score of 2, the PHQ-2 had a sensitivity of 66.7%, a specificity of 90.3%, a PPV of 74.3%, and a NPV of 86.6%. The scores of the PHQ-9 and PHQ-2 well correlated with the BDI-II score, the MIDAS score, the HIT-6 score, and the MSQoL score. The PHQ-9 and PHQ-2 are both reliable and valid screening instruments for MDD in patients with migraine.

Helicopter Air-to-Air Combat Test 4 (AACT 4) Maneuverability Analysis

DTIC Science & Technology

1992-07-01

histories during fuselage tail boom skin fatigue dam age ............................................................. 145 x LIST OF FIGURES (Continued...concerning X -Y-Z relative aircraft positions, velocities, headings, relative bearings, slant ranges (distance between aircraft), and closure rates. This...real-time hit feedback system such as a flashing aiming reticle would permit the pilot to assess the actual effort required to put hits on target

Alpha-latrotoxin induces exocytosis by inhibition of voltage-dependent K+ channels and by stimulation of L-type Ca2+ channels via latrophilin in beta-cells.

PubMed

Lajus, Sophie; Vacher, Pierre; Huber, Denise; Dubois, Mathilde; Benassy, Marie-Noëlle; Ushkaryov, Yuri; Lang, Jochen

2006-03-03

The spider venom alpha-latrotoxin (alpha-LTX) induces massive exocytosis after binding to surface receptors, and its mechanism is not fully understood. We have investigated its action using toxin-sensitive MIN6 beta-cells, which express endogenously the alpha-LTX receptor latrophilin (LPH), and toxin-insensitive HIT-T15 beta-cells, which lack endogenous LPH. alpha-LTX evoked insulin exocytosis in HIT-T15 cells only upon expression of full-length LPH but not of LPH truncated after the first transmembrane domain (LPH-TD1). In HIT-T15 cells expressing full-length LPH and in native MIN6 cells, alpha-LTX first induced membrane depolarization by inhibition of repolarizing K(+) channels followed by the appearance of Ca(2+) transients. In a second phase, the toxin induced a large inward current and a prominent increase in intracellular calcium ([Ca(2+)](i)) reflecting pore formation. Upon expression of LPH-TD1 in HIT-T15 cells just this second phase was observed. Moreover, the mutated toxin LTX(N4C), which is devoid of pore formation, only evoked oscillations of membrane potential by reversible inhibition of iberiotoxin-sensitive K(+) channels via phospholipase C, activated L-type Ca(2+) channels independently from its effect on membrane potential, and induced an inositol 1,4,5-trisphosphate receptor-dependent release of intracellular calcium in MIN6 cells. The combined effects evoked transient increases in [Ca(2+)](i) in these cells, which were sensitive to inhibitors of phospholipase C, protein kinase C, or L-type Ca(2+) channels. The latter agents also reduced toxin-induced insulin exocytosis. In conclusion, alpha-LTX induces signaling distinct from pore formation via full-length LPH and phospholipase C to regulate physiologically important K(+) and Ca(2+) channels as novel targets of its secretory activity.

A comparative analysis of standard microtiter plate reading versus imaging in cellular assays.

PubMed

Bushway, Paul J; Mercola, Mark; Price, Jeffrey H

2008-08-01

We evaluated the performance of two plate readers (the Beckman Coulter [Fullerton, CA] DTX and the PerkinElmer [Wellesley, MA] EnVision) and a plate imager (the General Electric [Fairfield, CT] IN Cell 1000 Analyzer) in a primary fluorescent cellular screen of 10,000 Molecular Libraries Screening Center Network library compounds for up- and down-regulation of vascular cell adhesion molecule (VCAM)-1, which has been shown to be up-regulated in atherothrombotic vascular disease and is a general indicator of chronic inflammatory disease. Prior to screening, imaging of a twofold, six-step titration of fluorescent cells in a 384-well test plate showed greater consistency, sensitivity, and dynamic range of signal detection curves throughout the detection range, as compared to the plate readers. With the same 384-well test plate, the detection limits for fluorescent protein-labeled cells on the DTX and EnVision instruments were 2,250 and 560 fluorescent cells per well, respectively, as compared to 280 on the IN Cell 1000. During VCAM screening, sensitivity was critical for detection of antagonists, which reduced brightness of the primary immunofluorescence readout; inhibitor controls yielded Z' values of 0.41 and 0.16 for the IN Cell 1000 and EnVision instruments, respectively. The best 1% of small molecule inhibitors from all platforms were visually confirmed using images from the IN Cell 1000. The EnVision and DTX plate readers mutually identified approximately 57% and 21%, respectively, of the VCAM-1 inhibitors visually confirmed in the IN Cell best 1% of inhibitors. Furthermore, the plate reader hits were largely exclusive, with only 6% agreement across all platforms (three hits out of 47). Taken together, the imager outperformed the plate readers at hit detection in this bimodal assay because of superior sensitivity and had the advantage of speeding hit confirmation during post-acquisition analysis.

Benchmarking GPU and CPU codes for Heisenberg spin glass over-relaxation

NASA Astrophysics Data System (ADS)

Bernaschi, M.; Parisi, G.; Parisi, L.

2011-06-01

We present a set of possible implementations for Graphics Processing Units (GPU) of the Over-relaxation technique applied to the 3D Heisenberg spin glass model. The results show that a carefully tuned code can achieve more than 100 GFlops/s of sustained performance and update a single spin in about 0.6 nanoseconds. A multi-hit technique that exploits the GPU shared memory further reduces this time. Such results are compared with those obtained by means of a highly-tuned vector-parallel code on latest generation multi-core CPUs.

Radio-sensitization by Piper longumine of human breast adenoma MDA-MB-231 cells in vitro.

PubMed

Yao, Jian-Xin; Yao, Zhi-Feng; Li, Zhan-Feng; Liu, Yong-Biao

2014-01-01

The current study investigated the effects of Piper longumine on radio-sensitization of human breast cancer MDA-MB-231 cells and underlying mechanisms. Human breast cancer MDA-MB-231 cells were cultured in vitro and those in logarithmic growth phase were selected for experiments divided into four groups: control, X-ray exposed, Piper longumine, and Piper longumine combined with X-rays. Conogenic assays were performed to determine the radio-sensitizing effects. Cell survival curves were fitted by single-hit multi-target model and then the survival fraction (SF), average lethal dose (D0), quasi-threshold dose (Dq) and sensitive enhancement ratio (SER) were calculated. Cell apoptosis was analyzed by flow cytometry (FCM).Western blot assays were employed for expression of apoptosis-related proteins (Bc1-2 and Bax) after treatment with Piper longumine and/or X-ray radiation. The intracellular reactive oxygen species (ROS) level was detected by FCM with a DCFH-DA probe. The cloning formation capacity was decreased in the group of piperlongumine plus radiation, which displayed the values of SF2, D0, Dq significantly lower than those of radiation alone group and the sensitive enhancement ratio (SER) of D0 was1.22 and 1.29, respectively. The cell apoptosis rate was increased by the combination treatment of Piper longumine and radiation. Piper longumine increased the radiation-induced intracellular levels of ROS. Compared with the control group and individual group, the combination group demonstrated significantly decreased expression of Bcl-2 with increased Bax. Piper longumine at a non-cytotoxic concentration can enhance the radio-sensitivity of MDA- MB-231cells, which may be related to its regulation of apoptosis-related protein expression and the increase of intracellular ROS level, thus increasing radiation-induced apoptosis.

Isolation and characterization of gallium resistant Pseudomonas aeruginosa mutants.

PubMed

García-Contreras, Rodolfo; Lira-Silva, Elizabeth; Jasso-Chávez, Ricardo; Hernández-González, Ismael L; Maeda, Toshinari; Hashimoto, Takahiro; Boogerd, Fred C; Sheng, Lili; Wood, Thomas K; Moreno-Sánchez, Rafael

2013-12-01

Pseudomonas aeruginosa PA14 cells resistant to the novel antimicrobial gallium nitrate (Ga) were developed using transposon mutagenesis and by selecting spontaneous mutants. The mutants showing the highest growth in the presence of Ga were selected for further characterization. These mutants showed 4- to 12-fold higher Ga minimal inhibitory growth concentrations and a greater than 8-fold increase in the minimum biofilm eliminating Ga concentration. Both types of mutants produced Ga resistant biofilms whereas the formation of wild-type biofilms was strongly inhibited by Ga. The gene interrupted in the transposon mutant was hitA, which encodes a periplasmic iron binding protein that delivers Fe³⁺ to the HitB iron permease; complementation of the mutant with the hitA gene restored the Ga sensitivity. This hitA mutant showed a 14-fold decrease in Ga internalization versus the wild-type strain, indicating that the HitAB system is also involved in the Ga uptake. Ga uptake in the spontaneous mutant was also lower, although no mutations were found in the hitAB genes. Instead, this mutant harbored 64 non-silent mutations in several genes including those of the phenazine pyocyanin biosynthesis. The spontaneous mutant produced 2-fold higher pyocyanin basal levels than the wild-type; the addition of this phenazine to wild-type cultures protected them from the Ga bacteriostatic effect. The present data indicate that mutations affecting Ga transport and probably pyocyanin biosynthesis enable cells to develop resistance to Ga. Copyright © 2013 Elsevier GmbH. All rights reserved.

A study of the feasibility of Internet administration of a computerized health survey: the headache impact test (HIT).

PubMed

Bayliss, M S; Dewey, J E; Dunlap, I; Batenhorst, A S; Cady, R; Diamond, M L; Sheftell, F

2003-12-01

Headache impact test (HIT) is a precise, practical tool that quantifies the impact of headache on respondents' lives. It is the first widely-available dynamic health assessment (DynHA). Applications of this brief, precise survey include population based screening for disabling headaches, tracking of individual patient scores over time, disease management programs and others. We use data from Internet HIT assessments during the fall of 2000 to (1) evaluate characteristics of respondents and assessments, (2) assess the utility of joint administration of HIT and the SF-8 Health Survey (SF-8) to screen for migraine and depression, and (3) explore associations between HIT scores and subsequent healthcare-related attitudes and behaviors. We analyzed Internet HIT surveys completed between 9/1 and 11/30/2000 (n = 19,195). Subsamples include respondents who also completed (1) a 12-item Internet survey assessing severity, frequency, cause and management of headaches; (2) an e-mail survey measuring healthcare-related behaviors; (3) the SF-8; or (4) the website registration process, providing age and gender data. We used analysis of variance (ANOVA) to evaluate HIT score differences associated with age, gender, headache severity or frequency, and healthcare-related behaviors and attitudes and chi2 tests to assess the prevalence and comorbidity of migraine and depression. Three-quarters of respondents achieved a precise HIT score in < or = 5 items. Most had moderate/severe headaches; 65% had headaches at least monthly. HIT scores were directly related to headache severity and frequency. Most respondents were females, with significantly higher HIT scores than males. Most HIT respondents were between ages 25 and 54 (HIT scores were higher for younger respondents). Sixty four percent screened positive for migraine; 20% for depression. Both conditions were more prevalent among females than males. Comorbid migraine and depression was 50% more prevalent among females and increased with age until age 50. Patients with worse headache impact were more likely to seek care, discuss headaches with their providers and find HIT useful. It is feasible to use Internet-based dynamic assessments to measure health status. These data complement previous results showing that HIT differentiates respondents according to headache characteristics (severity and frequency). HIT plus SF-8 yields a practical screen for migraine and depression in headache patients and may lead to more effective treatment for patients with these conditions. Preliminary findings suggest that the experience of taking HIT on the Internet may motivate headache patients to seek care and discuss headaches with their providers.

Phage display screening without repetitious selection rounds.

PubMed

't Hoen, Peter A C; Jirka, Silvana M G; Ten Broeke, Bradley R; Schultes, Erik A; Aguilera, Begoña; Pang, Kar Him; Heemskerk, Hans; Aartsma-Rus, Annemieke; van Ommen, Gertjan J; den Dunnen, Johan T

2012-02-15

Phage display screenings are frequently employed to identify high-affinity peptides or antibodies. Although successful, phage display is a laborious technology and is notorious for identification of false positive hits. To accelerate and improve the selection process, we have employed Illumina next generation sequencing to deeply characterize the Ph.D.-7 M13 peptide phage display library before and after several rounds of biopanning on KS483 osteoblast cells. Sequencing of the naive library after one round of amplification in bacteria identifies propagation advantage as an important source of false positive hits. Most important, our data show that deep sequencing of the phage pool after a first round of biopanning is already sufficient to identify positive phages. Whereas traditional sequencing of a limited number of clones after one or two rounds of selection is uninformative, the required additional rounds of biopanning are associated with the risk of losing promising clones propagating slower than nonbinding phages. Confocal and live cell imaging confirms that our screen successfully selected a peptide with very high binding and uptake in osteoblasts. We conclude that next generation sequencing can significantly empower phage display screenings by accelerating the finding of specific binders and restraining the number of false positive hits. Copyright © 2011 Elsevier Inc. All rights reserved.

A combination of 19F NMR and surface plasmon resonance for site-specific hit selection and validation of fragment molecules that bind to the ATP-binding site of a kinase.

PubMed

Nagatoishi, Satoru; Yamaguchi, Sou; Katoh, Etsuko; Kajita, Keita; Yokotagawa, Takane; Kanai, Satoru; Furuya, Toshio; Tsumoto, Kouhei

2018-05-01

19 F NMR has recently emerged as an efficient, sensitive tool for analyzing protein binding to small molecules, and surface plasmon resonance (SPR) is also a popular tool for this purpose. Herein a combination of 19 F NMR and SPR was used to find novel binders to the ATP-binding pocket of MAP kinase extracellular regulated kinase 2 (ERK2) by fragment screening with an original fluorinated-fragment library. The 19 F NMR screening yielded a high primary hit rate of binders to the ERK2 ATP-binding pocket compared with the rate for the SPR screening. Hit compounds were evaluated and categorized according to their ability to bind to different binding sites in the ATP-binding pocket. The binding manner was characterized by using isothermal titration calorimetry and docking simulation. Combining 19 F NMR with other biophysical methods allows the identification of multiple types of hit compounds, thereby increasing opportunities for drug design using preferred fragments. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effects of high aerobic intensity training in patients with schizophrenia: a controlled trial.

PubMed

Heggelund, Jørn; Nilsberg, Geir E; Hoff, Jan; Morken, Gunnar; Helgerud, Jan

2011-09-01

Patients with schizophrenia have a high risk of cardiovascular disease (CVD). High aerobic intensity training (HIT) improve peak oxygen uptake (VO(2peak)), net mechanical efficiency of walking and risk factors for CVD but has not been investigated in patients with schizophrenia. To investigate effects from HIT on VO(2peak), net mechanical efficiency of walking and risk factors for CVD in patients with schizophrenia. 25 inpatients (F20-29, ICD-10) were allocated to either HIT or playing computer games (CG), 3 days per week for 8 weeks. HIT consisted of 4 × 4-min intervals with 3-min break periods, at 85-95% and 70% of peak heart rate, respectively. 12 and seven patients completed HIT and CG, respectively. The baseline VO(2peak) in both groups combined (n = 19) was 36.8 ± 8.2 ml/kg/min and 3.12 ± 0.55 l/min. The HIT group improved VO(2peak) by 12% from 3.17 ± 0.59 to 3.56 ± 0.68 l/min (P < 0.001), more than the CG group (P = 0.014). Net mechanical efficiency of walking improved by 12% in the HIT group from 19.8 ± 3.0% to 22.2 ± 4.5% (P = 0.005), more than the CG group (P = 0.031). The psychiatric symptoms, expressed as the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS), did not improve in either group. VO(2peak) and net mechanical efficiency of walking improved significantly by 8 weeks of HIT. HIT should be included in rehabilitation in order to improve physical capacity and contribute risk reduction of CVD.

The role of chemicals and radiation in the etiology of cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huberman, E.; Barr, S.H.

In this volume, investigators consider the mechanisms of oncogenesis, cell transformation, and carcinogen metabolism and present new findings on chemical and radiation carcinogenesis and chemically induced mutagenesis and chromosomal changes. As background to the studies of chemical and radiation carcinogenesis, the book surveys knowledge of cell transformation and carcinogen metabolism. Among the topics reviewed are the transforming genes involved in human malignancy, the genetics and epigenetics of neoplasia, and the single-hit and multi-hit concepts of hepatocarcinogenesis. Also examined are organ, species, and interindividual differences in carcinogen metabolism; chemical and biochemical dosimetry of genotoxic chemical exposure; and the role of pharmacokineticsmore » and DNA dosimetry in relating in vitro to in vivo actions of N-nitroso compounds.« less

Effects of Device on Video Head Impulse Test (vHIT) Gain.

PubMed

Janky, Kristen L; Patterson, Jessie N; Shepard, Neil T; Thomas, Megan L A; Honaker, Julie A

2017-10-01

Numerous video head impulse test (vHIT) devices are available commercially; however, gain is not calculated uniformly. An evaluation of these devices/algorithms in healthy controls and patients with vestibular loss is necessary for comparing and synthesizing work that utilizes different devices and gain calculations. Using three commercially available vHIT devices/algorithms, the purpose of the present study was to compare: (1) horizontal canal vHIT gain among devices/algorithms in normal control subjects; (2) the effects of age on vHIT gain for each device/algorithm in normal control subjects; and (3) the clinical performance of horizontal canal vHIT gain between devices/algorithms for differentiating normal versus abnormal vestibular function. Prospective. Sixty-one normal control adult subjects (range 20-78) and eleven adults with unilateral or bilateral vestibular loss (range 32-79). vHIT was administered using three different devices/algorithms, randomized in order, for each subject on the same day: (1) Impulse (Otometrics, Schaumberg, IL; monocular eye recording, right eye only; using area under the curve gain), (2) EyeSeeCam (Interacoustics, Denmark; monocular eye recording, left eye only; using instantaneous gain), and (3) VisualEyes (MicroMedical, Chatham, IL, binocular eye recording; using position gain). There was a significant mean difference in vHIT gain among devices/algorithms for both the normal control and vestibular loss groups. vHIT gain was significantly larger in the ipsilateral direction of the eye used to measure gain; however, in spite of the significant mean differences in vHIT gain among devices/algorithms and the significant directional bias, classification of "normal" versus "abnormal" gain is consistent across all compared devices/algorithms, with the exception of instantaneous gain at 40 msec. There was not an effect of age on vHIT gain up to 78 years regardless of the device/algorithm. These findings support that vHIT gain is significantly different between devices/algorithms, suggesting that care should be taken when making direct comparisons of absolute gain values between devices/algorithms. American Academy of Audiology

Hurst exponent and prediction based on weak-form efficient market hypothesis of stock markets

NASA Astrophysics Data System (ADS)

Eom, Cheoljun; Choi, Sunghoon; Oh, Gabjin; Jung, Woo-Sung

2008-07-01

We empirically investigated the relationships between the degree of efficiency and the predictability in financial time-series data. The Hurst exponent was used as the measurement of the degree of efficiency, and the hit rate calculated from the nearest-neighbor prediction method was used for the prediction of the directions of future price changes. We used 60 market indexes of various countries. We empirically discovered that the relationship between the degree of efficiency (the Hurst exponent) and the predictability (the hit rate) is strongly positive. That is, a market index with a higher Hurst exponent tends to have a higher hit rate. These results suggested that the Hurst exponent is useful for predicting future price changes. Furthermore, we also discovered that the Hurst exponent and the hit rate are useful as standards that can distinguish emerging capital markets from mature capital markets.

Evaluation of an Automated Reader and Color Interpretation-Based Immunoassays for Multiplexed Drug-of-Abuse Testing in Urine.

PubMed

Kim, Seon Young; Kim, Hyunjin; Park, Yeongchun; Lim, Jinsook; Kim, Jimyung; Koo, Sun Hoe; Kwon, Gye Cheol

2017-06-01

On-site drugs of abuse testing devices have undergone continuous improvement. We evaluated three devices with different designs: an automated reader, the Multi-Drug Screen Test Device with DxLINK (DxLINK; Innovacon, Alere, San Diego, USA) and two colorimetric immunoassays, the One Step Multi-Line Screen Panel with Integrated E-Z Split Key Cup II (E-Z Cup; Innovacon, Alere) and the One Step Multi-Drug Screen Panel card (Multi4 card; Alere, Abon Biopharm, Hangzhou, China). Eleven drugs [amphetamine, secobarbital, oxazepam, buprenorphine, benzoylecgonine, methylenedioxymethamphetamine (MDMA), 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC), methamphetamine, methadone, morphine and nortriptyline] were tested using the DxLINK and E-Z Cup. Four drugs (benzoylecgonine, THC, methamphetamine and morphine) were tested using the Multi4 card using control materials (Detectabuse Stat-Skreen; Biochemical Diagnostics, Edgewood, NY, USA). The concentrations (-50%, -25%, +25%, +50% and 3× cut-off values) of the control materials were confirmed by mass spectrometry. Concordance rates were calculated around cut-offs. All devices showed high overall agreement rates of >90% with a few exceptions: the DxLINK exhibited lower sensitivity for benzoylecgonine, methadone and nortriptyline (60% and 30%, 92% and 40%, and 96% and 60% sensitivity at +50% and +25% cut-off levels, respectively). The E-Z Cup exhibited lower sensitivity for oxazepam and nortriptyline (97% and 50%, and 97% and 40% sensitivity at +50% and +25% cut-off levels, respectively). We additionally evaluated test-band color by visual inspection using a standard color-scale card. When detailed color criteria for determination of positivity were applied for the E-Z Cup, using slightly less stringent criteria, oxazepam, buprenorphine, MDMA and nortriptyline showed increases in sensitivity from 70-80% to 90-100%, all with a specificity above 98%. Overall, all devices exhibited satisfactory performance at ±50% cut-off levels for commonly used drugs, with the exception of lower sensitivity for cocaine testing for DxLINK. Careful evaluation of devices and elaborate calibration of visual interpretation for determining positivity may help improve the performance of these devices. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Being selective at the plate: processing dependence between perceptual variables relates to hitting goals and performance.

PubMed

Gray, Rob

2013-08-01

Performance of a skill that involves acting on a goal object (e.g., a ball to be hit) can influence one's judgment of the size and speed of that object. The present study examined how these action-specific effects are affected when the goal of the actor is varied and they are free to choose between alternative actions. In Experiment 1, expert baseball players were asked to perform three different directional hitting tasks in a batting simulation and make interleaved perceptual judgments about three ball parameters (speed, plate crossing location, and size). Perceived ball size was largest (and perceived speed was slowest) when the ball crossing location was optimal for the particular hitting task the batter was performing (e.g., an "outside" pitch for opposite-field hitting). The magnitude of processing dependency between variables (speed vs. location and size vs. location) was positively correlated with batting performance. In Experiment 2, the action-specific effects observed in Experiment 1 were mimicked by systematically changing the ball diameter in the simulation as a function of plate crossing location. The number of swing initiations was greater when ball size was larger, and batters were more successful in the hitting task for which the larger pitches were optimal (e.g., greater number of pull hits than opposite-field hits when "inside" pitches were larger). These findings suggest attentional accentuation of goal-relevant targets underlies action-related changes in perception and are consistent with an action selection role for these effects. 2013 APA, all rights reserved

Binding of radiation-induced phenylalanine radicals to DNA: influence on the biological activity of the DNA and on its sensitivity to the induction of breaks by gamma rays

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vanderschans, G.P.; Vanrijn, C.J.S.; Bleichrodt, J.F.

1975-11-01

When an aqueous solution of double-stranded deoxyribonucleic acid (DNA) of bacteriophage PM2 containing phenylalanine and saturated with N2O is irradiated with gamma rays, radiation induced phenylalanine radicals are bound covalently. Under the conditions used about 25 phenylalanine molecules may be bound per lethal hit. Also for single-stranded PM2 DNA most of the phenylalanine radicals bound are nonlethal. Evidence is presented that in double-stranded DNA an appreciable fraction of the single-strand breaks is induced by phenylalanine radicals. Radiation products of phenylalanine and the phenylalanine bound to the DNA decrease the sensitivity of the DNA to the induction of single-strand breaks. Theremore » are indications that the high efficiency of protection by radiation products of phenylalanine is due to their positive charge, which will result in a relatively high concentration of these compounds in the vicinity of the negatively charged DNA molecules. (Author) (GRA)« less

Machine-Learning Techniques Applied to Antibacterial Drug Discovery

PubMed Central

Durrant, Jacob D.; Amaro, Rommie E.

2014-01-01

The emergence of drug-resistant bacteria threatens to catapult humanity back to the pre-antibiotic era. Even now, multi-drug-resistant bacterial infections annually result in millions of hospital days, billions in healthcare costs, and, most importantly, tens of thousands of lives lost. As many pharmaceutical companies have abandoned antibiotic development in search of more lucrative therapeutics, academic researchers are uniquely positioned to fill the resulting vacuum. Traditional high-throughput screens and lead-optimization efforts are expensive and labor intensive. Computer-aided drug discovery techniques, which are cheaper and faster, can accelerate the identification of novel antibiotics in an academic setting, leading to improved hit rates and faster transitions to pre-clinical and clinical testing. The current review describes two machine-learning techniques, neural networks and decision trees, that have been used to identify experimentally validated antibiotics. We conclude by describing the future directions of this exciting field. PMID:25521642

Comparison of Health Information Technology Use Between American Adults With and Without Chronic Health Conditions: Findings From The National Health Interview Survey 2012

PubMed Central

Lauche, Romy; Sibbritt, David; Olaniran, Bolanle; Cook, Ronald; Adams, Jon

2017-01-01

Background Health information technology (HIT) is utilized by people with different chronic conditions such as diabetes and hypertension. However, there has been no comparison of HIT use between persons without a chronic condition, with one chronic condition, and multiple (≥2) chronic conditions (MCCs). Objective The aim of the study was to assess the difference in HIT use between persons without a chronic condition, with one chronic condition, and with MCCs, to describe the characteristics of HIT use among those with chronic conditions and to identify the predictors of HIT use of the persons with one chronic condition and MCCs. Methods A secondary data analysis was conducted in spring 2017 using the National Health Interview Survey (NHIS) 2012 Family Core and Sample Adult Core datasets that yielded 34,525 respondents aged 18 years and older. Measures included overall HIT use (ie, any use of the following five HIT on the Internet: seeking health information, ordering prescription, making appointment, emailing health provider, and using health chat groups), as well as sociodemographic and health-related characteristics. Sociodemographic and health characteristics were compared between HIT users and nonusers among those who reported having at least one chronic condition using chi-square tests. Independent predictors of HIT use were identified using multiple logistic regression analyses for those with one chronic condition, with MCCs, and without a chronic condition. Analyses were weighted and performed at significance level of .005. Results In 2012, adults with one health chronic condition (raw count 4147/8551, weighted percentage 48.54%) was significantly higher than among those with MCCs (3816/9637, 39.55%) and those with none of chronic condition (7254/16,337, 44.40%, P<.001). Seeking health information was the most prevalent HIT use. Chi-square tests revealed that among adults with chronic conditions, those who used HIT were significantly different from their counterpart peers who did not use HIT in terms of sociodemographic and health characteristics (P<.001). Overall, the significant factors related to HIT use were similar among the adults with one chronic condition, with MCCs, or without a chronic condition: younger age, female sex, non-Hispanic white, higher education level, and higher income level were shown to be positively related to the HIT use. Conclusions This study provides a snapshot of HIT use among those with chronic conditions and potential factors related to such use. Clinical care and public health communication efforts attempting to leverage more HIT use should acknowledge differential HIT usage as identified in this study to better address communication inequalities and persistent disparities in socioeconomic status. PMID:28982644

Comparison of Health Information Technology Use Between American Adults With and Without Chronic Health Conditions: Findings From The National Health Interview Survey 2012.

PubMed

Zhang, Yan; Lauche, Romy; Sibbritt, David; Olaniran, Bolanle; Cook, Ronald; Adams, Jon

2017-10-05

Health information technology (HIT) is utilized by people with different chronic conditions such as diabetes and hypertension. However, there has been no comparison of HIT use between persons without a chronic condition, with one chronic condition, and multiple (≥2) chronic conditions (MCCs). The aim of the study was to assess the difference in HIT use between persons without a chronic condition, with one chronic condition, and with MCCs, to describe the characteristics of HIT use among those with chronic conditions and to identify the predictors of HIT use of the persons with one chronic condition and MCCs. A secondary data analysis was conducted in spring 2017 using the National Health Interview Survey (NHIS) 2012 Family Core and Sample Adult Core datasets that yielded 34,525 respondents aged 18 years and older. Measures included overall HIT use (ie, any use of the following five HIT on the Internet: seeking health information, ordering prescription, making appointment, emailing health provider, and using health chat groups), as well as sociodemographic and health-related characteristics. Sociodemographic and health characteristics were compared between HIT users and nonusers among those who reported having at least one chronic condition using chi-square tests. Independent predictors of HIT use were identified using multiple logistic regression analyses for those with one chronic condition, with MCCs, and without a chronic condition. Analyses were weighted and performed at significance level of .005. In 2012, adults with one health chronic condition (raw count 4147/8551, weighted percentage 48.54%) was significantly higher than among those with MCCs (3816/9637, 39.55%) and those with none of chronic condition (7254/16,337, 44.40%, P<.001). Seeking health information was the most prevalent HIT use. Chi-square tests revealed that among adults with chronic conditions, those who used HIT were significantly different from their counterpart peers who did not use HIT in terms of sociodemographic and health characteristics (P<.001). Overall, the significant factors related to HIT use were similar among the adults with one chronic condition, with MCCs, or without a chronic condition: younger age, female sex, non-Hispanic white, higher education level, and higher income level were shown to be positively related to the HIT use. This study provides a snapshot of HIT use among those with chronic conditions and potential factors related to such use. Clinical care and public health communication efforts attempting to leverage more HIT use should acknowledge differential HIT usage as identified in this study to better address communication inequalities and persistent disparities in socioeconomic status. ©Yan Zhang, Romy Lauche, David Sibbritt, Bolanle Olaniran, Ronald Cook, Jon Adams. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 05.10.2017.

Development of a risk prediction model among professional hockey players with visible signs of concussion.

PubMed

Bruce, Jared M; Echemendia, Ruben J; Meeuwisse, Willem; Hutchison, Michael G; Aubry, Mark; Comper, Paul

2017-04-04

Little research examines how to best identify concussed athletes. The purpose of the present study was to develop a preliminary risk decision model that uses visible signs (VS) and mechanisms of injury (MOI) to predict the likelihood of subsequent concussion diagnosis. Coders viewed and documented VS and associated MOI for all NHL games over the course of the 2013-2014 and 2014-2015 regular seasons. After coding was completed, player concussions were identified from the NHL injury surveillance system and it was determined whether players exhibiting VS were subsequently diagnosed with concussions by club medical staff as a result of the coded event. Among athletes exhibiting VS, suspected loss of consciousness, motor incoordination or balance problems, being in a fight, having an initial hit from another player's shoulder and having a secondary hit on the ice were all associated with increased risk of subsequent concussion diagnosis. In contrast, having an initial hit with a stick was associated with decreased risk of subsequent concussion diagnosis. A risk prediction model using a combination of the above VS and MOI was superior to approaches that relied on individual VS and associated MOI (sensitivity=81%, specificity=72%, positive predictive value=26%). Combined use of VS and MOI significantly improves a clinician's ability to identify players who need to be evaluated for possible concussion. A preliminary concussion prediction log has been developed from these data. Pending prospective validation, the use of these methods may improve early concussion detection and evaluation. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The effects of health information technology adoption and hospital-physician integration on hospital efficiency.

PubMed

Cho, Na-Eun; Chang, Jongwha; Atems, Bebonchu

2014-11-01

To determine the impact of health information technology (HIT) adoption and hospital-physician integration on hospital efficiency. Using 2010 data from the American Hospital Association's (AHA) annual survey, the AHA IT survey, supplemented by the CMS Case Mix Index, and the US Census Bureau's small area income and poverty estimates, we examined how the adoption of HIT and employment of physicians affected hospital efficiency and whether they were substitutes or complements. The sample included 2173 hospitals. We employed a 2-stage approach. In the first stage, data envelopment analysis was used to estimate technical efficiency of hospitals. In the second stage, we used instrumental variable approaches, notably 2-stage least squares and the generalized method of moments, to examine the effects of IT adoption and integration on hospital efficiency. We found that HIT adoption and hospital-physician integration, when considered separately, each have statistically significant positive impacts on hospital efficiency. Also, we found that hospitals that adopted HIT with employed physicians will achieve less efficiency compared with hospitals that adopted HIT without employed physicians. Although HIT adoption and hospital-physician integration both seem to be key parts of improving hospital efficiency when one or the other is utilized individually, they can hurt hospital efficiency when utilized together.

Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics

NASA Astrophysics Data System (ADS)

Lau, Wan F.; Withka, Jane M.; Hepworth, David; Magee, Thomas V.; Du, Yuhua J.; Bakken, Gregory A.; Miller, Michael D.; Hendsch, Zachary S.; Thanabal, Venkataraman; Kolodziej, Steve A.; Xing, Li; Hu, Qiyue; Narasimhan, Lakshmi S.; Love, Robert; Charlton, Maura E.; Hughes, Samantha; van Hoorn, Willem P.; Mills, James E.

2011-07-01

Fragment Based Drug Discovery (FBDD) continues to advance as an efficient and alternative screening paradigm for the identification and optimization of novel chemical matter. To enable FBDD across a wide range of pharmaceutical targets, a fragment screening library is required to be chemically diverse and synthetically expandable to enable critical decision making for chemical follow-up and assessing new target druggability. In this manuscript, the Pfizer fragment library design strategy which utilized multiple and orthogonal metrics to incorporate structure, pharmacophore and pharmacological space diversity is described. Appropriate measures of molecular complexity were also employed to maximize the probability of detection of fragment hits using a variety of biophysical and biochemical screening methods. In addition, structural integrity, purity, solubility, fragment and analog availability as well as cost were important considerations in the selection process. Preliminary analysis of primary screening results for 13 targets using NMR Saturation Transfer Difference (STD) indicates the identification of uM-mM hits and the uniqueness of hits at weak binding affinities for these targets.

Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics.

PubMed

Lau, Wan F; Withka, Jane M; Hepworth, David; Magee, Thomas V; Du, Yuhua J; Bakken, Gregory A; Miller, Michael D; Hendsch, Zachary S; Thanabal, Venkataraman; Kolodziej, Steve A; Xing, Li; Hu, Qiyue; Narasimhan, Lakshmi S; Love, Robert; Charlton, Maura E; Hughes, Samantha; van Hoorn, Willem P; Mills, James E

2011-07-01

Fragment Based Drug Discovery (FBDD) continues to advance as an efficient and alternative screening paradigm for the identification and optimization of novel chemical matter. To enable FBDD across a wide range of pharmaceutical targets, a fragment screening library is required to be chemically diverse and synthetically expandable to enable critical decision making for chemical follow-up and assessing new target druggability. In this manuscript, the Pfizer fragment library design strategy which utilized multiple and orthogonal metrics to incorporate structure, pharmacophore and pharmacological space diversity is described. Appropriate measures of molecular complexity were also employed to maximize the probability of detection of fragment hits using a variety of biophysical and biochemical screening methods. In addition, structural integrity, purity, solubility, fragment and analog availability as well as cost were important considerations in the selection process. Preliminary analysis of primary screening results for 13 targets using NMR Saturation Transfer Difference (STD) indicates the identification of uM-mM hits and the uniqueness of hits at weak binding affinities for these targets.

Gating of memory encoding of time-delayed cross-frequency MEG networks revealed by graph filtration based on persistent homology

PubMed Central

Hahm, Jarang; Lee, Hyekyoung; Park, Hyojin; Kang, Eunjoo; Kim, Yu Kyeong; Chung, Chun Kee; Kang, Hyejin; Lee, Dong Soo

2017-01-01

To explain gating of memory encoding, magnetoencephalography (MEG) was analyzed over multi-regional network of negative correlations between alpha band power during cue (cue-alpha) and gamma band power during item presentation (item-gamma) in Remember (R) and No-remember (NR) condition. Persistent homology with graph filtration on alpha-gamma correlation disclosed topological invariants to explain memory gating. Instruction compliance (R-hits minus NR-hits) was significantly related to negative coupling between the left superior occipital (cue-alpha) and the left dorsolateral superior frontal gyri (item-gamma) on permutation test, where the coupling was stronger in R than NR. In good memory performers (R-hits minus false alarm), the coupling was stronger in R than NR between the right posterior cingulate (cue-alpha) and the left fusiform gyri (item-gamma). Gating of memory encoding was dictated by inter-regional negative alpha-gamma coupling. Our graph filtration over MEG network revealed these inter-regional time-delayed cross-frequency connectivity serve gating of memory encoding. PMID:28169281

Development of a novel class of B-RafV600E-selective inhibitors through virtual screening and hierarchical hit optimization

PubMed Central

Kong, Xiangqian; Qin, Jie; Li, Zeng; Vultur, Adina; Tong, Linjiang; Feng, Enguang; Rajan, Geena; Liu, Shien; Lu, Junyan; Liang, Zhongjie; Zheng, Mingyue; Zhu, Weiliang; Jiang, Hualiang; Herlyn, Meenhard; Liu, Hong; Marmorstein, Ronen; Luo, Cheng

2012-01-01

Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-RafV600E mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, we described the development of novel B-RafV600E selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC50 values were identified as B-RafV600E inhibitors through virtual screening. Subsequent scaffold-based analogue searching and medicinal chemistry efforts significantly improved both the inhibitor potency and oncogene selectivity. In particular, compounds 22f and 22q possess nanomolar IC50 values with selectivity for B-RafV600E in vitro and exclusive cytotoxicity against B-RafV600E harboring cancer cells. PMID:22875039

Development of a novel class of B-Raf(V600E)-selective inhibitors through virtual screening and hierarchical hit optimization.

PubMed

Kong, Xiangqian; Qin, Jie; Li, Zeng; Vultur, Adina; Tong, Linjiang; Feng, Enguang; Rajan, Geena; Liu, Shien; Lu, Junyan; Liang, Zhongjie; Zheng, Mingyue; Zhu, Weiliang; Jiang, Hualiang; Herlyn, Meenhard; Liu, Hong; Marmorstein, Ronen; Luo, Cheng

2012-09-28

Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-Raf(V600E) mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, we describe the development of novel B-Raf(V600E) selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC(50) values were identified as B-Raf(V600E) inhibitors through virtual screening. Subsequent scaffold-based analogue searching and medicinal chemistry efforts significantly improved both the inhibitor potency and oncogene selectivity. In particular, compounds 22f and 22q possess nanomolar IC(50) values with selectivity for B-Raf(V600E)in vitro and exclusive cytotoxicity against B-Raf(V600E) harboring cancer cells.

Beliefs and ideologies linked with approval of corporal punishment: a content analysis of online comments

PubMed Central

Taylor, C. A.; Al-Hiyari, R.; Lee, S. J.; Priebe, A.; Guerrero, L. W.; Bales, A.

2016-01-01

This study employs a novel strategy for identifying points of resistance to education efforts aimed at reducing rates of child physical abuse and use of corporal punishment (CP). We analyzed online comments (n = 581) generated in response to media coverage of a study linking CP with increased child aggression. Most comments (71%) reflected approval of hitting children for disciplinary purposes. Reasons for this approval were rooted in beliefs linking the use of CP with positive or neutral outcomes such as: ‘I was spanked and I am okay’, spanking improves child behavior, spanking is more effective than other forms of discipline and spanking is not abuse. However, also linked with approval were more macro-ideological beliefs about society such as: today’s generation is worse off than previous ones, outside interference with parenting is wrong, one cause leads to an outcome, justifications for hitting children rooted in religious doctrine, bad parents cannot control their children and children have too much power. Our results suggest a need to better translate and disseminate empirical findings regarding the negative effects of CP to the public in a way that is highly sensitive to parents’ needs to feel in control and effective when parenting. PMID:27312115

Does framing the hot hand belief change decision-making behavior in volleyball?

PubMed

Raab, Markus; MacMahon, Clare

2015-06-01

Previous discussions of the hot hand belief, wherein athletes believe that they have a greater chance of scoring after 2 or 3 hits (successes) compared with 2 or 3 misses, have focused on whether this is the case within game statistics. Researchers have argued that the perception of the hot hand in random sequences is a bias of the cognitive system. Yet most have failed to explore the impact of framing on the stability of the belief and the behavior based on it. The authors conducted 2 studies that manipulated the frame of a judgment task. In Study 1, framing was manipulated via instructions in a playmaker allocation paradigm in volleyball. In Study 2, the frame was manipulated by presenting videos for allocation decisions from either the actor or observer perspective. Both manipulations changed the hot hand belief and sequential choices. We found in both studies that the belief in continuation of positive or negative streaks is nonlinear and allocations to the same player after 3 successive hits are reduced. The authors argue that neither the hot hand belief nor hot hand behavior is stable, but rather, both are sensitive to decision frames. The results can inform coaches on the importance of how to provide information to athletes.

Development of monolithic pixel detector with SOI technology for the ILC vertex detector

NASA Astrophysics Data System (ADS)

Yamada, M.; Ono, S.; Tsuboyama, T.; Arai, Y.; Haba, J.; Ikegami, Y.; Kurachi, I.; Togawa, M.; Mori, T.; Aoyagi, W.; Endo, S.; Hara, K.; Honda, S.; Sekigawa, D.

2018-01-01

We have been developing a monolithic pixel sensor for the International Linear Collider (ILC) vertex detector with the 0.2 μm FD-SOI CMOS process by LAPIS Semiconductor Co., Ltd. We aim to achieve a 3 μm single-point resolution required for the ILC with a 20×20 μm2 pixel. Beam bunch crossing at the ILC occurs every 554 ns in 1-msec-long bunch trains with an interval of 200 ms. Each pixel must record the charge and time stamp of a hit to identify a collision bunch for event reconstruction. Necessary functions include the amplifier, comparator, shift register, analog memory and time stamp implementation in each pixel, and column ADC and Zero-suppression logic on the chip. We tested the first prototype sensor, SOFIST ver.1, with a 120 GeV proton beam at the Fermilab Test Beam Facility in January 2017. SOFIST ver.1 has a charge sensitive amplifier and two analog memories in each pixel, and an 8-bit Wilkinson-type ADC is implemented for each column on the chip. We measured the residual of the hit position to the reconstructed track. The standard deviation of the residual distribution fitted by a Gaussian is better than 3 μm.

Effect of emotional valence on retrieval-related recapitulation of encoding activity in the ventral visual stream

PubMed Central

Kark, Sarah M.; Kensinger, Elizabeth A.

2015-01-01

While prior work has shown greater retrieval-related reactivation in the ventral visual stream for emotional stimuli compared to neutral stimuli, the effects of valence on retrieval-related recapitulation of successful encoding processes (Dm effects) have yet to be investigated. Here, seventeen participants (aged 19–35) studied line drawings of negative, positive, or neutral images followed immediately by the complete photo. After a 20-minute delay, participants performed a challenging recognition memory test, distinguishing the studied line drawing outlines from novel ones. First, results replicated earlier work by demonstrating that negative and positive hits elicited greater ventral occipito-temporal cortex (VOTC) activity than neutral hits during both encoding and retrieval. Moreover, the amount of activation in portions of the VOTC correlated with the magnitude of participants’ emotional memory enhancement. Second, results revealed significant retrieval-related recapitulation of Dm effects (Hits > Misses) in VOTC (anterior inferior temporal gyri) only for negative stimuli. Third, connectivity between the amygdala and fusiform gyrus during the encoding of negative stimuli increased the likelihood of fusiform activation during successful retrieval. Together, these results suggest that recapitulation in posterior VOTC reflects memory for the affective dimension of the stimuli (Emotional Hits > Neutral Hits) and the magnitude of activation in some of these regions is related to superior emotional memory. Moreover, for negative stimuli, recapitulation in more anterior portions of the VOTC is greater for remembered than forgotten items. The current study offers new evidence for effects of emotion on recapitulation of activity and functional connectivity in support of memory. PMID:26459096

High-intensity interval training evokes larger serum BDNF levels compared with intense continuous exercise.

PubMed

Saucedo Marquez, Cinthia Maria; Vanaudenaerde, Bart; Troosters, Thierry; Wenderoth, Nicole

2015-12-15

Exercise can have a positive effect on the brain by activating brain-derived neurotrophic factor (BDNF)-related processes. In healthy humans there appears to be a linear relationship between exercise intensity and the positive short-term effect of acute exercise on BDNF levels (i.e., the highest BDNF levels are reported after high-intensity exercise protocols). Here we performed two experiments to test the effectiveness of two high-intensity exercise protocols, both known to improve cardiovascular health, to determine whether they have a similar efficacy in affecting BDNF levels. Participants performed a continuous exercise (CON) protocol at 70% of maximal work rate and a high-intensity interval-training (HIT) protocol at 90% of maximal work rate for periods of 1 min alternating with 1 min of rest (both protocols lasted 20 min). We observed similar BDNF kinetics in both protocols, with maximal BDNF concentrations being reached toward the end of training (experiment 1). We then showed that both exercise protocols significantly increase BDNF levels compared with a rest condition (CON P = 0.04; HIT P < 0.001), with HIT reaching higher BDNF levels than CON (P = 0.035) (experiment 2). These results suggest that shorter bouts of high intensity exercise are slightly more effective than continuous high-intensity exercise for elevating serum BDNF. Additionally, 73% of the participants preferred the HIT protocol (P = 0.02). Therefore, we suggest that the HIT protocol might represent an effective and preferred intervention for elevating BDNF levels and potentially promoting brain health. Copyright © 2015 the American Physiological Society.

Effect of emotional valence on retrieval-related recapitulation of encoding activity in the ventral visual stream.

PubMed

Kark, Sarah M; Kensinger, Elizabeth A

2015-11-01

While prior work has shown greater retrieval-related reactivation in the ventral visual stream for emotional stimuli compared to neutral stimuli, the effects of valence on retrieval-related recapitulation of successful encoding processes (Dm effects) have yet to be investigated. Here, seventeen participants (aged 19-35) studied line drawings of negative, positive, or neutral images followed immediately by the complete photo. After a 20-min delay, participants performed a challenging recognition memory test, distinguishing the studied line drawing outlines from novel ones. First, results replicated earlier work by demonstrating that negative and positive hits elicited greater ventral occipito-temporal cortex (VOTC) activity than neutral hits during both encoding and retrieval. Moreover, the amount of activation in portions of the VOTC correlated with the magnitude of participants' emotional memory enhancement. Second, results revealed significant retrieval-related recapitulation of Dm effects (Hits>Misses) in VOTC (anterior inferior temporal gyri) only for negative stimuli. Third, connectivity between the amygdala and fusiform gyrus during the encoding of negative stimuli increased the likelihood of fusiform activation during successful retrieval. Together, these results suggest that recapitulation in posterior VOTC reflects memory for the affective dimension of the stimuli (Emotional Hits>Neutral Hits) and the magnitude of activation in some of these regions is related to superior emotional memory. Moreover, for negative stimuli, recapitulation in more anterior portions of the VOTC is greater for remembered than forgotten items. The current study offers new evidence for effects of emotion on recapitulation of activity and functional connectivity in support of memory. Copyright © 2015 Elsevier Ltd. All rights reserved.

Azimuthal correlations between directed and elliptic flow in heavy ion collisions

NASA Astrophysics Data System (ADS)

Wu, Feng-Juan; Shan, Lian-Qiang; Zhang, Jing-Bo; Tang, Gui-Xin; Huo, Lei

2008-12-01

A method for investigating the azimuthal correlations between directed and elliptic flow in heavy ion collisions is described. The transverse anisotropy of particle emission at AGS energies is investigated within the RQMD model. It is found that the azimuthal correlations between directed and elliptic flow are sensitive to the incident energy and impact parameter. The fluctuations in the initial stage and dynamical evolution of heavy ion collisions are not negligible. Supported by Natural Science Foundation of Heilongjiang Province (A0208) and Science Foundation of Harbin Institute of Technology (HIT.2002.47, HIT.2003.33)

An Automatic Detection System of Lung Nodule Based on Multi-Group Patch-Based Deep Learning Network.

PubMed

Jiang, Hongyang; Ma, He; Qian, Wei; Gao, Mengdi; Li, Yan

2017-07-14

High-efficiency lung nodule detection dramatically contributes to the risk assessment of lung cancer. It is a significant and challenging task to quickly locate the exact positions of lung nodules. Extensive work has been done by researchers around this domain for approximately two decades. However, previous computer aided detection (CADe) schemes are mostly intricate and time-consuming since they may require more image processing modules, such as the computed tomography (CT) image transformation, the lung nodule segmentation and the feature extraction, to construct a whole CADe system. It is difficult for those schemes to process and analyze enormous data when the medical images continue to increase. Besides, some state of the art deep learning schemes may be strict in the standard of database. This study proposes an effective lung nodule detection scheme based on multi-group patches cut out from the lung images, which are enhanced by the Frangi filter. Through combining two groups of images, a four-channel convolution neural networks (CNN) model is designed to learn the knowledge of radiologists for detecting nodules of four levels. This CADe scheme can acquire the sensitivity of 80.06% with 4.7 false positives per scan and the sensitivity of 94% with 15.1 false positives per scan. The results demonstrate that the multi-group patch-based learning system is efficient to improve the performance of lung nodule detection and greatly reduce the false positives under a huge amount of image data.

Synthesis and evaluation of a series of 6-chloro-4-methylumbelliferyl glycosides as fluorogenic reagents for screening metagenomic libraries for glycosidase activity.

PubMed

Chen, Hong-Ming; Armstrong, Zachary; Hallam, Steven J; Withers, Stephen G

2016-02-08

Screening of large enzyme libraries such as those derived from metagenomic sources requires sensitive substrates. Fluorogenic glycosides typically offer the best sensitivity but typically must be used in a stopped format to generate good signal. Use of fluorescent phenols of pKa < 7, such as halogenated coumarins, allows direct screening at neutral pH. The synthesis and characterisation of a set of nine different glycosides of 6-chloro-4-methylumbelliferone are described. The use of these substrates in a pooled format for screening of expressed metagenomic libraries yielded a "hit rate" of 1 in 60. Hits were then readily deconvoluted with the individual substrates in a single plate to identify specific activities within each clone. The use of such a collection of substrates greatly accelerates the screening process. Copyright © 2015 Elsevier Ltd. All rights reserved.

Engineering Design Handbook: Recoilless Rifle Weapon Systems.

DTIC Science & Technology

1976-01-15

rifles also creates danger of physiological damage also exists. psychological factors which may be signifi- The extent and nature of the damage caused...the intensity of the bla&st, its disruption often cause psychological effects impulse, the position of the subject with of extreme lethargy and...General. 6. AD 3S 1 905, Capt. L. R. Creelman , A 2. David E. Walters and Edith F. Reilly, Parameiric Study of the Probability of Hit Hitting

Effects of a Multi-Ingredient Energy Supplement on Cognitive Performance and Cerebral-Cortical Activation.

PubMed

Daou, Marcos; Sassi, Julia Montagner; Miller, Matthew W; Gonzalez, Adam M

2018-03-13

This study assessed whether a multi-ingredient energy supplement (MIES) could enhance cerebral-cortical activation and cognitive performance during an attention-switching task. Cerebral-cortical activation was recorded in 24 young adults (12 males, 12 females; 22.8 ± 3.8 yrs) via electroencephalography (EEG) both at rest and during the attention-switching task before (pretest) and 30 min after (posttest) consumption of a single serving of a MIES (MIES-1), two servings of a MIES (MIES-2), or a placebo (PL) in a double-blinded, randomized crossover experimental design. EEG upper-alpha power was assessed at rest and during the task, wherein d' (Z[hit rate]-Z[false alarm rate]) and median reaction time (RT) for correct responses to targets on attention-hold and attention-switch trials were analyzed. For both d' and RT, the Session (MIES-1, MIES-2, PL) × Time (pretest, posttest) interaction approached statistical significance (p = .07, η 2 p = 0.106). Exploring these interactions with linear contrasts, a significant linear effect of supplement dose on the linear effect of time was observed (ps ≤.034), suggesting the pretest-to-posttest improvement in sensitivity to task target stimuli (d') and RT increased as a function of supplement dose. With respect to upper-alpha power, the Session × Time interaction was significant (p < .001, η 2 p = 0.422). Exploring this interaction with linear contrasts, a significant linear effect of supplement dose on the linear effect of time was observed (p < .001), suggesting pretest-to-posttest increases in cerebral-cortical activation were a function of supplement dose. In conclusion, our findings suggest that MIES can increase cerebral-cortical activation and RT during task performance while increasing sensitivity to target stimuli in a dose-dependent manner.

Neural strategies for selective attention distinguish fast-action video game players.

PubMed

Krishnan, Lavanya; Kang, Albert; Sperling, George; Srinivasan, Ramesh

2013-01-01

We investigated the psychophysical and neurophysiological differences between fast-action video game players (specifically first person shooter players, FPS) and non-action players (role-playing game players, RPG) in a visual search task. We measured both successful detections (hit rates) and steady-state visually evoked EEG potentials (SSVEPs). Search difficulty was varied along two dimensions: number of adjacent attended and ignored regions (1, 2 and 4), and presentation rate of novel search arrays (3, 8.6 and 20 Hz). Hit rates decreased with increasing presentation rates and number of regions, with the FPS players performing on average better than the RPG players. The largest differences in hit rate, between groups, occurred when four regions were simultaneously attended. We computed signal-to-noise ratio (SNR) of SSVEPs and used partial least squares regression to model hit rates, SNRs and their relationship at 3 Hz and 8.6 Hz. The following are the most significant results: RPG players' parietal responses to the attended 8.6 Hz flicker were predictive of hit rate and were positively correlated with it, indicating attentional signal enhancement. FPS players' parietal responses to the ignored 3 Hz flicker were predictive of hit rate and were positively correlated with it, indicating distractor suppression. Consistent with these parietal responses, RPG players' frontal responses to the attended 8.6 Hz flicker, increased as task difficulty increased with number of regions; FPS players' frontal responses to the ignored 3 Hz flicker increased with number of regions. Thus the FPS players appear to employ an active suppression mechanism to deploy selective attention simultaneously to multiple interleaved regions, while RPG primarily use signal enhancement. These results suggest that fast-action gaming can affect neural strategies and the corresponding networks underlying attention, presumably by training mechanisms of distractor suppression.

Biophysics: for HTS hit validation, chemical lead optimization, and beyond.

PubMed

Genick, Christine C; Wright, S Kirk

2017-09-01

There are many challenges to the drug discovery process, including the complexity of the target, its interactions, and how these factors play a role in causing the disease. Traditionally, biophysics has been used for hit validation and chemical lead optimization. With its increased throughput and sensitivity, biophysics is now being applied earlier in this process to empower target characterization and hit finding. Areas covered: In this article, the authors provide an overview of how biophysics can be utilized to assess the quality of the reagents used in screening assays, to validate potential tool compounds, to test the integrity of screening assays, and to create follow-up strategies for compound characterization. They also briefly discuss the utilization of different biophysical methods in hit validation to help avoid the resource consuming pitfalls caused by the lack of hit overlap between biophysical methods. Expert opinion: The use of biophysics early on in the drug discovery process has proven crucial to identifying and characterizing targets of complex nature. It also has enabled the identification and classification of small molecules which interact in an allosteric or covalent manner with the target. By applying biophysics in this manner and at the early stages of this process, the chances of finding chemical leads with novel mechanisms of action are increased. In the future, focused screens with biophysics as a primary readout will become increasingly common.

A GEM readout with radial zigzag strips and linear charge-sharing response

DOE PAGES

Zhang, Aiwu; Hohlmann, Marcus; Azmoun, Babak; ...

2018-01-10

Here, we study the position sensitivity of radial zigzag strips intended to read out large GEM detectors for tracking at future experiments. Zigzag strips can cover a readout area with fewer strips than regular straight strips while maintaining good spatial resolution. Consequently, they can reduce the number of required electronic channels and related cost for large-area GEM detector systems. A non-linear relation between incident particle position and hit position measured from charge sharing among zigzag strips was observed in a previous study. We significantly reduce this non-linearity by improving the interleaving of adjacent physical zigzag strips. Zigzag readout structures aremore » implemented on PCBs and on a flexible foil and are tested using a 10 cm × 10 cm triple-GEM detector scanned with a strongly collimated X-ray gun on a 2D motorized stage. Lastly, angular resolutions of 60–84 μrad are achieved with a 1.37 mrad angular strip pitch at a radius of 784 mm. On a linear scale this corresponds to resolutions below 100 μm.« less

A GEM readout with radial zigzag strips and linear charge-sharing response

NASA Astrophysics Data System (ADS)

Zhang, Aiwu; Hohlmann, Marcus; Azmoun, Babak; Purschke, Martin L.; Woody, Craig

2018-04-01

We study the position sensitivity of radial zigzag strips intended to read out large GEM detectors for tracking at future experiments. Zigzag strips can cover a readout area with fewer strips than regular straight strips while maintaining good spatial resolution. Consequently, they can reduce the number of required electronic channels and related cost for large-area GEM detector systems. A non-linear relation between incident particle position and hit position measured from charge sharing among zigzag strips was observed in a previous study. We significantly reduce this non-linearity by improving the interleaving of adjacent physical zigzag strips. Zigzag readout structures are implemented on PCBs and on a flexible foil and are tested using a 10 cm × 10 cm triple-GEM detector scanned with a strongly collimated X-ray gun on a 2D motorized stage. Angular resolutions of 60-84 μrad are achieved with a 1.37 mrad angular strip pitch at a radius of 784 mm. On a linear scale this corresponds to resolutions below 100 μm.

Neuroelectrical signs of selective attention to color in boys with attention-deficit hyperactivity disorder.

PubMed

van der Stelt, O; van der Molen, M; Boudewijn Gunning, W; Kok, A

2001-10-01

In order to gain insight into the functional and macroanatomical loci of visual selective processing deficits that may be basic to attention-deficit hyperactivity disorder (ADHD), the present study examined multi-channel event-related potentials (ERPs) recorded from 7- to 11-year-old boys clinically diagnosed as having ADHD (n=24) and age-matched healthy control boys (n=24) while they performed a visual (color) selective attention task. The spatio-temporal dynamics of several ERP components related to attention to color were characterized using topographic profile analysis, topographic mapping of the ERP and associated scalp current density distributions, and spatio-temporal source potential modeling. Boys with ADHD showed a lower target hit rate, a higher false-alarm rate, and a lower perceptual sensitivity than controls. Also, whereas color attention induced in the ERPs from controls a characteristic early frontally maximal selection positivity (FSP), ADHD boys displayed little or no FSP. Similarly, ADHD boys manifested P3b amplitude decrements that were partially lateralized (i.e., maximal at left temporal scalp locations) as well as affected by maturation. These results indicate that ADHD boys suffer from deficits at both relatively early (sensory) and late (semantic) levels of visual selective information processing. The data also support the hypothesis that the visual selective processing deficits observed in the ADHD boys originate from deficits in the strength of activation of a neural network comprising prefrontal and occipito-temporal brain regions. This network seems to be actively engaged during attention to color and may contain the major intracerebral generating sources of the associated scalp-recorded ERP components.

Effects of High-Intensity Training on Anaerobic and Aerobic Contributions to Total Energy Release During Repeated Supramaximal Exercise in Obese Adults.

PubMed

Jabbour, Georges; Iancu, Horia-Daniel; Paulin, Anne

Studying relative anaerobic and aerobic metabolism contributions to total energy release during exercise may be valuable in understanding exercise energetic demands and the energetic adaptations that occur in response to acute or chronic exercise in obese adults. The aim of the present study is to evaluate the effects of 6 weeks of high-intensity training (HIT) on relative anaerobic and aerobic contributions to total energy release and on peak power output during repeated supramaximal cycling exercises (SCE) in obese adults. Twenty-four obese adults (body mass index = ± 33 kg.m -2 ) were randomized into a control group ( n  = 12) and an HIT group ( n  = 12). Accumulated oxygen deficits (ml.min -1 ) and anaerobic and aerobic contributions (%) were measured in all groups before and after training via repeated SCE. In addition, the peak power output performed during SCE was determined using the force-velocity test. Before HIT, anaerobic contributions to repeated SCE did not differ between the groups and decreased significantly during the third and fourth repetitions. After HIT, anaerobic contributions increased significantly in the HIT group (+11 %, p  < 0.01) and were significantly higher than those of the control group ( p  < 0.01). Moreover, the peak power obtained during SCE increased significantly in the HIT group (+110 W.kg -1 , p  < 0.01) and correlated positively with increases in anaerobic contributions ( r  = 0.9, p  < 0.01). In obese adults, HIT increased anaerobic contributions to energy release which were associated with peak power enhancement in response to repeated SCE. Consequently, HIT may be an appropriate approach for improving energy contributions and muscle power among obese adults.

Vestibular evoked myogenic potentials and video head impulse test in patients with vertigo, dizziness and imbalance.

PubMed

Skorić, Magdalena Krbot; Adamec, Ivan; Pavičić, Tin; Pavlović, Ivan; Ruška, Berislav; Crnošija, Luka; Habek, Mario

2017-05-01

The aim of this study was to compare vestibular evoked myogenic potentials (VEMP) and video head impulse test (vHIT) results in patients presenting with vertigo and dizziness. We retrospectively analyzed data of all patients with the chief complaint of vertigo, dizziness, or imbalance that underwent VEMP and vHIT from January 2015 to January 2016. A total of 117 patients (73 females, mean age 53.92±16.76) fulfilled inclusion criteria: group 1 included patients with the final diagnosis of vestibular neuritis (VN) (N=31 (16 right and 15 left VN)), group 2 included patients with the final diagnosis of vertigo of central origin (N=23) and group 3 included patients with the final diagnosis of unspecified dizziness (N=63). There was significant correlation between oVEMP asymmetry and asymmetry of the lateral canals 60ms gains on vHIT (r=0.225, p=0.026). Significant correlation between oVEMP and vHIT asymmetry was present in VN patients (r=0.749, p<0.001), while no correlation was found in the groups 2 and 3. oVEMP and vHIT lateral canals asymmetries were significantly greater in patients with vestibular neuritis. Furthermore, positive correlations of oVEMP amplitudes with 60ms gain of the lateral semicircular canal and slope of the anterior semicircular canal on vHIT, and cVEMP with slope of the posterior semicircular canal on the vHIT were found. These changes were significantly more pronounced in patients with vestibular neuritis. In conclusion, VEMPs and vHIT data should be used complementarily; asymmetry on both tests strongly supports peripheral vestibular system involvement. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cost and surface optimization of a remote photovoltaic system for two kinds of panels' technologies

NASA Astrophysics Data System (ADS)

Avril, S.; Arnaud, G.; Colin, H.; Montignac, F.; Mansilla, C.; Vinard, M.

2011-10-01

Stand alone photovoltaic (PV) systems comprise one of the promising electrification solutions to cover the demand of remote consumers, especially when it is coupled with a storage solution that would both increase the productivity of power plants and reduce the areas dedicated to energy production. This short communication presents a multi-objective design of a remote PV system coupled to battery and hydrogen storages systems simultaneously minimizing the total levelized cost and the occupied area, while fulfilling a constraint of consumer satisfaction. For this task, a multi-objective code based on particle swarm optimization has been used to find the best combination of different energy devices. Both short and mid terms based on forecasts assumptions have been investigated. An application for the site of La Nouvelle in the French overseas island of La Réunion is proposed. It points up a strong cost advantage by using Heterojunction with Intrinsic Thin layer (HIT) rather than crystalline silicon (c-Si) cells for the short term. However, the discrimination between these two PV cell technologies is less obvious for the mid term: a strong constraint on the occupied area will promote HIT, whereas a strong constraint on the cost will promote c-Si.

Research on monitoring system of water resources in Shiyang River Basin based on Multi-agent

NASA Astrophysics Data System (ADS)

Zhao, T. H.; Yin, Z.; Song, Y. Z.

2012-11-01

The Shiyang River Basin is the most populous, economy relatively develop, the highest degree of development and utilization of water resources, water conflicts the most prominent, ecological environment problems of the worst hit areas in Hexi inland river basin in Gansu province. the contradiction between people and water is aggravated constantly in the basin. This text combines multi-Agent technology with monitoring system of water resource, the establishment of a management center, telemetry Agent Federation, as well as the communication network between the composition of the Shiyang River Basin water resources monitoring system. By taking advantage of multi-agent system intelligence and communications coordination to improve the timeliness of the basin water resources monitoring.

Binding-Site Assessment by Virtual Fragment Screening

PubMed Central

Huang, Niu; Jacobson, Matthew P.

2010-01-01

The accurate prediction of protein druggability (propensity to bind high-affinity drug-like small molecules) would greatly benefit the fields of chemical genomics and drug discovery. We have developed a novel approach to quantitatively assess protein druggability by computationally screening a fragment-like compound library. In analogy to NMR-based fragment screening, we dock ∼11000 fragments against a given binding site and compute a computational hit rate based on the fraction of molecules that exceed an empirically chosen score cutoff. We perform a large-scale evaluation of the approach on four datasets, totaling 152 binding sites. We demonstrate that computed hit rates correlate with hit rates measured experimentally in a previously published NMR-based screening method. Secondly, we show that the in silico fragment screening method can be used to distinguish known druggable and non-druggable targets, including both enzymes and protein-protein interaction sites. Finally, we explore the sensitivity of the results to different receptor conformations, including flexible protein-protein interaction sites. Besides its original aim to assess druggability of different protein targets, this method could be used to identifying druggable conformations of flexible binding site for lead discovery, and suggesting strategies for growing or joining initial fragment hits to obtain more potent inhibitors. PMID:20404926

Multi-centre evaluation of the Determine HIV Combo assay when used for point of care testing in a high risk clinic-based population.

PubMed

Conway, Damian P; Holt, Martin; McNulty, Anna; Couldwell, Deborah L; Smith, Don E; Davies, Stephen C; Cunningham, Philip; Keen, Phillip; Guy, Rebecca

2014-01-01

Determine HIV Combo (DHC) is the first point of care assay designed to increase sensitivity in early infection by detecting both HIV antibody and antigen. We conducted a large multi-centre evaluation of DHC performance in Sydney sexual health clinics. We compared DHC performance (overall, by test component and in early infection) with conventional laboratory HIV serology (fourth generation screening immunoassay, supplementary HIV antibody, p24 antigen and Western blot tests) when testing gay and bisexual men attending four clinic sites. Early infection was defined as either acute or recent HIV infection acquired within the last six months. Of 3,190 evaluation specimens, 39 were confirmed as HIV-positive (12 with early infection) and 3,133 were HIV-negative by reference testing. DHC sensitivity was 87.2% overall and 94.4% and 0% for the antibody and antigen components, respectively. Sensitivity in early infection was 66.7% (all DHC antibody reactive) and the DHC antigen component detected none of nine HIV p24 antigen positive specimens. Median HIV RNA was higher in false negative than true positive cases (238,025 vs. 37,591 copies/ml; p = 0.022). Specificity overall was 99.4% with the antigen component contributing to 33% of false positives. The DHC antibody component detected two thirds of those with early infection, while the DHC antigen component did not enhance performance during point of care HIV testing in a high risk clinic-based population.

Ultrasonographic evaluation of the shoulder in elite Italian beach volleyball players.

PubMed

Monteleone, G; Tramontana, A; Mc Donald, K; Sorge, R; Tiloca, A; Foti, C

2015-10-01

Beach volleyball is an overhead sport that subjects the hitting shoulder to intense functional loads. The purpose of this study is to identify ultrasonographically the prevalence of myotendinous alterations in professional Italian beach volleyball players at the Italian championship and to look for associations between ultrasound findings and the other data collected. Fifty-three beach volleyball players (31 women, 22 men) were recruited during the second stage of the Italian championship held in July 2012 in Rome, Italy. Clinical history was obtained from all subjects, followed by physical exam. Each athlete completed a questionnaire regarding sports activities. Bilateral ultrasonographic evaluation of the shoulders was then performed. Calcific tendinopathy of the rotator cuff of the hitting shoulder was identified ultrasonographically in 30% of the athletes. The mean age of the athletes with calcific tendinopathy was older than subjects with other abnormalities on ultrasonographic examination (33.1 years vs. 25.8 years, t-test; P<0.0001). Impingement was recognized ultrasonographically in the hitting shoulder in 10 of the athletes (18.8%). The Neer's test was positive in the cases of anterior impingement (χ2; P<0.002). Calcific tendinopathy of the rotator cuff of the hitting shoulder in professional beach volleyball players has a prevalence of 30% ultrasonographically, greater than that reported in the general population. In these athletes, the presence of calcific tendinopathy correlates positively with age.

[Fragment-based drug discovery: concept and aim].

PubMed

Tanaka, Daisuke

2010-03-01

Fragment-Based Drug Discovery (FBDD) has been recognized as a newly emerging lead discovery methodology that involves biophysical fragment screening and chemistry-driven fragment-to-lead stages. Although fragments, defined as structurally simple and small compounds (typically <300 Da), have not been employed in conventional high-throughput screening (HTS), the recent significant progress in the biophysical screening methods enables fragment screening at a practical level. The intention of FBDD primarily turns our attention to weakly but specifically binding fragments (hit fragments) as the starting point of medicinal chemistry. Hit fragments are then promoted to more potent lead compounds through linking or merging with another hit fragment and/or attaching functional groups. Another positive aspect of FBDD is ligand efficiency. Ligand efficiency is a useful guide in screening hit selection and hit-to-lead phases to achieve lead-likeness. Owing to these features, a number of successful applications of FBDD to "undruggable targets" (where HTS and other lead identification methods failed to identify useful lead compounds) have been reported. As a result, FBDD is now expected to complement more conventional methodologies. This review, as an introduction of the following articles, will summarize the fundamental concepts of FBDD and will discuss its advantages over other conventional drug discovery approaches.

Health information technology vendor selection strategies and total factor productivity.

PubMed

Ford, Eric W; Huerta, Timothy R; Menachemi, Nir; Thompson, Mark A; Yu, Feliciano

2013-01-01

The aim of this study was to compare health information technology (HIT) adoption strategies' relative performance on hospital-level productivity measures. The American Hospital Association's Annual Survey and Healthcare Information and Management Systems Society Analytics for fiscal years 2002 through 2007 were used for this study. A two-stage approach is employed. First, a Malmquist model is specified to calculate hospital-level productivity measures. A logistic regression model is then estimated to compare the three HIT adoption strategies' relative performance on the newly constructed productivity measures. The HIT vendor selection strategy impacts the amount of technological change required of an organization but does not appear to have either a positive or adverse impact on technical efficiency or total factor productivity. The higher levels in technological change experienced by hospitals using the best of breed and best of suite HIT vendor selection strategies may have a more direct impact on the organization early on in the process. However, these gains did not appear to translate into either increased technical efficiency or total factor productivity during the period studied. Over a longer period, one HIT vendor selection strategy may yet prove to be more effective at improving efficiency and productivity.

An Information-Theoretical Approach to Image Resolution Applied to Neutron Imaging Detectors Based Upon Individual Discriminator Signals

NASA Astrophysics Data System (ADS)

Clergeau, Jean-François; Ferraton, Matthieu; Guérard, Bruno; Khaplanov, Anton; Piscitelli, Francesco; Platz, Martin; Rigal, Jean-Marie; Van Esch, Patrick; Daullé, Thibault

2017-01-01

1D or 2D neutron position sensitive detectors with individual wire or strip readout using discriminators have the advantage of being able to treat several neutron impacts partially overlapping in time, hence reducing global dead time. A single neutron impact usually gives rise to several discriminator signals. In this paper, we introduce an information-theoretical definition of image resolution. Two point-like spots of neutron impacts with a given distance between them act as a source of information (each neutron hit belongs to one spot or the other), and the detector plus signal treatment is regarded as an imperfect communication channel that transmits this information. The maximal mutual information obtained from this channel as a function of the distance between the spots allows to define a calibration-independent measure of position resolution. We then apply this measure to quantify the power of position resolution of different algorithms treating these individual discriminator signals which can be implemented in firmware. The method is then applied to different detectors existing at the ILL. Center-of-gravity methods usually improve the position resolution over best-wire algorithms which are the standard way of treating these signals.

Impact of information technology reliance and innovativeness on rural healthcare services: study of dindigul district in Tamilnadu, India.

PubMed

Lakshmi, K Bhagya; Rajaram, M

2012-06-01

The aim of this report was to analyze the influence of information technology (IT) applications and innovativeness on the acceptance of rural healthcare services. The impact of IT application, domain-specific innovativeness, and technology acceptance model (TAM) variables on future health IT (HIT) utilization intention has been tested through structural equation modeling techniques. The sample consisted of 465 rural health personnel from the Dindigul District of Tamilnadu, India, who had never had access to IT. Data analysis showed that health workers' innovativeness and IT application have a direct and positive influence on future HIT utilization intention and that the basic TAM hypotheses are fulfilled. IT application can be increased with interfaces that are easier to use, but only if perceived usefulness remains high. Health personnel's innovativeness positively influences technology exposure and the ease of use perception of the IT medium, referred to throughout this article as the "health channel." This research enables health departments to know which aspects of their communication strategies to highlight in order to get health personnel and other service providers to adopt IT. Perceived ease of use and IT application has a significant influence on health personnel's willingness to adopt HIT. This shows that health information and adoption by health personnel are key tools in the increase of future HIT. It is also recommended that health directors target some of their health campaigns to the more innovative beneficiaries. There are still too few studies that have analyzed the effects of innovativeness and IT adoption on behavior of health personnel. This work aimed to combine the influence of IT adoption, innovativeness, and the traditional TAM in order to construct an improved model for HIT acceptance. It will require an integrated model to do so.

Designing small molecules to target cryptic pockets yields both positive and negative allosteric modulators

PubMed Central

Moeder, Katelyn E.; Ho, Chris M. W.; Zimmerman, Maxwell I.; Frederick, Thomas E.; Bowman, Gregory R.

2017-01-01

Allosteric drugs, which bind to proteins in regions other than their main ligand-binding or active sites, make it possible to target proteins considered “undruggable” and to develop new therapies that circumvent existing resistance. Despite growing interest in allosteric drug discovery, rational design is limited by a lack of sufficient structural information about alternative binding sites in proteins. Previously, we used Markov State Models (MSMs) to identify such “cryptic pockets,” and here we describe a method for identifying compounds that bind in these cryptic pockets and modulate enzyme activity. Experimental tests validate our approach by revealing both an inhibitor and two activators of TEM β-lactamase (TEM). To identify hits, a library of compounds is first virtually screened against either the crystal structure of a known cryptic pocket or an ensemble of structures containing the same cryptic pocket that is extracted from an MSM. Hit compounds are then screened experimentally and characterized kinetically in individual assays. We identify three hits, one inhibitor and two activators, demonstrating that screening for binding to allosteric sites can result in both positive and negative modulation. The hit compounds have modest effects on TEM activity, but all have higher affinities than previously identified inhibitors, which bind the same cryptic pocket but were found, by chance, via a computational screen targeting the active site. Site-directed mutagenesis of key contact residues predicted by the docking models is used to confirm that the compounds bind in the cryptic pocket as intended. Because hit compounds are identified from docking against both the crystal structure and structures from the MSM, this platform should prove suitable for many proteins, particularly targets whose crystal structures lack obvious druggable pockets, and for identifying both inhibitory and activating small-molecule modulators. PMID:28570708

Effects of Sweet Flavorings and Nicotine on the Appeal and Sensory Properties of e-Cigarettes Among Young Adult Vapers: Application of a Novel Methodology*

PubMed Central

Goldenson, Nicholas I.; Kirkpatrick, Matthew G.; Barrington-Trimis, Jessica L.; Pang, Raina D.; McBeth, Julia F.; Pentz, Mary Ann; Samet, Jonathan M.; Leventhal, Adam M.

2016-01-01

Introduction Product characteristics that impact e-cigarette appeal by altering the sensory experience of vaping need to be identified to formulate evidence-based regulatory policies. While products that contain sweet flavorings and produce a “throat hit” (i.e., desirable airway irritation putatively caused by nicotine) are anecdotally cited as desirable reasons for vaping among young adults, experimental evidence of their impact on user appeal is lacking. This experiment applied a novel laboratory protocol to assess whether: (1) sweet flavorings and nicotine affect e-cigarette appeal; (2) sweet flavorings increase perceived sweetness; (3) nicotine increases throat hit; and (4) perceived sweetness and throat hit are associated with appeal. Methods Young adult vapers (N=20; age 19–34) self-administered 20 standardized doses of aerosolized e-cigarette solutions varied according to a 3 flavor (sweet [e.g., cotton candy] vs. non-sweet [e.g., tobacco-flavored] vs. flavorless) × 2 nicotine (6 mg/mL nicotine vs. 0 mg/mL [placebo]) double-blind, cross-over design. Participants rated appeal (liking, willingness to use again and perceived monetary value), perceived sweetness and throat hit strength after each administration. Results Sweet-flavored (vs. non-sweet and flavorless) solutions produced greater appeal and perceived sweetness ratings. Nicotine produced greater throat hit ratings than placebo, but did not significantly increase appeal nor interact with flavor effects on appeal. Controlling for flavor and nicotine, perceived sweetness was positively associated with appeal ratings; throat hit was not positively associated with appeal. Conclusions Further identification of compounds in e-cigarette solutions that enhance sensory perceptions of sweetness, appeal, and utilization of e-cigarettes are warranted to inform evidence-based regulatory policies. PMID:27676583

Performance of Ultrasound in the Diagnosis of Gout in a Multi-Center Study: Comparison with Monosodium Urate Crystal Analysis as the Gold Standard

PubMed Central

Ogdie, Alexis; Taylor, William J; Neogi, Tuhina; Fransen, Jaap; Jansen, Tim L; Schumacher, H. Ralph; Louthrenoo, Worawit; Vazquez-Mellado, Janitzia; Eliseev, Maxim; McCarthy, Geraldine; Stamp, Lisa K.; Perez-Ruiz, Fernando; Sivera, Francisca; Ea, Hang-Korng; Gerritsen, Martijn; Cagnotto, Giovanni; Cavagna, Lorenzo; Lin, Chingtsai; Chou, Yin-Yi; Tausche, Anne-Kathrin; Ochtrop, Manuella Lima Gomes; Janssen, Matthijs; Chen, Jiunn-Horng; Slot, Ole; Lazovskis, Juris; White, Douglas; Cimmino, Marco A.; Uhlig, Till; Dalbeth, Nicola

2017-01-01

Objectives To examine the performance of ultrasound for the diagnosis of gout using presence of monosodium urate (MSU) crystals as the gold standard. Methods We analyzed data from the Study for Updated Gout Classification Criteria (SUGAR), a large, multi-center observational cross-sectional study of consecutive subjects with at least one swollen joint who conceivably may have gout. All subjects underwent arthrocentesis; cases were subjects with MSU crystal confirmation. Rheumatologists or radiologists, blinded to the results of the MSU crystal analysis, performed ultrasound on one or more clinically affected joints. Ultrasound findings of interest were: double contour sign (DCS), tophus, and ‘snowstorm’ appearance. Sensitivity, specificity, positive and negative predictive values (PPV and NPV) were calculated. Multivariable logistic regression models were used to examine factors associated with positive ultrasound results among subjects with gout. Results Ultrasound was performed in 824 subjects (416 cases and 408 controls). The sensitivity, specificity, PPV and NPV for the presence of any one of the features were 76.9%, 84.3%, 83.3% and 78.1% respectively. Sensitivity was higher among subjects with disease ≥2 years duration and among subjects with subcutaneous nodules on exam (suspected tophus). Associations with a positive ultrasound finding included suspected clinical tophus (odds ratio 4.77; 95% CI 2.23–10.21), any abnormal plain film radiograph (4.68; 2.68–8.17) and serum urate (1.31; 1.06–1.62). Conclusions Ultrasound features of MSU crystal deposition had high specificity and high positive predictive value but more limited sensitivity for early gout. The specificity remained high in subjects with early disease and without clinical signs of tophi. PMID:27748084

PLASMA OXYTOCIN LEVELS PREDICT SOCIAL CUE RECOGNITION IN INDIVIDUALS WITH SCHIZOPHRENIA

PubMed Central

Strauss, Gregory P.; Keller, William R.; Koenig, James I.; Gold, James M.; Frost, Katherine H.; Buchanan, Robert W.

2015-01-01

Lower endogenous levels of the neuropeptide oxytocin may be an important biological predictor of social cognition impairments in schizophrenia (SZ). Prior studies have demonstrated that lower-level social cognitive processes (e.g., facial affect perception) are significantly associated with reduced plasma oxytocin levels in SZ; however, it is unclear whether higher-level social cognition, which requires inferential processes and knowledge not directly presented in the stimulus, is associated with endogenous oxytocin. The current study explored the association between endogenous oxytocin levels and lower- and higher-level social cognition in 40 individuals diagnosed with SZ and 22 demographically matched healthy controls (CN). All participants received the Social Cue Recognition Test (SCRT), which presents participants with videotaped interpersonal vignettes and subsequent true/false questions related to concrete or abstract aspects of social interactions in the vignettes. Results indicated that SZ had significantly higher plasma oxytocin concentrations than CN. SZ and CN did not differ on SCRT hits, but SZ had more false positives and lower sensitivity scores than CN. Higher plasma oxytocin levels were associated with better sensitivity scores for abstract items in CN and fewer false positives for concrete items in individuals with SZ. Findings indicate that endogenous oxytocin levels predict accurate encoding of lower-level socially relevant information in SZ. PMID:25673435

A high-performance liquid chromatography method for the serotonin release assay is equivalent to the radioactive method.

PubMed

Sono-Koree, N K; Crist, R A; Frank, E L; Rodgers, G M; Smock, K J

2016-02-01

The serotonin release assay (SRA) is considered the gold standard laboratory test for heparin-induced thrombocytopenia (HIT). The historic SRA method uses platelets loaded with radiolabeled serotonin to evaluate platelet activation by HIT immune complexes. However, a nonradioactive method is desirable. We report the performance characteristics of a high-performance liquid chromatography (HPLC) SRA method. We validated the performance characteristics of an HPLC-SRA method, including correlation with a reference laboratory using the radioactive method. Serotonin released from reagent platelets was quantified by HPLC using fluorescent detection. Results were expressed as % release and classified as positive, negative, or indeterminate based on previously published cutoffs. Serum samples from 250 subjects with suspected HIT were tested in the HPLC-SRA and with the radioactive method. Concordant classifications were observed in 230 samples (92%). Sera from 41 healthy individuals tested negative. Between-run imprecision studies showed standard deviation of <6 (% release) for positive, weak positive, and negative serum pools. Stability studies demonstrated stability after two freeze-thaw cycles or up to a week of refrigeration. The HPLC-SRA has robust performance characteristics, equivalent to the historic radioactive method, but avoids the complexities of working with radioactivity. © 2015 John Wiley & Sons Ltd.

Clinicopathological and genomic analysis of double-hit follicular lymphoma: comparison with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements.

PubMed

Miyaoka, Masashi; Kikuti, Yara Y; Carreras, Joaquim; Ikoma, Haruka; Hiraiwa, Shinichiro; Ichiki, Akifumi; Kojima, Minoru; Ando, Kiyoshi; Yokose, Tomoyuki; Sakai, Rika; Hoshikawa, Masahiro; Tomita, Naoto; Miura, Ikuo; Takata, Katsuyoshi; Yoshino, Tadashi; Takizawa, Jun; Bea, Silvia; Campo, Elias; Nakamura, Naoya

2018-02-01

Most high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are aggressive B-cell lymphomas. Occasional double-hit follicular lymphomas have been described but the clinicopathological features of these tumors are not well known. To clarify the characteristics of double-hit follicular lymphomas, we analyzed 10 cases of double-hit follicular lymphomas and 15 cases of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements for clinicopathological and genome-wide copy-number alterations and copy-neutral loss-of-heterozygosity profiles. For double-hit follicular lymphomas, the median age was 67.5 years (range: 48-82 years). The female/male ratio was 2.3. Eight patients presented with advanced clinical stage. The median follow-up time was 20 months (range: 1-132 months). At the end of the follow-up, 8 patients were alive, 2 patients were dead including 1 patient with diffuse large B-cell lymphoma transformation. Rearrangements of MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6 were seen in 8, 1, and 1 cases, respectively. The partner of MYC was IGH in 6 cases. There were no cases of histological grade 1, 4 cases of grade 2, 5 cases of grade 3a, and 1 case of grade 3b. Two cases of grade 3a exhibited immunoblast-like morphology. Immunohistochemistry demonstrated 9 cases with ≥50% MYC-positive cells. There was significant difference in MYC intensity (P=0.00004) and MIB-1 positivity (P=0.001) between double-hit follicular lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. The genome profile of double-hit follicular lymphomas was comparable with conventional follicular lymphomas (GSE67385, n=198) with characteristic gains of 2p25.3-p11.1, 7p22.3-q36.3, 12q11-q24.33, and loss of 18q21.32-q23 (P<0.05). In comparison with high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements, double-hit follicular lymphomas had fewer copy-number alterations and minimal common region of gain at 2p16.1 (70%), locus also significant against conventional follicular lymphomas (P=0.0001). In summary, double-hit follicular lymphomas tended to be high-grade histology, high MYC protein expression, high MYC/IGH fusion, and minimal common region of gain at 2p16.1. Double-hit follicular lymphomas seemed to be a different disease from high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements and have an indolent clinical behavior similar to follicular lymphomas without MYC rearrangement.

A fluorescent approach for identifying P2X1 ligands

PubMed Central

Ruepp, Marc-David; Brozik, James A.; de Esch, Iwan J.P.; Farndale, Richard W.; Murrell-Lagnado, Ruth D.; Thompson, Andrew J.

2015-01-01

There are no commercially available, small, receptor-specific P2X1 ligands. There are several synthetic derivatives of the natural agonist ATP and some structurally-complex antagonists including compounds such as PPADS, NTP-ATP, suramin and its derivatives (e.g. NF279, NF449). NF449 is the most potent and selective ligand, but potencies of many others are not particularly high and they can also act at other P2X, P2Y and non-purinergic receptors. While there is clearly scope for further work on P2X1 receptor pharmacology, screening can be difficult owing to rapid receptor desensitisation. To reduce desensitisation substitutions can be made within the N-terminus of the P2X1 receptor, but these could also affect ligand properties. An alternative is the use of fluorescent voltage-sensitive dyes that respond to membrane potential changes resulting from channel opening. Here we utilised this approach in conjunction with fragment-based drug-discovery. Using a single concentration (300 μM) we identified 46 novel leads from a library of 1443 fragments (hit rate = 3.2%). These hits were independently validated by measuring concentration-dependence with the same voltage-sensitive dye, and by visualising the competition of hits with an Alexa-647-ATP fluorophore using confocal microscopy; confocal yielded kon (1.142 × 106 M−1 s−1) and koff (0.136 s−1) for Alexa-647-ATP (Kd = 119 nM). The identified hit fragments had promising structural diversity. In summary, the measurement of functional responses using voltage-sensitive dyes was flexible and cost-effective because labelled competitors were not needed, effects were independent of a specific binding site, and both agonist and antagonist actions were probed in a single assay. The method is widely applicable and could be applied to all P2X family members, as well as other voltage-gated and ligand-gated ion channels. This article is part of the Special Issue entitled ‘Fluorescent Tools in Neuropharmacology’. PMID:26026951

A fluorescent approach for identifying P2X1 ligands.

PubMed

Ruepp, Marc-David; Brozik, James A; de Esch, Iwan J P; Farndale, Richard W; Murrell-Lagnado, Ruth D; Thompson, Andrew J

2015-11-01

There are no commercially available, small, receptor-specific P2X1 ligands. There are several synthetic derivatives of the natural agonist ATP and some structurally-complex antagonists including compounds such as PPADS, NTP-ATP, suramin and its derivatives (e.g. NF279, NF449). NF449 is the most potent and selective ligand, but potencies of many others are not particularly high and they can also act at other P2X, P2Y and non-purinergic receptors. While there is clearly scope for further work on P2X1 receptor pharmacology, screening can be difficult owing to rapid receptor desensitisation. To reduce desensitisation substitutions can be made within the N-terminus of the P2X1 receptor, but these could also affect ligand properties. An alternative is the use of fluorescent voltage-sensitive dyes that respond to membrane potential changes resulting from channel opening. Here we utilised this approach in conjunction with fragment-based drug-discovery. Using a single concentration (300 μM) we identified 46 novel leads from a library of 1443 fragments (hit rate = 3.2%). These hits were independently validated by measuring concentration-dependence with the same voltage-sensitive dye, and by visualising the competition of hits with an Alexa-647-ATP fluorophore using confocal microscopy; confocal yielded kon (1.142 × 10(6) M(-1) s(-1)) and koff (0.136 s(-1)) for Alexa-647-ATP (Kd = 119 nM). The identified hit fragments had promising structural diversity. In summary, the measurement of functional responses using voltage-sensitive dyes was flexible and cost-effective because labelled competitors were not needed, effects were independent of a specific binding site, and both agonist and antagonist actions were probed in a single assay. The method is widely applicable and could be applied to all P2X family members, as well as other voltage-gated and ligand-gated ion channels. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Performance and field tests of a handheld Compton camera using 3-D position-sensitive scintillators coupled to multi-pixel photon counter arrays

NASA Astrophysics Data System (ADS)

Kishimoto, A.; Kataoka, J.; Nishiyama, T.; Fujita, T.; Takeuchi, K.; Okochi, H.; Ogata, H.; Kuroshima, H.; Ohsuka, S.; Nakamura, S.; Hirayanagi, M.; Adachi, S.; Uchiyama, T.; Suzuki, H.

2014-11-01

After the nuclear disaster in Fukushima, radiation decontamination has become particularly urgent. To help identify radiation hotspots and ensure effective decontamination operation, we have developed a novel Compton camera based on Ce-doped Gd3Al2Ga3O12 scintillators and multi-pixel photon counter (MPPC) arrays. Even though its sensitivity is several times better than that of other cameras being tested in Fukushima, we introduce a depth-of-interaction (DOI) method to further improve the angular resolution. For gamma rays, the DOI information, in addition to 2-D position, is obtained by measuring the pulse-height ratio of the MPPC arrays coupled to ends of the scintillator. We present the detailed performance and results of various field tests conducted in Fukushima with the prototype 2-D and DOI Compton cameras. Moreover, we demonstrate stereo measurement of gamma rays that enables measurement of not only direction but also approximate distance to radioactive hotspots.

Cutaneous double-hit B-cell lymphoma: an aggressive form of B-cell lymphoma with a propensity for cutaneous dissemination.

PubMed

Magro, Cynthia M; Wang, Xuan; Subramaniyam, Shivakumar; Darras, Natasha; Mathew, Susan

2014-04-01

Diffuse large cell B-cell lymphoma of the skin is most commonly represented by diffuse large cell variants of primary cutaneous follicle center cell lymphoma and the leg-type lymphoma. In a minority of cases, the infiltrates are an expression of stage 4 disease of established extracutaneous B-cell lymphoma. We describe 3 patients with an aggressive form of B-cell lymphoma secondarily involving the skin. Two of the patients were in the ninth decade of life, whereas 1 patient was 34 years of age. In the elderly patients, there was an antecedent and/or concurrent history of follicular lymphoma, whereas in the younger patient, the tumor was a de novo presentation of this aggressive form of lymphoma. The elderly patients succumbed to their disease within less than a year from the time of diagnosis, whereas 1 patient is alive but with persistent and progressive disease despite chemotherapeutic intervention. The infiltrates in all 3 cases were diffuse and composed of large malignant hematopoietic cells that exhibited a round nucleus with a finely dispersed chromatin. Phenotypically, the tumor cells were Bcl-2 and CD10 positive, whereas Bcl-6 and Mum-1 showed variable positivity. One case showed combined Mum-1 positivity along with an acute lymphoblastic lymphoma phenotype, including the absence of CD20 expression. In each case, there was a c-MYC and BCL2/IGH rearrangement diagnostic of double-hit lymphoma. In one case, there was an additional BCL6 rearrangement, defining what is in essence triple-hit lymphoma. In conclusion, double-hit lymphoma is an aggressive form of B-cell neoplasia resistant to standard chemotherapy regimens, which in many but not all cases represents tumor progression in the setting of a lower grade B-cell malignancy.

Assessing HTS Performance Using BioAssay Ontology: Screening and Analysis of a Bacterial Phospho-N-Acetylmuramoyl-Pentapeptide Translocase Campaign

PubMed Central

Moberg, Andreas; Hansson, Eva; Boyd, Helen

2014-01-01

Abstract With the public availability of biochemical assays and screening data constantly increasing, new applications for data mining and method analysis are evolving in parallel. One example is BioAssay Ontology (BAO) for systematic classification of assays based on screening setup and metadata annotations. In this article we report a high-throughput screening (HTS) against phospho-N-acetylmuramoyl-pentapeptide translocase (MraY), an attractive antibacterial drug target involved in peptidoglycan synthesis. The screen resulted in novel chemistry identification using a fluorescence resonance energy transfer assay. To address a subset of the false positive hits, a frequent hitter analysis was performed using an approach in which MraY hits were compared with hits from similar assays, previously used for HTS. The MraY assay was annotated according to BAO and three internal reference assays, using a similar assay design and detection technology, were identified. Analyzing the assays retrospectively, it was clear that both MraY and the three reference assays all showed a high false positive rate in the primary HTS assays. In the case of MraY, false positives were efficiently identified by applying a method to correct for compound interference at the hit-confirmation stage. Frequent hitter analysis based on the three reference assays with similar assay method identified additional false actives in the primary MraY assay as frequent hitters. This article demonstrates how assays annotated using BAO terms can be used to identify closely related reference assays, and that analysis based on these assays clearly can provide useful data to influence assay design, technology, and screening strategy. PMID:25415593

Double-hit lymphoma demonstrating t(6;14;18)(p25;q32;q21), suggesting two independent dual-hit translocations, MYC/BCL-2 and IRF4/BCL-2.

PubMed

Tabata, Rie; Yasumizu, Ryoji; Tabata, Chiharu; Kojima, Masaru

2013-01-01

Here, we report a rare case of double-hit lymphoma, demonstrating t(6;14;18)(p25;q32;q21), suggesting two independent dual-translocations, c-MYC/BCL-2 and IRF4/BCL-2. The present case had a rare abnormal chromosome, t(6;14;18)(p25;q32;q21), independently, in addition to known dual-hit chromosomal abnormalities, t(14;18)(q32;q21) and t(8;22)(q24;q11.2). Lymph node was characterized by a follicular and diffuse growth pattern with variously sized neoplastic follicles. The intrafollicular area was composed of centrocytes with a few centroblasts and the interfollicular area was occupied by uniformly spread medium- to large-sized lymphocytes. CD23 immunostaining demonstrated a disrupted follicular dendritic cell meshwork. The intrafollicular tumor cells had a germinal center phenotype with the expression of surface IgM, CD10, Bcl-2, Bcl-6, and MUM1/IRF4. However, the interfollicular larger cells showed plasmacytic differentiation with diminished CD20, Bcl-2, Bcl-6, and positive intracytoplasmic IgM, and co-expression of MUM1/IRF4 and CD138 with increased Ki-67-positive cells (> 90%). MUM1/IRF4 has been found to induce c-MYC expression, and in turn, MYC transactivates MUM1/IRF4, creating a positive autoregulatory feedback loop. On the other hand, MUM1/IRF4 functions as a tumor suppressor in c-MYC-induced B-cell leukemia. The present rare case arouses interest in view of the possible "dual" activation of both c-MYC and MUM1/IRF4 through two independent dual-translocations, c-MYC/BCL-2 and IRF4/BCL-2.

The Effectiveness of Health Care Information Technologies: Evaluation of Trust, Security Beliefs, and Privacy as Determinants of Health Care Outcomes.

PubMed

Kisekka, Victoria; Giboney, Justin Scott

2018-04-11

The diffusion of health information technologies (HITs) within the health care sector continues to grow. However, there is no theory explaining how success of HITs influences patient care outcomes. With the increase in data breaches, HITs' success now hinges on the effectiveness of data protection solutions. Still, empirical research has only addressed privacy concerns, with little regard for other factors of information assurance. The objective of this study was to study the effectiveness of HITs using the DeLone and McLean Information Systems Success Model (DMISSM). We examined the role of information assurance constructs (ie, the role of information security beliefs, privacy concerns, and trust in health information) as measures of HIT effectiveness. We also investigated the relationships between information assurance and three aspects of system success: attitude toward health information exchange (HIE), patient access to health records, and perceived patient care quality. Using structural equation modeling, we analyzed the data from a sample of 3677 cancer patients from a public dataset. We used R software (R Project for Statistical Computing) and the Lavaan package to test the hypothesized relationships. Our extension of the DMISSM to health care was supported. We found that increased privacy concerns reduce the frequency of patient access to health records use, positive attitudes toward HIE, and perceptions of patient care quality. Also, belief in the effectiveness of information security increases the frequency of patient access to health records and positive attitude toward HIE. Trust in health information had a positive association with attitudes toward HIE and perceived patient care quality. Trust in health information had no direct effect on patient access to health records; however, it had an indirect relationship through privacy concerns. Trust in health information and belief in the effectiveness of information security safeguards increases perceptions of patient care quality. Privacy concerns reduce patients' frequency of accessing health records, patients' positive attitudes toward HIE exchange, and overall perceived patient care quality. Health care organizations are encouraged to implement security safeguards to increase trust, the frequency of health record use, and reduce privacy concerns, consequently increasing patient care quality. ©Victoria Kisekka, Justin Scott Giboney. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 11.04.2018.

High-Throughput Screening of Myometrial Calcium-Mobilization to Identify Modulators of Uterine Contractility

PubMed Central

Herington, Jennifer L.; Swale, Daniel R.; Brown, Naoko; Shelton, Elaine L.; Choi, Hyehun; Williams, Charles H.; Hong, Charles C.; Paria, Bibhash C.; Denton, Jerod S.; Reese, Jeff

2015-01-01

The uterine myometrium (UT-myo) is a therapeutic target for preterm labor, labor induction, and postpartum hemorrhage. Stimulation of intracellular Ca2+-release in UT-myo cells by oxytocin is a final pathway controlling myometrial contractions. The goal of this study was to develop a dual-addition assay for high-throughput screening of small molecular compounds, which could regulate Ca2+-mobilization in UT-myo cells, and hence, myometrial contractions. Primary murine UT-myo cells in 384-well plates were loaded with a Ca2+-sensitive fluorescent probe, and then screened for inducers of Ca2+-mobilization and inhibitors of oxytocin-induced Ca2+-mobilization. The assay exhibited robust screening statistics (Z´ = 0.73), DMSO-tolerance, and was validated for high-throughput screening against 2,727 small molecules from the Spectrum, NIH Clinical I and II collections of well-annotated compounds. The screen revealed a hit-rate of 1.80% for agonist and 1.39% for antagonist compounds. Concentration-dependent responses of hit-compounds demonstrated an EC50 less than 10μM for 21 hit-antagonist compounds, compared to only 7 hit-agonist compounds. Subsequent studies focused on hit-antagonist compounds. Based on the percent inhibition and functional annotation analyses, we selected 4 confirmed hit-antagonist compounds (benzbromarone, dipyridamole, fenoterol hydrobromide and nisoldipine) for further analysis. Using an ex vivo isometric contractility assay, each compound significantly inhibited uterine contractility, at different potencies (IC50). Overall, these results demonstrate for the first time that high-throughput small-molecules screening of myometrial Ca2+-mobilization is an ideal primary approach for discovering modulators of uterine contractility. PMID:26600013

α-lipoic acid inhibits high glucose-induced apoptosis in HIT-T15 cells.

PubMed

Yang, Yi; Wang, Weiping; Liu, Yinan; Guo, Ting; Chen, Ping; Ma, Kangtao; Zhou, Chunyan

2012-06-01

High blood glucose plays an important role in the pathogenesis of diabetes. α-lipoic acid (LA) has been used to prevent and treat diabetes, and is thought to act by increasing insulin sensitivity in many tissues. However, whether LA also has a cytoprotective effect on pancreatic islet beta cells remains unclear. In this study, we assessed whether LA could inhibit apoptosis in beta cells exposed to high glucose concentrations. HIT-T15 pancreatic beta cells were treated with 30 mmol/L glucose in the presence or absence of 0.5 mmol/L LA for 8 days. LA significantly reduced the numbers of apoptotic HIT-T15 cells and inhibited the cell overgrowth normally induced by high glucose treatment. Additionally, LA inhibited insulin expression and secretion in HIT-T15 cells induced by high glucose. Further study demonstrated that LA upregulated Pdx1 and Bcl2 gene expression, reduced Bax gene expression, and promoted phosphorylation of Akt in HIT-T15 cells treated with high glucose. Intriguingly, knockdown of Pdx1 expression partially offset the anti-apoptotic effect of LA. However, inhibition of Akt by PI3K/AKT antagonist LY294002 only slightly reversed the anti-apoptosis effect of LA and mildly decreased the gene expression level of Pdx1 (P > 0.05). Moreover, LA only slightly attenuated reactive oxygen species (ROS) production and augmented mitochondrial membrane potential. Therefore, our data suggest that α-lipoic acid can effectively attenuate high glucose-induced HIT-T15 cell apoptosis probably by increasing Pdx1 expression. These findings provide a new interpretation on the role of LA in the treatment of diabetes. © 2012 The Authors Development, Growth & Differentiation © 2012 Japanese Society of Developmental Biologists.

Using a Regression Method for Estimating Performance in a Rapid Serial Visual Presentation Target-Detection Task

DTIC Science & Technology

2017-12-01

values designating each stimulus as a target ( true ) or nontarget (false). Both stim_time and stim_label should have length equal to the number of...position unless so designated by other authorized documents. Citation of manufacturer’s or trade names does not constitute an official endorsement or...depend strongly on the true values of hit rate and false-alarm rate. Based on its better estimation of hit rate and false-alarm rate, the regression

High-sensitivity virus and mycoplasma screening test reveals high prevalence of parvovirus B19 infection in human synovial tissues and bone marrow.

PubMed

Watanabe, Ken; Otabe, Koji; Shimizu, Norio; Komori, Keiichirou; Mizuno, Mitsuru; Katano, Hisako; Koga, Hideyuki; Sekiya, Ichiro

2018-03-27

Latent microorganism infection is a safety concern for the clinical application of mesenchymal stem cells (MSCs). The aim of this study is to investigate the frequencies and sensitivities of the latent virus and mycoplasma infections in synovium, bone marrow, peripheral blood cells, and blood plasma and cultured synovial MSCs. Total DNA and RNA of the synovium (n = 124), bone marrow (n = 123), peripheral blood cells (n = 121), plasma (n = 121), and 14-day cultured synovial MSCs (n = 63) were collected from patients who underwent total knee arthroplasty or anterior ligament reconstruction after written informed consents were obtained. The multiplex polymerase chain reaction (PCR) primers were designed to quantitatively measure the representative genomes of 13 DNA viruses, 6 RNA viruses, and 9 mycoplasmas. Multi-spliced mRNA detection and virus spike test were also performed to demonstrate the sensitivity of synovial MSCs to the candidate pathogens. In synovium and bone marrow, the positive rates of parvovirus B19 genome were significantly higher than in peripheral blood cells (18.7% and 22% vs. 0.8%, respectively). Multi-alignment analysis of amplified and sequenced viral target genes showed the proximity of the parvovirus B19 gene from different tissue in the same patients. Synovial MSCs cultured for 14 days were positive for virus infection only in two patients (2/62 = 3%). Parvovirus B19 multi-spliced mRNAs were not detected in these two samples. Virus spike test demonstrated the sensitivity of synovial MSCs to herpes simplex virus (HSV)1 and cytomegalovirus (CMV), but not to parvovirus B19. This study revealed a relatively high incidence of latent parvovirus B19 in synovium and bone marrow tissue.

Accuracy and Acceptability of a Screening Tool for Identifying Intimate Partner Violence Perpetration among Women Veterans: A Pre-Implementation Evaluation.

PubMed

Portnoy, Galina A; Haskell, Sally G; King, Matthew W; Maskin, Rachel; Gerber, Megan R; Iverson, Katherine M

2018-06-06

Veterans are at heightened risk for perpetrating intimate partner violence (IPV), yet there is limited evidence to inform practice and policy for the detection of IPV perpetration. The present study evaluated the accuracy and acceptability of a potential IPV perpetration screening tool for use with women veterans. A national sample of women veterans completed a 2016 web-based survey that included a modified 5-item Extended-Hurt/Insult/Threaten/Scream (Modified E-HITS) and the Revised Conflict Tactics Scales (CTS-2). Items also assessed women's perceptions of the acceptability and appropriateness of the modified E-HITS questions for use in healthcare settings. Accuracy statistics, including sensitivity and specificity, were calculated using the CTS-2 as the reference standard. Primary measures included the Modified E-HITS (index test), CTS-2 (reference standard), and items assessing acceptability. This study included 187 women, of whom 31 women veterans (16.6%) reported past-6-month IPV perpetration on the CTS-2. The Modified E-HITS demonstrated good overall accuracy (area under the curve, 0.86; 95% confidence interval, 0.78-0.94). In addition, the majority of women perceived the questions to be acceptable and appropriate. Findings demonstrate that the Modified E-HITS is promising as a low-burden tool for detecting of IPV perpetration among women veterans. This tool may help the Veterans Health Administration and other health care providers detect IPV perpetration and offer appropriate referrals for comprehensive assessment and services. Published by Elsevier Inc.

The potential for high-intensity interval training to reduce cardiometabolic disease risk.

PubMed

Kessler, Holly S; Sisson, Susan B; Short, Kevin R

2012-06-01

In the US, 34% of adults currently meet the criteria for the metabolic syndrome defined by elevated waist circumference, plasma triglycerides (TG), fasting glucose and/or blood pressure, and decreased high-density lipoprotein cholesterol (HDL-C). While these cardiometabolic risk factors can be treated with medication, lifestyle modification is strongly recommended as a first-line approach. The purpose of this review is to focus on the effect of physical activity interventions and, specifically, on the potential benefits of incorporating higher intensity exercise. Several recent studies have suggested that compared with continuous moderate exercise (CME), high-intensity interval training (HIT) may result in a superior or equal improvement in fitness and cardiovascular health. HIT is comprised of brief periods of high-intensity exercise interposed with recovery periods at a lower intensity. The premise of using HIT in both healthy and clinical populations is that the vigorous activity segments promote greater adaptations via increased cellular stress, yet their short length, and the ensuing recovery intervals, allow even untrained individuals to work harder than would otherwise be possible at steady-state intensity. In this review, we examine the impact of HIT on cardiometabolic risk factors, anthropometric measures of obesity and cardiovascular fitness in both healthy and clinical populations with cardiovascular and metabolic disease. The effects of HIT versus CME on health outcomes were compared in 14 of the 24 studies featuring HIT. Exercise programmes ranged from 2 weeks to 6 months. All 17 studies that measured aerobic fitness and all seven studies that measured insulin sensitivity showed significant improvement in response to HIT, although these changes did not always exceed responses to CME comparison groups. A minimum duration of 12 weeks was necessary to demonstrate improvement in fasting glucose in four of seven studies (57%). A minimum duration of 8 weeks of HIT was necessary to demonstrate improvement in HDL-C in three of ten studies (30%). No studies reported that HIT resulted in improvement of total cholesterol, low-density lipoprotein cholesterol (LDL-C), or TG. At least 12 weeks of HIT was required for reduction in blood pressure to emerge in five studies of participants not already being treated for hypertension. A minimum duration of 12 weeks was necessary to see consistent improvement in the six studies that examined anthropometric measures of obesity in overweight/obese individuals. In the 13 studies with a matched-exercise-volume CME group, improvement in aerobic fitness in response to HIT was equal to (5 studies), or greater than (8 studies) in response to CME. Additionally, HIT has been shown to be safe and effective in patients with a range of cardiac and metabolic dysfunction. In conclusion, HIT appears to promote superior improvements in aerobic fitness and similar improvements in some cardiometabolic risk factors in comparison to CME, when performed by healthy subjects or clinical patients for at least 8-12 weeks. Future studies need to address compliance and efficacy of HIT in the real world with a variety of populations.

Multi-Absorber Transition-Edge Sensors for X-Ray Astronomy Applications

NASA Technical Reports Server (NTRS)

Smith, S. J.; Adams, J. S.; Bandler, S. R.; Busch, S. E.; Chervenak, J. A.; Eckart, M. E.; Ewin, A. J.; Finkbeiner, F. M.; Kelley, R. L.; Kelly, D. P.;

Health information technology needs help from primary care researchers.

PubMed

Krist, Alex H; Green, Lee A; Phillips, Robert L; Beasley, John W; DeVoe, Jennifer E; Klinkman, Michael S; Hughes, John; Puro, Jon; Fox, Chester H; Burdick, Tim

2015-01-01

While health information technology (HIT) efforts are beginning to yield measurable clinical benefits, more is needed to meet the needs of patients and clinicians. Primary care researchers are uniquely positioned to inform the evidence-based design and use of technology. Research strategies to ensure success include engaging patient and clinician stakeholders, working with existing practice-based research networks, and using established methods from other fields such as human factors engineering and implementation science. Policies are needed to help support primary care researchers in evaluating and implementing HIT into everyday practice, including expanded research funding, strengthened partnerships with vendors, open access to information systems, and support for the Primary Care Extension Program. Through these efforts, the goal of improved outcomes through HIT can be achieved. © Copyright 2015 by the American Board of Family Medicine.

Judgement on "hit or non-hit" of CHO cells exposed to accelerated heavy-ions (Fe- or Ar-ions) using division delay and CR-39 plastics as an indicator.

PubMed

Mehnati, P; Yatagai, F; Tsuzuki, T; Hanaoka, F; Sasaki, H

2001-03-01

The cell killing effect of ionizing radiation depends on the degree of linear energy transfer (LET). The relative biological effectiveness (RBE) reaches a maximum at LET of around 100-200 keV/micron and decreases at higher levels. The ion clusters produced by high-LET radiation are not uniformly distributed. The incidence of non-hit cell events is higher in high LET irradiation than in the cases of low-LET irradiation. This fact could explain the decrease in the cell killing effect at higher levels of LET irradiation. Since the cell killing effect may be related to the nuclear traversal of heavy-ions, it is necessary to establish methods to distinguish the hit cells from the non-hit cells, especially in case with high LET irradiation. Using time-lapse photography, we first examined the hit events by observing the division delay in the cells caused by high-LET irradiation. In addition, we explored the use of CR-39 plastics to detect the exact position of heavy-ion traversal on the surface of a flask where cells were growing. When Chinese hamster ovary (CHO-K1) cells were exposed to 4 Gy of accelerated Fe-ions (2000 keV/micron) or Ar (1640 keV/micron)-ions, the surviving fraction decreased to about 30% in both cases of irradiation. Eighty percent of the irradiated cells, suffered a division delay in contrast to the remaining 20% of the cells which showed a normal division time (12-13 hrs). The later 20% of the cells is considered to be a population of cells which were not actually traversed by heavy-ions. The difference between the higher values of the surviving fraction (approximately 30%) and the non-hit cell population (20%) indicates that some hit cells can grow even after being hit by heavy-ions. The fraction of recovered cells determined by the time-lapse photography method was 10%, and this value closely correlated with the difference between the surviving fraction and the non-hit cells. We used the Poisson distribution of the hit-events by heavy-ions among the cell population in order to calculate the fraction of cells receiving at least a single-hit in the cell nucleus (130 micron 2 in average size). From this calculation we determined that 80% of the cells had a single hit to their nuclei by a heavy-ion which induced such early cellular responses as division delay. Our finding in the experiments using CR-39 plastics as a detector for hit-sites further supported the idea that the hit lethality of a cell is related to heavy-ion traversal through its nucleus. This study indicates the possible usefulness of both the division delay and CR-39 plastic methods for evaluating the biological effects of heavy-ions, especially when these two methods are combined.

Beliefs and ideologies linked with approval of corporal punishment: a content analysis of online comments.

PubMed

Taylor, C A; Al-Hiyari, R; Lee, S J; Priebe, A; Guerrero, L W; Bales, A

2016-08-01

This study employs a novel strategy for identifying points of resistance to education efforts aimed at reducing rates of child physical abuse and use of corporal punishment (CP). We analyzed online comments (n = 581) generated in response to media coverage of a study linking CP with increased child aggression. Most comments (71%) reflected approval of hitting children for disciplinary purposes. Reasons for this approval were rooted in beliefs linking the use of CP with positive or neutral outcomes such as: 'I was spanked and I am okay', spanking improves child behavior, spanking is more effective than other forms of discipline and spanking is not abuse. However, also linked with approval were more macro-ideological beliefs about society such as: today's generation is worse off than previous ones, outside interference with parenting is wrong, one cause leads to an outcome, justifications for hitting children rooted in religious doctrine, bad parents cannot control their children and children have too much power. Our results suggest a need to better translate and disseminate empirical findings regarding the negative effects of CP to the public in a way that is highly sensitive to parents' needs to feel in control and effective when parenting. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Development of a High-Throughput Gene Expression Screen for Modulators of RAS-MAPK Signaling in a Mutant RAS Cellular Context.

PubMed

Severyn, Bryan; Nguyen, Thi; Altman, Michael D; Li, Lixia; Nagashima, Kumiko; Naumov, George N; Sathyanarayanan, Sriram; Cook, Erica; Morris, Erick; Ferrer, Marc; Arthur, Bill; Benita, Yair; Watters, Jim; Loboda, Andrey; Hermes, Jeff; Gilliland, D Gary; Cleary, Michelle A; Carroll, Pamela M; Strack, Peter; Tudor, Matt; Andersen, Jannik N

2016-10-01

The RAS-MAPK pathway controls many cellular programs, including cell proliferation, differentiation, and apoptosis. In colorectal cancers, recurrent mutations in this pathway often lead to increased cell signaling that may contribute to the development of neoplasms, thereby making this pathway attractive for therapeutic intervention. To this end, we developed a 26-member gene signature of RAS-MAPK pathway activity utilizing the Affymetrix QuantiGene Plex 2.0 reagent system and performed both primary and confirmatory gene expression-based high-throughput screens (GE-HTSs) using KRAS mutant colon cancer cells (SW837) and leveraging a highly annotated chemical library. The screen achieved a hit rate of 1.4% and was able to enrich for hit compounds that target RAS-MAPK pathway members such as MEK and EGFR. Sensitivity and selectivity performance measurements were 0.84 and 1.00, respectively, indicating high true-positive and true-negative rates. Active compounds from the primary screen were confirmed in a dose-response GE-HTS assay, a GE-HTS assay using 14 additional cancer cell lines, and an in vitro colony formation assay. Altogether, our data suggest that this GE-HTS assay will be useful for larger unbiased chemical screens to identify novel compounds and mechanisms that may modulate the RAS-MAPK pathway. © 2016 Society for Laboratory Automation and Screening.

Sesquiterpene lactone mix as a diagnostic tool for Asteraceae allergic contact dermatitis: chemical explanation for its poor performance and Sesquiterpene lactone mix II as a proposed improvement.

PubMed

Jacob, Mathias; Brinkmann, Jürgen; Schmidt, Thomas J

2012-05-01

Two preparations are currently in use for the diagnosis of allergic contact dermatitis caused by Asteraceae: (i) Sesquiterpene lactone (SL) mix [three pure sesquiterpene lactones (STLs)], whose use has been questioned, owing to an insufficient rate of true-positive results; and (ii) Compositae mix, consisting of five Asteraceae extracts, which is problematic because of lack of standardization and questionable reproducibility. To analyse the reasons for the narrow sensitivity of SL mix from a chemoinformatic point of view, and to propose a solution by rational selection of alternative constituents for a new SL mix II covering a broader cohort of allergic patients. Structural and biological information on allergenic STLs was retrieved from databases and the literature, and molecular modelling and chemoinformatic computations were performed. An explanation for the insufficient hit rate of SL mix is that the three constituents possess extremely similar molecular structures/properties and do not represent well the structural diversity of allergenic STLs. STLs that are known as constituents of Compositae mix plants show much a wider diversity, which explains the higher positive rate. On the basis of their positions in chemical property space, a new collection of STLs that more evenly cover the overall structural diversity spectrum is proposed. SL mix II is likely to detect a larger number of patients sensitized to Asteraceae. © 2012 John Wiley & Sons A/S.

Compact Torus Injection Experiments on the H.I.T. teststand and the JFT-2M tokamak

NASA Astrophysics Data System (ADS)

Fukumoto, Naoyuki; Fujiwara, Makoto; Kuramoto, Keiji; Ageishi, Masaya; Nagata, Masayoshi; Uyama, Tadao; Ogawa, Hiroaki; Kasai, Satoshi; Hasegawa, Kouichi; Shibata, Takatoshi

1997-11-01

A spheromak-type compact torus (CT) acceleration and injection experiment has been carried out using the Himeji Institute of Technology Compact Torus Injector (HIT-CTI). We investigate the possibility of refueling, density control, current drive, and edge electric field control of tokamak plasmas by means of CT injection. The HIT-CTI produces a CT with a speed of 200 km/s and a density of 1× 10^21m-3. We have constructed new electrodes and power supplies, and will install the HIT-CTI on the JFT-2M tokamak at JAERI in Autumn 1997. The outer electrode serves as a common ground for both the formation bank (144μF, 20kV) and the acceleration bank (92.4μF, 40kV). If the external toroidal field of the tokamak is applied across the CT acceleration region, the CT kinetic energy might decrease during penetration into the field lines joining the inner and outer electrode. This could result in the CT not being able to reach the core of the tokamak plasma. Determining the optimum position of the inner electrode is one of the near term goals of this research. We will present magnetic probe, He-Ne interferometer and fast framing camera data from experiments at H.I.T., where a CT was accelerated into a transverse field. We will also present initial results from the operation of the HIT-CTI on the JFT-2M tokamak.

Multi-class geospatial object detection based on a position-sensitive balancing framework for high spatial resolution remote sensing imagery

NASA Astrophysics Data System (ADS)

Zhong, Yanfei; Han, Xiaobing; Zhang, Liangpei

2018-04-01

Multi-class geospatial object detection from high spatial resolution (HSR) remote sensing imagery is attracting increasing attention in a wide range of object-related civil and engineering applications. However, the distribution of objects in HSR remote sensing imagery is location-variable and complicated, and how to accurately detect the objects in HSR remote sensing imagery is a critical problem. Due to the powerful feature extraction and representation capability of deep learning, the deep learning based region proposal generation and object detection integrated framework has greatly promoted the performance of multi-class geospatial object detection for HSR remote sensing imagery. However, due to the translation caused by the convolution operation in the convolutional neural network (CNN), although the performance of the classification stage is seldom influenced, the localization accuracies of the predicted bounding boxes in the detection stage are easily influenced. The dilemma between translation-invariance in the classification stage and translation-variance in the object detection stage has not been addressed for HSR remote sensing imagery, and causes position accuracy problems for multi-class geospatial object detection with region proposal generation and object detection. In order to further improve the performance of the region proposal generation and object detection integrated framework for HSR remote sensing imagery object detection, a position-sensitive balancing (PSB) framework is proposed in this paper for multi-class geospatial object detection from HSR remote sensing imagery. The proposed PSB framework takes full advantage of the fully convolutional network (FCN), on the basis of a residual network, and adopts the PSB framework to solve the dilemma between translation-invariance in the classification stage and translation-variance in the object detection stage. In addition, a pre-training mechanism is utilized to accelerate the training procedure and increase the robustness of the proposed algorithm. The proposed algorithm is validated with a publicly available 10-class object detection dataset.

Muver, a computational framework for accurately calling accumulated mutations.

PubMed

Burkholder, Adam B; Lujan, Scott A; Lavender, Christopher A; Grimm, Sara A; Kunkel, Thomas A; Fargo, David C

2018-05-09

Identification of mutations from next-generation sequencing data typically requires a balance between sensitivity and accuracy. This is particularly true of DNA insertions and deletions (indels), that can impart significant phenotypic consequences on cells but are harder to call than substitution mutations from whole genome mutation accumulation experiments. To overcome these difficulties, we present muver, a computational framework that integrates established bioinformatics tools with novel analytical methods to generate mutation calls with the extremely low false positive rates and high sensitivity required for accurate mutation rate determination and comparison. Muver uses statistical comparison of ancestral and descendant allelic frequencies to identify variant loci and assigns genotypes with models that include per-sample assessments of sequencing errors by mutation type and repeat context. Muver identifies maximally parsimonious mutation pathways that connect these genotypes, differentiating potential allelic conversion events and delineating ambiguities in mutation location, type, and size. Benchmarking with a human gold standard father-son pair demonstrates muver's sensitivity and low false positive rates. In DNA mismatch repair (MMR) deficient Saccharomyces cerevisiae, muver detects multi-base deletions in homopolymers longer than the replicative polymerase footprint at rates greater than predicted for sequential single-base deletions, implying a novel multi-repeat-unit slippage mechanism. Benchmarking results demonstrate the high accuracy and sensitivity achieved with muver, particularly for indels, relative to available tools. Applied to an MMR-deficient Saccharomyces cerevisiae system, muver mutation calls facilitate mechanistic insights into DNA replication fidelity.

On line separation of overlapped signals from multi-time photons for the GEM-based detection system

NASA Astrophysics Data System (ADS)

Czarski, T.; Pozniak, K. T.; Chernyshova, M.; Malinowski, K.; Kasprowicz, G.; Kolasinski, P.; Krawczyk, R.; Wojenski, A.; Zabolotny, W.

2015-09-01

The Triple Gas Electron Multiplier (T-GEM) is presented as soft X-ray (SXR) energy and position sensitive detector for high-resolution X-ray diagnostics of magnetic confinement fusion plasmas. Multi-channel measurement system and serial data acquisition for X-ray energy and position recognition is described. Fundamental characteristics are presented for two dimensional detector structure. Typical signals of ADC - Analog to Digital Converter are considered for charge value and position estimation. Coinciding signals for high flux radiation cause the problem for cluster charge identification. The amplifier with shaper determines time characteristics and limits the pulses frequency. Separation of coincided signals was introduced and verified for simulation experiments. On line separation of overlapped signals was implemented applying the FPGA technology with relatively simple firmware procedure. Representative results for reconstruction of coinciding signals are demonstrated.

Target immobilization as a strategy for NMR-based fragment screening: comparison of TINS, STD, and SPR for fragment hit identification.

PubMed

Kobayashi, Masakazu; Retra, Kim; Figaroa, Francis; Hollander, Johan G; Ab, Eiso; Heetebrij, Robert J; Irth, Hubertus; Siegal, Gregg

2010-09-01

Fragment-based drug discovery (FBDD) has become a widely accepted tool that is complementary to high-throughput screening (HTS) in developing small-molecule inhibitors of pharmaceutical targets. Because a fragment campaign can only be as successful as the hit matter found, it is critical that the first stage of the process be optimized. Here the authors compare the 3 most commonly used methods for hit discovery in FBDD: high concentration screening (HCS), solution ligand-observed nuclear magnetic resonance (NMR), and surface plasmon resonance (SPR). They selected the commonly used saturation transfer difference (STD) NMR spectroscopy and the proprietary target immobilized NMR screening (TINS) as representative of the array of possible NMR methods. Using a target typical of FBDD campaigns, the authors find that HCS and TINS are the most sensitive to weak interactions. They also find a good correlation between TINS and STD for tighter binding ligands, but the ability of STD to detect ligands with affinity weaker than 1 mM K(D) is limited. Similarly, they find that SPR detection is most suited to ligands that bind with K(D) better than 1 mM. However, the good correlation between SPR and potency in a bioassay makes this a good method for hit validation and characterization studies.

On multi-sensitivity with respect to a vector

NASA Astrophysics Data System (ADS)

Jiao, Lixin; Wang, Lidong; Li, Fengquan; Liu, Heng

2018-05-01

Consider the surjective continuous map f: X → X defined on a compact metric space X. Let 𝒦(X) be the space of all non-empty compact subsets of X equipped with the Hausdorff metric and define f¯: 𝒦(X) →𝒦(X) by f¯(A) = {f(a),a ∈ A} for any A ∈𝒦(X). In this paper, we introduce several stronger versions of sensitivities, such as multi-sensitivity with respect to a vector, 𝒩-sensitivity, strong multi-sensitivity. We obtain some basic properties of the concepts of these sensitivities and discuss the relationships with other sensitivities for continuous self-map on [0,1]. Some sufficient conditions for a dynamical system to be 𝒩-sensitive are presented. Also, it is shown that the strong multi-sensitivity of f implies that f¯ is 𝒩-sensitive. In turn, the 𝒩-sensitivity of f¯ implies that f is 𝒩-sensitive. In particular, it is proved that if f is a multi-transitive map with dense periodic sets, then f is 𝒩-sensitive. Finally, we give a multi-sensitive example which is not 𝒩-sensitive.

The impact of health information technology on organ transplant care: A systematic review.

PubMed

Niazkhani, Zahra; Pirnejad, Habibollah; Rashidi Khazaee, Parviz

2017-04-01

Health Information Technology (HIT) has a potential to promote transplant care. However, a systematic appraisal on how HIT application has so far affected transplant care is greatly missing from the literature. We systematically reviewed trials that evaluated HIT impact on process and patient outcomes as well as costs in organ transplant care. A systematic search was conducted in OVID versions of MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane, and IEEE databases from January 1990 to December 2015. Studies were included if they: (i) evaluated HIT interventions; (ii) reported results for organ transplant population; (iii) reported quantitative data on process, patient, and cost outcomes; and (iv) used a randomized controlled trial or quasi-experimental study design. Primarily, 12,440 publications were identified; from which ten met inclusion criteria. Among HIT systems, uses of clinical decision support systems (CDSS) targeting different aspects of the complex organ transplant care were common. In terms of process outcomes, HIT positively impacted the timeliness of care, laboratory and medication management practices such as promoting therapeutic or diagnostic protocol compliance by clinicians, and reducing medication errors. Regarding patient outcomes, HIT demonstrated a beneficial impact on the percentage of post-transplant patients with normal lab values and decreasing immunosuppressive toxicity and also deviation from the predefined immunosuppressive therapeutic window. However, in terms of mortality, readmission, rejection, and antiviral resistance rates, the impact was not clearly established in the literature. Finally, these systems were associated with savings in the costs of transplant care in three studies. This is the first study reviewing HIT impact on transplant care outcomes. CDSSs have mainly been reported to support transplant care in realizing the above-mentioned benefits. However, to make conclusions, more evidence with less risk of bias is warranted. Several gaps in the literature, including comparison of the impact of commercial systems in different transplant settings, was identified which can motivate future research. Copyright © 2017 Elsevier B.V. All rights reserved.

Hospital implementation of health information technology and quality of care: are they related?

PubMed

Restuccia, Joseph D; Cohen, Alan B; Horwitt, Jedediah N; Shwartz, Michael

2012-09-27

Recently, there has been considerable effort to promote the use of health information technology (HIT) in order to improve health care quality. However, relatively little is known about the extent to which HIT implementation is associated with hospital patient care quality. We undertook this study to determine the association of various HITs with: hospital quality improvement (QI) practices and strategies; adherence to process of care measures; risk-adjusted inpatient mortality; patient satisfaction; and assessment of patient care quality by hospital quality managers and front-line clinicians. We conducted surveys of quality managers and front-line clinicians (physicians and nurses) in 470 short-term, general hospitals to obtain data on hospitals' extent of HIT implementation, QI practices and strategies, assessments of quality performance, commitment to quality, and sufficiency of resources for QI. Of the 470 hospitals, 401 submitted complete data necessary for analysis. We also developed measures of hospital performance from several publicly data available sources: Hospital Compare adherence to process of care measures; Medicare Provider Analysis and Review (MEDPAR) file; and Hospital Consumer Assessment of Healthcare Providers and Systems HCAHPS® survey. We used Poisson regression analysis to examine the association between HIT implementation and QI practices and strategies, and general linear models to examine the relationship between HIT implementation and hospital performance measures. Controlling for potential confounders, we found that hospitals with high levels of HIT implementation engaged in a statistically significant greater number of QI practices and strategies, and had significantly better performance on mortality rates, patient satisfaction measures, and assessments of patient care quality by hospital quality managers; there was weaker evidence of higher assessments of patient care quality by front-line clinicians. Hospital implementation of HIT was positively associated with activities intended to improve patient care quality and with higher performance on four of six performance measures.

Health information technology capacity at federally qualified health centers: a mechanism for improving quality of care

PubMed Central

2013-01-01

Background The adoption of health information technology has been recommended as a viable mechanism for improving quality of care and patient health outcomes. However, the capacity of health information technology (i.e., availability and use of multiple and advanced functionalities), particularly in federally qualified health centers (FQHCs) on improving quality of care is not well understood. We examined associations between health information technology (HIT) capacity at FQHCs and quality of care, measured by the receipt of discharge summary, frequency of patients receiving reminders/notifications for preventive care/follow-up care, and timely appointment for specialty care. Methods The analyses used 2009 data from the National Survey of Federally Qualified Health Centers. The study included 776 of the FQHCs that participated in the survey. We examined the extent of HIT use and tested the hypothesis that level of HIT capacity is associated with quality of care. Multivariable logistic regressions, reporting unadjusted and adjusted odds ratios, were used to examine whether ‘FQHCs’ HIT capacity’ is associated with the outcome measures. Results The results showed a positive association between health information technology capacity and quality of care. FQHCs with higher HIT capacity were significantly more likely to have improved quality of care, measured by the receipt of discharge summaries (OR=1.43; CI=1.01, 2.40), the use of a patient notification system for preventive and follow-up care (OR=1.74; CI=1.23, 2.45), and timely appointment for specialty care (OR=1.77; CI=1.24, 2.53). Conclusions Our findings highlight the promise of HIT in improving quality of care, particularly for vulnerable populations who seek care at FQHCs. The results also show that FQHCs may not be maximizing the benefits of HIT. Efforts to implement HIT must include strategies that facilitate the implementation of comprehensive and advanced functionalities, as well as promote meaningful use of these systems. Further examination of the role of health information systems in clinical decision-making and improvements in patient outcomes are needed to better understand the benefits of HIT in improving overall quality of care. PMID:23363660

Health information technology capacity at federally qualified health centers: a mechanism for improving quality of care.

PubMed

Frimpong, Jemima A; Jackson, Bradford E; Stewart, LaShonda M; Singh, Karan P; Rivers, Patrick A; Bae, Sejong

2013-01-31

The adoption of health information technology has been recommended as a viable mechanism for improving quality of care and patient health outcomes. However, the capacity of health information technology (i.e., availability and use of multiple and advanced functionalities), particularly in federally qualified health centers (FQHCs) on improving quality of care is not well understood. We examined associations between health information technology (HIT) capacity at FQHCs and quality of care, measured by the receipt of discharge summary, frequency of patients receiving reminders/notifications for preventive care/follow-up care, and timely appointment for specialty care. The analyses used 2009 data from the National Survey of Federally Qualified Health Centers. The study included 776 of the FQHCs that participated in the survey. We examined the extent of HIT use and tested the hypothesis that level of HIT capacity is associated with quality of care. Multivariable logistic regressions, reporting unadjusted and adjusted odds ratios, were used to examine whether 'FQHCs' HIT capacity' is associated with the outcome measures. The results showed a positive association between health information technology capacity and quality of care. FQHCs with higher HIT capacity were significantly more likely to have improved quality of care, measured by the receipt of discharge summaries (OR=1.43; CI=1.01, 2.40), the use of a patient notification system for preventive and follow-up care (OR=1.74; CI=1.23, 2.45), and timely appointment for specialty care (OR=1.77; CI=1.24, 2.53). Our findings highlight the promise of HIT in improving quality of care, particularly for vulnerable populations who seek care at FQHCs. The results also show that FQHCs may not be maximizing the benefits of HIT. Efforts to implement HIT must include strategies that facilitate the implementation of comprehensive and advanced functionalities, as well as promote meaningful use of these systems. Further examination of the role of health information systems in clinical decision-making and improvements in patient outcomes are needed to better understand the benefits of HIT in improving overall quality of care.

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity.

PubMed

Rabanal, Francesc; Grau-Campistany, Ariadna; Vila-Farrés, Xavier; Gonzalez-Linares, Javier; Borràs, Miquel; Vila, Jordi; Manresa, Angeles; Cajal, Yolanda

2015-05-29

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

A wearable multipoint ultrasonic travel aids for visually impaired

NASA Astrophysics Data System (ADS)

Ercoli, Ilaria; Marchionni, Paolo; Scalise, Lorenzo

2013-09-01

In 2010, the World Health Organization estimates that there were about 285 million people in the world with disabling eyesight loss (246 millions are visually impaired (VI) and 39 millions are totally blind). For such users, hits during mobility tasks are the reason of major concerns and can reduce the quality of their life. The white cane is the primary device used by the majority of blind or VI users to explore and possibly avoid obstacles; it can monitor only the ground (< 1m) and it does not provide protection for the legs, the trunk and the head. In this paper, authors propose a novel stand-alone Electronic Travel Aid (ETA) device for obstacle detection based on multi- sensing (by 4 ultrasonic transducers) and a microcontroller. Portability, simplicity, reduced dimensions and cost are among the major pros of the reported system, which can detect and localize (angular position and distance from the user) obstacles eventually present in the volume in front of him and on the ground in front of him.

Combined Application of Shallow Seismic Reflection and High-resolution Refraction Exploration Approach to Active Fault Survey, Central Orogenic Belt, China

NASA Astrophysics Data System (ADS)

Lin, S.; Luo, D.; Yanlin, F.; Li, Y.

2016-12-01

Shallow Seismic Reflection (SSR) is a major geophysical exploration method with its exploration depth range, high-resolution in urban active fault exploration. In this paper, we carried out (SSR) and High-resolution refraction (HRR) test in the Liangyun Basin to explore a buried fault. We used NZ distributed 64 channel seismic instrument, 60HZ high sensitivity detector, Geode multi-channel portable acquisition system and hammer source. We selected single side hammer hit multiple overlay, 48 channels received and 12 times of coverage. As there are some coincidence measuring lines of SSR and HRR, we chose multi chase and encounter observation system. Based on the satellite positioning, we arranged 11 survey lines in our study area with total length for 8132 meters. GEOGIGA seismic reflection data processing software was used to deal with the SSR data. After repeated tests from the aspects of single shot record compilation, interference wave pressing, static correction, velocity parameter extraction, dynamic correction, eventually got the shallow seismic reflection profile images. Meanwhile, we used Canadian technology company good refraction and tomographic imaging software to deal with HRR seismic data, which is based on nonlinear first arrival wave travel time tomography. Combined with drilling geological profiles, we explained 11 measured seismic profiles. Results show 18 obvious fault feature breakpoints, including 4 normal faults of south-west, 7 reverse faults of south-west, one normal fault of north-east and 6 reverse faults of north-east. Breakpoints buried depth is 15-18 meters, and the inferred fault distance is 3-12 meters. Comprehensive analysis shows that the fault property is reverse fault with northeast incline section, and fewer branch normal faults presenting southwest incline section. Since good corresponding relationship between the seismic interpretation results, drilling data and SEM results on the property, occurrence, broken length of the fault, we considered the Liangyun fault to be an active fault which has strong activity during the Neogene Pliocene and early Pleistocene, Middle Pleistocene period. The combined application of SSR and HRR can provide more parameters to explain the seismic results, and improve the accuracy of the interpretation.

MultiMiTar: a novel multi objective optimization based miRNA-target prediction method.

PubMed

Mitra, Ramkrishna; Bandyopadhyay, Sanghamitra

2011-01-01

Machine learning based miRNA-target prediction algorithms often fail to obtain a balanced prediction accuracy in terms of both sensitivity and specificity due to lack of the gold standard of negative examples, miRNA-targeting site context specific relevant features and efficient feature selection process. Moreover, all the sequence, structure and machine learning based algorithms are unable to distribute the true positive predictions preferentially at the top of the ranked list; hence the algorithms become unreliable to the biologists. In addition, these algorithms fail to obtain considerable combination of precision and recall for the target transcripts that are translationally repressed at protein level. In the proposed article, we introduce an efficient miRNA-target prediction system MultiMiTar, a Support Vector Machine (SVM) based classifier integrated with a multiobjective metaheuristic based feature selection technique. The robust performance of the proposed method is mainly the result of using high quality negative examples and selection of biologically relevant miRNA-targeting site context specific features. The features are selected by using a novel feature selection technique AMOSA-SVM, that integrates the multi objective optimization technique Archived Multi-Objective Simulated Annealing (AMOSA) and SVM. MultiMiTar is found to achieve much higher Matthew's correlation coefficient (MCC) of 0.583 and average class-wise accuracy (ACA) of 0.8 compared to the others target prediction methods for a completely independent test data set. The obtained MCC and ACA values of these algorithms range from -0.269 to 0.155 and 0.321 to 0.582, respectively. Moreover, it shows a more balanced result in terms of precision and sensitivity (recall) for the translationally repressed data set as compared to all the other existing methods. An important aspect is that the true positive predictions are distributed preferentially at the top of the ranked list that makes MultiMiTar reliable for the biologists. MultiMiTar is now available as an online tool at www.isical.ac.in/~bioinfo_miu/multimitar.htm. MultiMiTar software can be downloaded from www.isical.ac.in/~bioinfo_miu/multimitar-download.htm.

Monitoring Hitting Load in Tennis Using Inertial Sensors and Machine Learning.

PubMed

Whiteside, David; Cant, Olivia; Connolly, Molly; Reid, Machar

2017-10-01

Quantifying external workload is fundamental to training prescription in sport. In tennis, global positioning data are imprecise and fail to capture hitting loads. The current gold standard (manual notation) is time intensive and often not possible given players' heavy travel schedules. To develop an automated stroke-classification system to help quantify hitting load in tennis. Nineteen athletes wore an inertial measurement unit (IMU) on their wrist during 66 video-recorded training sessions. Video footage was manually notated such that known shot type (serve, rally forehand, slice forehand, forehand volley, rally backhand, slice backhand, backhand volley, smash, or false positive) was associated with the corresponding IMU data for 28,582 shots. Six types of machine-learning models were then constructed to classify true shot type from the IMU signals. Across 10-fold cross-validation, a cubic-kernel support vector machine classified binned shots (overhead, forehand, or backhand) with an accuracy of 97.4%. A second cubic-kernel support vector machine achieved 93.2% accuracy when classifying all 9 shot types. With a view to monitoring external load, the combination of miniature inertial sensors and machine learning offers a practical and automated method of quantifying shot counts and discriminating shot types in elite tennis players.

Multi-window detection for P-wave in electrocardiograms based on bilateral accumulative area.

PubMed

Chen, Riqing; Huang, Yingsong; Wu, Jian

2016-11-01

P-wave detection is one of the most challenging aspects in electrocardiograms (ECGs) due to its low amplitude, low frequency, and variable waveforms. This work introduces a novel multi-window detection method for P-wave delineation based on the bilateral accumulative area. The bilateral accumulative area is calculated by summing the areas covered by the P-wave curve with left and right sliding windows. The onset and offset of a positive P-wave correspond to the local maxima of the area detector. The position drift and difference in area variation of local extreme points with different windows are used to systematically combine multi-window and 12-lead synchronous detection methods, which are used to screen the optimization boundary points from all extreme points of different window widths and adaptively match the P-wave location. The proposed method was validated with ECG signals from various databases, including the Standard CSE Database, T-Wave Alternans Challenge Database, PTB Diagnostic ECG Database, and the St. Petersburg Institute of Cardiological Technics 12-Lead Arrhythmia Database. The average sensitivity Se was 99.44% with a positive predictivity P+ of 99.37% for P-wave detection. Standard deviations of 3.7 and 4.3ms were achieved for the onset and offset of P-waves, respectively, which is in agreement with the accepted tolerances required by the CSE committee. Compared with well-known delineation methods, this method can achieve high sensitivity and positive predictability using a simple calculation process. The experiment results suggest that the bilateral accumulative area could be an effective detection tool for ECG signal analysis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Multi-Conformer Ensemble Docking to Difficult Protein Targets

DOE PAGES

Ellingson, Sally R.; Miao, Yinglong; Baudry, Jerome; ...

2014-09-08

We investigate large-scale ensemble docking using five proteins from the Directory of Useful Decoys (DUD, dud.docking.org) for which docking to crystal structures has proven difficult. Molecular dynamics trajectories are produced for each protein and an ensemble of representative conformational structures extracted from the trajectories. Docking calculations are performed on these selected simulation structures and ensemble-based enrichment factors compared with those obtained using docking in crystal structures of the same protein targets or random selection of compounds. We also found simulation-derived snapshots with improved enrichment factors that increased the chemical diversity of docking hits for four of the five selected proteins.more » A combination of all the docking results obtained from molecular dynamics simulation followed by selection of top-ranking compounds appears to be an effective strategy for increasing the number and diversity of hits when using docking to screen large libraries of chemicals against difficult protein targets.« less

[Selection of a melanine concentrating hormone receptor-1 (MCHR1) antagonists' focused library and its biological screening with AequoScreen].

PubMed

Flachner, Beáta; Hajdú, István; Dobi, Krisztina; Lorincz, Zsolt; Cseh, Sándor; Dormán, György

2013-01-01

Target focused libraries can be rapidly selected by 2D virtual screening methods from multimillion compounds' repositories if structures of active compounds are available. In the present study a multi-step virtual and in vitro screening cascade is reported to select Melanin Concentrating Hormone Receptor-1 (MCHR1) antagonists. The 2D similarity search combined with physicochemical parameter filtering is suitable for selecting candidates from multimillion compounds' repository. The seeds of the first round virtual screening were collected from the literature and commercial databases, while the seeds of the second round were the hits of the first round. In vitro screening underlined the efficiency of our approach, as in the second screening round the hit rate (8.6 %) significantly improved compared to the first round (1.9%), reaching the antagonist activity even below 10 nM.

The Impact of Satellite Time Group Delay and Inter-Frequency Differential Code Bias Corrections on Multi-GNSS Combined Positioning

PubMed Central

Ge, Yulong; Zhou, Feng; Sun, Baoqi; Wang, Shengli; Shi, Bo

2017-01-01

We present quad-constellation (namely, GPS, GLONASS, BeiDou and Galileo) time group delay (TGD) and differential code bias (DCB) correction models to fully exploit the code observations of all the four global navigation satellite systems (GNSSs) for navigation and positioning. The relationship between TGDs and DCBs for multi-GNSS is clearly figured out, and the equivalence of TGD and DCB correction models combining theory with practice is demonstrated. Meanwhile, the TGD/DCB correction models have been extended to various standard point positioning (SPP) and precise point positioning (PPP) scenarios in a multi-GNSS and multi-frequency context. To evaluate the effectiveness and practicability of broadcast TGDs in the navigation message and DCBs provided by the Multi-GNSS Experiment (MGEX), both single-frequency GNSS ionosphere-corrected SPP and dual-frequency GNSS ionosphere-free SPP/PPP tests are carried out with quad-constellation signals. Furthermore, the author investigates the influence of differential code biases on GNSS positioning estimates. The experiments show that multi-constellation combination SPP performs better after DCB/TGD correction, for example, for GPS-only b1-based SPP, the positioning accuracies can be improved by 25.0%, 30.6% and 26.7%, respectively, in the N, E, and U components, after the differential code biases correction, while GPS/GLONASS/BDS b1-based SPP can be improved by 16.1%, 26.1% and 9.9%. For GPS/BDS/Galileo the 3rd frequency based SPP, the positioning accuracies are improved by 2.0%, 2.0% and 0.4%, respectively, in the N, E, and U components, after Galileo satellites DCB correction. The accuracy of Galileo-only b1-based SPP are improved about 48.6%, 34.7% and 40.6% with DCB correction, respectively, in the N, E, and U components. The estimates of multi-constellation PPP are subject to different degrees of influence. For multi-constellation combination SPP, the accuracy of single-frequency is slightly better than that of dual-frequency combinations. Dual-frequency combinations are more sensitive to the differential code biases, especially for the 2nd and 3rd frequency combination, such as for GPS/BDS SPP, accuracy improvements of 60.9%, 26.5% and 58.8% in the three coordinate components is achieved after DCB parameters correction. For multi-constellation PPP, the convergence time can be reduced significantly with differential code biases correction. And the accuracy of positioning is slightly better with TGD/DCB correction. PMID:28300787

The Impact of Satellite Time Group Delay and Inter-Frequency Differential Code Bias Corrections on Multi-GNSS Combined Positioning.

PubMed

Ge, Yulong; Zhou, Feng; Sun, Baoqi; Wang, Shengli; Shi, Bo

2017-03-16

We present quad-constellation (namely, GPS, GLONASS, BeiDou and Galileo) time group delay (TGD) and differential code bias (DCB) correction models to fully exploit the code observations of all the four global navigation satellite systems (GNSSs) for navigation and positioning. The relationship between TGDs and DCBs for multi-GNSS is clearly figured out, and the equivalence of TGD and DCB correction models combining theory with practice is demonstrated. Meanwhile, the TGD/DCB correction models have been extended to various standard point positioning (SPP) and precise point positioning (PPP) scenarios in a multi-GNSS and multi-frequency context. To evaluate the effectiveness and practicability of broadcast TGDs in the navigation message and DCBs provided by the Multi-GNSS Experiment (MGEX), both single-frequency GNSS ionosphere-corrected SPP and dual-frequency GNSS ionosphere-free SPP/PPP tests are carried out with quad-constellation signals. Furthermore, the author investigates the influence of differential code biases on GNSS positioning estimates. The experiments show that multi-constellation combination SPP performs better after DCB/TGD correction, for example, for GPS-only b1-based SPP, the positioning accuracies can be improved by 25.0%, 30.6% and 26.7%, respectively, in the N, E, and U components, after the differential code biases correction, while GPS/GLONASS/BDS b1-based SPP can be improved by 16.1%, 26.1% and 9.9%. For GPS/BDS/Galileo the 3rd frequency based SPP, the positioning accuracies are improved by 2.0%, 2.0% and 0.4%, respectively, in the N, E, and U components, after Galileo satellites DCB correction. The accuracy of Galileo-only b1-based SPP are improved about 48.6%, 34.7% and 40.6% with DCB correction, respectively, in the N, E, and U components. The estimates of multi-constellation PPP are subject to different degrees of influence. For multi-constellation combination SPP, the accuracy of single-frequency is slightly better than that of dual-frequency combinations. Dual-frequency combinations are more sensitive to the differential code biases, especially for the 2nd and 3rd frequency combination, such as for GPS/BDS SPP, accuracy improvements of 60.9%, 26.5% and 58.8% in the three coordinate components is achieved after DCB parameters correction. For multi-constellation PPP, the convergence time can be reduced significantly with differential code biases correction. And the accuracy of positioning is slightly better with TGD/DCB correction.

A multi-scale tensor voting approach for small retinal vessel segmentation in high resolution fundus images.

PubMed

Christodoulidis, Argyrios; Hurtut, Thomas; Tahar, Houssem Ben; Cheriet, Farida

2016-09-01

Segmenting the retinal vessels from fundus images is a prerequisite for many CAD systems for the automatic detection of diabetic retinopathy lesions. So far, research efforts have concentrated mainly on the accurate localization of the large to medium diameter vessels. However, failure to detect the smallest vessels at the segmentation step can lead to false positive lesion detection counts in a subsequent lesion analysis stage. In this study, a new hybrid method for the segmentation of the smallest vessels is proposed. Line detection and perceptual organization techniques are combined in a multi-scale scheme. Small vessels are reconstructed from the perceptual-based approach via tracking and pixel painting. The segmentation was validated in a high resolution fundus image database including healthy and diabetic subjects using pixel-based as well as perceptual-based measures. The proposed method achieves 85.06% sensitivity rate, while the original multi-scale line detection method achieves 81.06% sensitivity rate for the corresponding images (p<0.05). The improvement in the sensitivity rate for the database is 6.47% when only the smallest vessels are considered (p<0.05). For the perceptual-based measure, the proposed method improves the detection of the vasculature by 7.8% against the original multi-scale line detection method (p<0.05). Copyright © 2016 Elsevier Ltd. All rights reserved.

Chronic β2 -adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men.

PubMed

Hostrup, Morten; Onslev, Johan; Jacobson, Glenn A; Wilson, Richard; Bangsbo, Jens

2018-01-15

While several studies have investigated the effects of exercise training in human skeletal muscle and the chronic effect of β 2 -agonist treatment in rodent muscle, their effects on muscle proteome signature with related functional measures in humans are still incompletely understood. Herein we show that daily β 2 -agonist treatment attenuates training-induced enhancements in exercise performance and maximal oxygen consumption, and alters muscle proteome signature and phenotype in trained young men. Daily β 2 -agonist treatment abolished several of the training-induced enhancements in muscle oxidative capacity and caused a repression of muscle metabolic pathways; furthermore, β 2 -agonist treatment induced a slow-to-fast twitch muscle phenotype transition. The present study indicates that chronic β 2 -agonist treatment confounds the positive effect of high intensity training on exercise performance and oxidative capacity, which is of interest for the large proportion of persons using inhaled β 2 -agonists on a daily basis, including athletes. Although the effects of training have been studied for decades, data on muscle proteome signature remodelling induced by high intensity training in relation to functional changes in humans remains incomplete. Likewise, β 2 -agonists are frequently used to counteract exercise-induced bronchoconstriction, but the effects β 2 -agonist treatment on muscle remodelling and adaptations to training are unknown. In a placebo-controlled parallel study, we randomly assigned 21 trained men to 4 weeks of high intensity training with (HIT+β 2 A) or without (HIT) daily inhalation of β 2 -agonist (terbutaline, 4 mg dose -1 ). Of 486 proteins identified by mass-spectrometry proteomics of muscle biopsies sampled before and after the intervention, 32 and 85 were changing (false discovery rate (FDR) ≤5%) with the intervention in HIT and HIT+β 2 A, respectively. Proteome signature changes were different in HIT and HIT+β 2 A (P = 0.005), wherein β 2 -agonist caused a repression of 25 proteins in HIT+β 2 A compared to HIT, and an upregulation of 7 proteins compared to HIT. β 2 -Agonist repressed or even downregulated training-induced enrichment of pathways related to oxidative phosphorylation and glycogen metabolism, but upregulated pathways related to histone trimethylation and the nucleosome. Muscle contractile phenotype changed differently in HIT and HIT+β 2 A (P ≤ 0.001), with a fast-to-slow twitch transition in HIT and a slow-to-fast twitch transition in HIT+β 2 A. β 2 -Agonist attenuated training-induced enhancements in maximal oxygen consumption (P ≤ 0.01) and exercise performance (6.1 vs. 11.6%, P ≤ 0.05) in HIT+β 2 A compared to HIT. These findings indicate that daily β 2 -agonist treatment attenuates the beneficial effects of high intensity training on exercise performance and oxidative capacity, and causes remodelling of muscle proteome signature towards a fast-twitch phenotype. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Intimate partner violence among female drug users admitted to the general hospital: screening and prevalence.

PubMed

Caldentey, Clara; Tirado Muñoz, Judit; Ferrer, Tessie; Fonseca Casals, Francina; Rossi, Paola; Mestre-Pintó, Juan Ignacio; Torrens Melich, Marta

2017-06-28

Intimate partner violence (IPV) is a public health problem worldwide. Several factors have been found to be associated with an increased prevalence of IPV, such as substance use. A cross-sectional study was conducted with the aim of determining the prevalence of IPV among women entering Hospital del Mar (Barcelona) for any medical/surgical reason, and who had a diagnosis of substance use disorder. Secondly, it was intended to psychometrically validate the Spanish version of the Hurt, Insulted, Threatened with Harm, Screamed (HITS) questionnaire. All patients were assessed by two IPV questionnaires, the Composite Abuse Scale (CAS) and HITS. Out of 52 patients interviewed, 46 answered both questionnaires. According to the CAS questionnaire, 23 patients (50%) experienced IPV at some point in their lives and 11 (23.9%) in the last year. Cannabis consumption was also associated with an increased severity of IPV (95% CI 3.5-28.9, p = .013).According to the HITS questionnaire, there was a prevalence of 39.1% (18 patients) in the last 12 months. HITS had a specificity of 100% and a sensitivity of 78% relative to the CAS questionnaire. A cut-off score x∈ [6.7], derived through ROC analysis, correctly discriminated 91% of the victims and 100% of the non-victims. The results obtained showed that the prevalence of IPV was very high among women who suffered from more than one substance use disorder. Therefore, it is highly recommended to systematically screen for IPV victimization by putting the HITS questionnaire into practice.

Embryogenesis and organogenesis of Carausius morosus under spaceflight conditions.

PubMed

Bucker, H; Facius, R; Horneck, G; Reitz, G; Graul, E H; Berger, H; Hoffken, H; Ruther, W; Heinrich, W; Beaujean, R; Enge, W

1986-01-01

The influence of cosmic radiation and/or microgravity on insect development was studied during the 7 day German Spacelab Mission D1. Eggs of Carausius morosus of five stages differing in sensitivity to radiation and in capacity to regeneration were allowed to continue their development in the BIORACK 22 degrees C incubator, either at microgravity conditions or on the 1 g reference centrifuge. Using the Biostack concept--eggs in monolayers were sandwiched between visual track detectors--and the 1 g reference centrifuge, we were able to separate radiation effects from microgravity effects and also from combined effects of these two factors in space. After retrieval, hatching rates, growth kinetics and anomaly frequencies were determined in the different test samples. The early stages of development turned out to be highly sensitive to single hits of cosmic ray particles as well as to the temporary exposure to microgravity during their development. In some cases, the combined action of radiation and microgravity even amplified the effects exerted by the single parameters of space. Hits by single HZE particles caused early effects, such as body anomalies, as well as late effects, such as retarded growth after hatching. Microgravity exposure lead to a reduced hatching rate. A synergistic action of HZE particle hits and microgravity was established in the unexpectedly high frequency of anomal larvae. However, it cannot be excluded, that cosmic background radiation or low LET HZE particles are also causally involved in damage observed in the microgravity samples.

Radiocytogenetic effects on bone marrow cells of opossum in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prasad, N.; Bushong, S.C.; MacIntyre, R.S.

1973-03-01

Bone marrow cells of the opossum, Didelphis virginiana, were examined 24 hr following a whole-body /sup 60/Co radiation dosc of 100, and the chromosomal aberrations resulted in a radiation sensitivity of 0.000605 aberrations/cell/rad/ sup 2/ for single-hit and multihit type damage respectively. (auth)

Preventive effect of α-lipoic acid on prepulse inhibition deficits in a juvenile two-hit model of schizophrenia.

PubMed

Deslauriers, J; Racine, W; Sarret, P; Grignon, S

2014-07-11

Some pathophysiological models of schizophrenia posit that prenatal inflammation sensitizes the developing brain to second insults in early life and enhances brain vulnerability, thereby increasing the risk of developing the disorder during adulthood. We previously developed a two-hit animal model, based on the well-established prenatal immune challenge with poly-inosinic/cytidylic acid (polyI:C), followed by juvenile restraint stress (RS). We observed an additive disruption of prepulse inhibition (PPI) of acoustic startle in juvenile mice submitted to both insults. Previous studies have also reported that oxidative stress is associated with pathophysiological mechanisms of psychiatric disorders, including schizophrenia. We report here that PPI disruption in our two-hit animal model of schizophrenia is associated with an increase in oxidative stress. These findings led us to assess whether α-lipoic acid, an antioxidant, can prevent both increase in oxidative status and PPI deficits in our juvenile in vivo model of schizophrenia. In the offspring submitted to prenatal injection of polyI:C and to RS, treatment with α-lipoic acid prevented the development of PPI deficits 24h after the last period of RS. α-Lipoic acid also improved PPI performance in control mice. The reversal effect of α-lipoic acid pretreatment on these behavioral alterations was further accompanied by a normalization of the associated oxidative status and dopaminergic and GABAergic abnormalities in the prefrontal cortex. Based on our double insult paradigm, these results support the hypothesis that oxidative stress plays an important role in the development of PPI deficits, a well-known behavior associated with schizophrenia. These findings form the basis of future studies aiming to unravel mechanistic insights of the putative role of antioxidants in the treatment of schizophrenia, especially during the prodromal stage. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Robust Optimization and Sensitivity Analysis with Multi-Objective Genetic Algorithms: Single- and Multi-Disciplinary Applications

DTIC Science & Technology

2007-01-01

multi-disciplinary optimization with uncertainty. Robust optimization and sensitivity analysis is usually used when an optimization model has...formulation is introduced in Section 2.3. We briefly discuss several definitions used in the sensitivity analysis in Section 2.4. Following in...2.5. 2.4 SENSITIVITY ANALYSIS In this section, we discuss several definitions used in Chapter 5 for Multi-Objective Sensitivity Analysis . Inner

A Field-Programmable Gate Array (FPGA) TDC for the Fermilab SeaQuest (E906) Experiment and Its Test with a Novel External Wave Union Launcher

NASA Astrophysics Data System (ADS)

Wang, Su-Yin; Wu, Jinyuan; Yao, Shi-Hong; Chang, Wen-Chen

2014-12-01

We developed a field-programmable gate array (FPGA) TDC module for the tracking detectors of the Fermilab SeaQuest (E906) experiment, including drift chambers, proportional tubes, and hodoscopes. This 64-channel TDC module had a 6U VMEbus form factor and was equipped with a low-power, radiation-hardened Microsemi ProASIC3 Flash-based FPGA. The design of the new FPGA firmware (Run2-TDC) aimed to reduce the data volume and data acquisition (DAQ) deadtime. The firmware digitized multiple input hits of both polarities while allowing users to turn on a multiple-hit elimination logic to remove after-pulses in the wire chambers and proportional tubes. A scaler was implemented in the firmware to allow for recording the number of hits in each channel. The TDC resolution was determined by an internal cell delay of 450 ps. A measurement precision of 200 ps was achieved. We used five kinds of tests to ensure the qualification of 93 TDCs in mass production. We utilized the external wave union launcher in our test to improve the TDC's measurement precision and also to illustrate how to construct the Wave Union TDC using an existing multi-hit TDC without modifying its firmware. Measurement precision was improved by a factor of about two (108 ps) based on the four-edge wave union. Better measurement precision (69 ps) was achieved by combining the approaches of Wave Union TDC and multiple-channel ganging.

Student Use of Scaffolding Software: Relationships with Motivation and Conceptual Understanding

NASA Astrophysics Data System (ADS)

Butler, Kyle A.; Lumpe, Andrew

2008-10-01

This study was designed to theoretically articulate and empirically assess the role of computer scaffolds. In this project, several examples of educational software were developed to scaffold the learning of students performing high level cognitive activities. The software used in this study, Artemis, focused on scaffolding the learning of students as they performed information seeking activities. As 5th grade students traveled through a project-based science unit on photosynthesis, researchers used a pre-post design to test for both student motivation and student conceptual understanding of photosynthesis. To measure both variables, a motivation survey and three methods of concept map analysis were used. The student use of the scaffolding features was determined using a database that tracked students' movement between scaffolding tools. The gain scores of each dependent variable was then correlated to the students' feature use (time and hits) embedded in the Artemis Interface. This provided the researchers with significant relationships between the scaffolding features represented in the software and student motivation and conceptual understanding of photosynthesis. There were a total of three significant correlations in comparing the scaffolding use by hits (clicked on) with the dependent variables and only one significant correlation when comparing the scaffold use in time. The first significant correlation ( r = .499, p < .05) was between the saving/viewing features hits and the students' task value. This correlation supports the assumption that there is a positive relationship between the student use of the saving/viewing features and the students' perception of how interesting, how important, and how useful the task is. The second significant correlation ( r = 0.553, p < 0.01) was between the searching features hits and the students' self-efficacy for learning and performance. This correlation supports the assumption that there is a positive relationship between the student use of the searching features and the students' perception of their ability to accomplish a task as well as their confidence in their skills to perform that task. The third significant correlation ( r = 0.519, p < 0.05) was between the collaborative features hits and the students' essay performance scores. This correlation supports the assumption that there is a positive relationship between the student use of the collaborative features and the students' ability to perform high cognitive tasks. Finally, the last significant correlation ( r = 0.576, p < 0.01) was between the maintenance features time and the qualitative analysis of the concept maps. This correlation supports the assumption that there is a positive relationship between the student use of the maintenance features and student conceptual understanding of photosynthesis.

Why hospitals adopt patient engagement functionalities at different speeds? A moderated trend analysis.

PubMed

Asagbra, O Elijah; Burke, Darrell; Liang, Huigang

2018-03-01

To investigate acute care hospitals' adoption speed of patient engagement health information technology (HIT) functionalities from 2008 to 2013 and how this speed is contingent on environmental factors and hospital characteristics. Data on non-government acute care hospitals located in the United States was obtained from merging three databases: the American Hospital Association's (AHA) annual survey information technology supplement, AHA annual survey, and the Area Health Resource File (AHRF). The variables obtained from these datasets were the amount of annually adopted patient engagement HIT functionalities and environmental and organizational characteristics. Environmental factors included were uncertainty, munificence, and complexity. Hospital characteristics included size, system membership, ownership, and teaching status. A regression analysis of 4176 hospital-year observations revealed a positive trend in the adoption of HIT functionalities for patient engagement (β= 1.109, p < 0.05). Moreover, the study showed that large, system-affiliated, not-for-profit, teaching hospitals adopt patient engagement HIT functionalities at a faster speed than their counterparts. Environmental munificence and uncertainty were also associated with an accelerating speed of adoption. Environmental complexity however did not show a significant impact on the speed of adoption. From 2008 to 2013, there was a significant acceleration in the speed of adopting patient engagement HIT functionalities. Further efforts should be made to ensure proper adoption and consistent use by patients in order to reap the benefits of these IT investments. Hospitals adopted at least one HIT functionality for patient engagement per year. The adoption speed varied across hospitals, depending on both environmental and organizational factors. Copyright © 2017 Elsevier B.V. All rights reserved.

Blocking Lymphocyte Trafficking with FTY720 Prevents Inflammation-Sensitized Hypoxic–Ischemic Brain Injury in Newborns

PubMed Central

Yang, Dianer; Sun, Yu-Yo; Bhaumik, Siddhartha Kumar; Li, Yikun; Baumann, Jessica M.; Lin, Xiaoyi; Zhang, Yujin; Lin, Shang-Hsuan; Dunn, R. Scott; Liu, Chia-Yang; Shie, Feng-Shiun; Lee, Yi-Hsuan; Wills-Karp, Marsha; Chougnet, Claire A.; Kallapur, Suhas G.; Lewkowich, Ian P.; Lindquist, Diana M.; Murali-Krishna, Kaja

2014-01-01

Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic–ischemic (HI) brain injury, but the mechanisms linking systemic inflammation to the CNS damage remain uncertain. Here we report evidence for brain influx of T-helper 17 (TH17)-like lymphocytes to coordinate neuroinflammatory responses in lipopolysaccharide (LPS)-sensitized HI injury in neonates. We found that both infants with histological chorioamnionitis and rat pups challenged by LPS/HI have elevated expression of the interleukin-23 (IL-23) receptor, a marker of early TH17 lymphocytes, in the peripheral blood mononuclear cells. Post-LPS/HI administration of FTY720 (fingolimod), a sphingosine-1-phosphate receptor agonist that blocks lymphocyte trafficking, mitigated the influx of leukocytes through the choroid plexus and acute induction of nuclear factor-κB signaling in the brain. Subsequently, the FTY720 treatment led to attenuated blood–brain barrier damage, fewer cluster of differentiation 4-positive, IL-17A-positive T-cells in the brain, less proinflammatory cytokine, and better preservation of growth and white matter functions. The FTY720 treatment also provided dose-dependent reduction of brain atrophy, rescuing >90% of LPS/HI-induced brain tissue loss. Interestingly, FTY720 neither opposed pure-HI brain injury nor directly inhibited microglia in both in vivo and in vitro models, highlighting its unique mechanism against inflammation-sensitized HI injury. Together, these results suggest that the dual hit of systemic inflammation and neonatal HI injury triggers early onset of the TH17/IL-17-mediated immunity, which causes severe brain destruction but responds remarkably to the therapeutic blockade of lymphocyte trafficking. PMID:25471584

Health Literacy and Health Information Technology Adoption: The Potential for a New Digital Divide.

PubMed

Mackert, Michael; Mabry-Flynn, Amanda; Champlin, Sara; Donovan, Erin E; Pounders, Kathrynn

2016-10-04

Approximately one-half of American adults exhibit low health literacy and thus struggle to find and use health information. Low health literacy is associated with negative outcomes including overall poorer health. Health information technology (HIT) makes health information available directly to patients through electronic tools including patient portals, wearable technology, and mobile apps. The direct availability of this information to patients, however, may be complicated by misunderstanding of HIT privacy and information sharing. The purpose of this study was to determine whether health literacy is associated with patients' use of four types of HIT tools: fitness and nutrition apps, activity trackers, and patient portals. Additionally, we sought to explore whether health literacy is associated with patients' perceived ease of use and usefulness of these HIT tools, as well as patients' perceptions of privacy offered by HIT tools and trust in government, media, technology companies, and health care. This study is the first wide-scale investigation of these interrelated concepts. Participants were 4974 American adults (n=2102, 42.26% male, n=3146, 63.25% white, average age 43.5, SD 16.7 years). Participants completed the Newest Vital Sign measure of health literacy and indicated their actual use of HIT tools, as well as the perceived ease of use and usefulness of these applications. Participants also answered questions regarding information privacy and institutional trust, as well as demographic items. Cross-tabulation analysis indicated that adequate versus less than adequate health literacy was significantly associated with use of fitness apps (P=.02), nutrition apps (P<.001), activity trackers (P<.001), and patient portals (P<.001). Additionally, greater health literacy was significantly associated with greater perceived ease of use and perceived usefulness across all HIT tools after controlling for demographics. Regarding privacy perceptions of HIT and institutional trust, patients with greater health literacy often demonstrated decreased privacy perceptions for HIT tools including fitness apps (P<.001) and nutrition apps (P<.001). Health literacy was negatively associated with trust in government (P<.001), media (P<.001), and technology companies (P<.001). Interestingly, health literacy score was positively associated with trust in health care (P=.03). Patients with low health literacy were less likely to use HIT tools or perceive them as easy or useful, but they perceived information on HIT as private. Given the fast-paced evolution of technology, there is a pressing need to further the understanding of how health literacy is related to HIT app adoption and usage. This will ensure that all users receive the full health benefits from these technological advances, in a manner that protects health information privacy, and that users engage with organizations and providers they trust.

Health Literacy and Health Information Technology Adoption: The Potential for a New Digital Divide

PubMed Central

Mabry-Flynn, Amanda; Champlin, Sara; Donovan, Erin E; Pounders, Kathrynn

2016-01-01

Background Approximately one-half of American adults exhibit low health literacy and thus struggle to find and use health information. Low health literacy is associated with negative outcomes including overall poorer health. Health information technology (HIT) makes health information available directly to patients through electronic tools including patient portals, wearable technology, and mobile apps. The direct availability of this information to patients, however, may be complicated by misunderstanding of HIT privacy and information sharing. Objective The purpose of this study was to determine whether health literacy is associated with patients’ use of four types of HIT tools: fitness and nutrition apps, activity trackers, and patient portals. Additionally, we sought to explore whether health literacy is associated with patients’ perceived ease of use and usefulness of these HIT tools, as well as patients’ perceptions of privacy offered by HIT tools and trust in government, media, technology companies, and health care. This study is the first wide-scale investigation of these interrelated concepts. Methods Participants were 4974 American adults (n=2102, 42.26% male, n=3146, 63.25% white, average age 43.5, SD 16.7 years). Participants completed the Newest Vital Sign measure of health literacy and indicated their actual use of HIT tools, as well as the perceived ease of use and usefulness of these applications. Participants also answered questions regarding information privacy and institutional trust, as well as demographic items. Results Cross-tabulation analysis indicated that adequate versus less than adequate health literacy was significantly associated with use of fitness apps (P=.02), nutrition apps (P<.001), activity trackers (P<.001), and patient portals (P<.001). Additionally, greater health literacy was significantly associated with greater perceived ease of use and perceived usefulness across all HIT tools after controlling for demographics. Regarding privacy perceptions of HIT and institutional trust, patients with greater health literacy often demonstrated decreased privacy perceptions for HIT tools including fitness apps (P<.001) and nutrition apps (P<.001). Health literacy was negatively associated with trust in government (P<.001), media (P<.001), and technology companies (P<.001). Interestingly, health literacy score was positively associated with trust in health care (P=.03). Conclusions Patients with low health literacy were less likely to use HIT tools or perceive them as easy or useful, but they perceived information on HIT as private. Given the fast-paced evolution of technology, there is a pressing need to further the understanding of how health literacy is related to HIT app adoption and usage. This will ensure that all users receive the full health benefits from these technological advances, in a manner that protects health information privacy, and that users engage with organizations and providers they trust. PMID:27702738

The development and test of ultra-large-format multi-anode microchannel array detector systems

NASA Technical Reports Server (NTRS)

Timothy, J. G.

1984-01-01

The specific tasks that were accomplished with each of the key elements of the multi-anode microchannel array detector system are described. The modes of operation of position-sensitive electronic readout systems for use with high-gain microchannel plates are described and their performance characteristics compared and contrasted. Multi-anode microchannel array detector systems with formats as large as 256 x 1024 pixels are currently under evaluation. Preliminary performance data for sealed ultraviolet and visible-light detector tubes show that the detector systems have unique characteristics which make them complementary to photoconductive array detectors, such as CCDs, and superior to alternative pulse-counting detector systems employing high-gain MCPs.

The Effectiveness of Health Care Information Technologies: Evaluation of Trust, Security Beliefs, and Privacy as Determinants of Health Care Outcomes

PubMed Central

2018-01-01

Background The diffusion of health information technologies (HITs) within the health care sector continues to grow. However, there is no theory explaining how success of HITs influences patient care outcomes. With the increase in data breaches, HITs’ success now hinges on the effectiveness of data protection solutions. Still, empirical research has only addressed privacy concerns, with little regard for other factors of information assurance. Objective The objective of this study was to study the effectiveness of HITs using the DeLone and McLean Information Systems Success Model (DMISSM). We examined the role of information assurance constructs (ie, the role of information security beliefs, privacy concerns, and trust in health information) as measures of HIT effectiveness. We also investigated the relationships between information assurance and three aspects of system success: attitude toward health information exchange (HIE), patient access to health records, and perceived patient care quality. Methods Using structural equation modeling, we analyzed the data from a sample of 3677 cancer patients from a public dataset. We used R software (R Project for Statistical Computing) and the Lavaan package to test the hypothesized relationships. Results Our extension of the DMISSM to health care was supported. We found that increased privacy concerns reduce the frequency of patient access to health records use, positive attitudes toward HIE, and perceptions of patient care quality. Also, belief in the effectiveness of information security increases the frequency of patient access to health records and positive attitude toward HIE. Trust in health information had a positive association with attitudes toward HIE and perceived patient care quality. Trust in health information had no direct effect on patient access to health records; however, it had an indirect relationship through privacy concerns. Conclusions Trust in health information and belief in the effectiveness of information security safeguards increases perceptions of patient care quality. Privacy concerns reduce patients’ frequency of accessing health records, patients’ positive attitudes toward HIE exchange, and overall perceived patient care quality. Health care organizations are encouraged to implement security safeguards to increase trust, the frequency of health record use, and reduce privacy concerns, consequently increasing patient care quality. PMID:29643052

Biosensor-based small molecule fragment screening with biolayer interferometry

NASA Astrophysics Data System (ADS)

Wartchow, Charles A.; Podlaski, Frank; Li, Shirley; Rowan, Karen; Zhang, Xiaolei; Mark, David; Huang, Kuo-Sen

2011-07-01

Biosensor-based fragment screening is a valuable tool in the drug discovery process. This method is advantageous over many biochemical methods because primary hits can be distinguished from non-specific or non-ideal interactions by examining binding profiles and responses, resulting in reduced false-positive rates. Biolayer interferometry (BLI), a technique that measures changes in an interference pattern generated from visible light reflected from an optical layer and a biolayer containing proteins of interest, is a relatively new method for monitoring small molecule interactions. The BLI format is based on a disposable sensor that is immersed in 96-well or 384-well plates. BLI has been validated for small molecule detection and fragment screening with model systems and well-characterized targets where affinity constants and binding profiles are generally similar to those obtained with surface plasmon resonsance (SPR). Screens with challenging targets involved in protein-protein interactions including BCL-2, JNK1, and eIF4E were performed with a fragment library of 6,500 compounds, and hit rates were compared for these targets. For eIF4E, a protein containing a PPI site and a nucleotide binding site, results from a BLI fragment screen were compared to results obtained in biochemical HTS screens. Overlapping hits were observed for the PPI site, and hits unique to the BLI screen were identified. Hit assessments with SPR and BLI are described.

An Integrated Microfluidic Processor for DNA-Encoded Combinatorial Library Functional Screening

PubMed Central

2017-01-01

DNA-encoded synthesis is rekindling interest in combinatorial compound libraries for drug discovery and in technology for automated and quantitative library screening. Here, we disclose a microfluidic circuit that enables functional screens of DNA-encoded compound beads. The device carries out library bead distribution into picoliter-scale assay reagent droplets, photochemical cleavage of compound from the bead, assay incubation, laser-induced fluorescence-based assay detection, and fluorescence-activated droplet sorting to isolate hits. DNA-encoded compound beads (10-μm diameter) displaying a photocleavable positive control inhibitor pepstatin A were mixed (1920 beads, 729 encoding sequences) with negative control beads (58 000 beads, 1728 encoding sequences) and screened for cathepsin D inhibition using a biochemical enzyme activity assay. The circuit sorted 1518 hit droplets for collection following 18 min incubation over a 240 min analysis. Visual inspection of a subset of droplets (1188 droplets) yielded a 24% false discovery rate (1166 pepstatin A beads; 366 negative control beads). Using template barcoding strategies, it was possible to count hit collection beads (1863) using next-generation sequencing data. Bead-specific barcodes enabled replicate counting, and the false discovery rate was reduced to 2.6% by only considering hit-encoding sequences that were observed on >2 beads. This work represents a complete distributable small molecule discovery platform, from microfluidic miniaturized automation to ultrahigh-throughput hit deconvolution by sequencing. PMID:28199790

An Integrated Microfluidic Processor for DNA-Encoded Combinatorial Library Functional Screening.

PubMed

MacConnell, Andrew B; Price, Alexander K; Paegel, Brian M

2017-03-13

DNA-encoded synthesis is rekindling interest in combinatorial compound libraries for drug discovery and in technology for automated and quantitative library screening. Here, we disclose a microfluidic circuit that enables functional screens of DNA-encoded compound beads. The device carries out library bead distribution into picoliter-scale assay reagent droplets, photochemical cleavage of compound from the bead, assay incubation, laser-induced fluorescence-based assay detection, and fluorescence-activated droplet sorting to isolate hits. DNA-encoded compound beads (10-μm diameter) displaying a photocleavable positive control inhibitor pepstatin A were mixed (1920 beads, 729 encoding sequences) with negative control beads (58 000 beads, 1728 encoding sequences) and screened for cathepsin D inhibition using a biochemical enzyme activity assay. The circuit sorted 1518 hit droplets for collection following 18 min incubation over a 240 min analysis. Visual inspection of a subset of droplets (1188 droplets) yielded a 24% false discovery rate (1166 pepstatin A beads; 366 negative control beads). Using template barcoding strategies, it was possible to count hit collection beads (1863) using next-generation sequencing data. Bead-specific barcodes enabled replicate counting, and the false discovery rate was reduced to 2.6% by only considering hit-encoding sequences that were observed on >2 beads. This work represents a complete distributable small molecule discovery platform, from microfluidic miniaturized automation to ultrahigh-throughput hit deconvolution by sequencing.

Memory bias in health anxiety is related to the emotional valence of health-related words.

PubMed

Ferguson, Eamonn; Moghaddam, Nima G; Bibby, Peter A

2007-03-01

A model based on the associative strength of object evaluations is tested to explain why those who score higher on health anxiety have a better memory for health-related words. Sixty participants observed health and nonhealth words. A recognition memory task followed a free recall task and finally subjects provided evaluations (emotionality, imageability, and frequency) for all the words. Hit rates for health words, d', c, and psychological response times (PRTs) for evaluations were examined using multi-level modelling (MLM) and regression. Health words had a higher hit rate, which was greater for those with higher levels of health anxiety. The higher hit rate for health words is partly mediated by the extent to which health words are evaluated as emotionally unpleasant, and this was stronger for (moderated by) those with higher levels of health anxiety. Consistent with the associative strength model, those with higher levels of health anxiety demonstrated faster PRTs when making emotional evaluations of health words compared to nonhealth words, while those lower in health anxiety were slower to evaluate health words. Emotional evaluations speed the recognition of health words for high health anxious individuals. These findings are discussed with respect to the wider literature on cognitive processes in health anxiety, automatic processing, implicit attitudes, and emotions in decision making.

Cost-effectiveness of 64-slice CT angiography compared to conventional coronary angiography based on a coverage with evidence development study in Ontario.

PubMed

Goeree, Ron; Blackhouse, Gord; Bowen, James M; O'Reilly, Daria; Sutherland, Simone; Hopkins, Robert; Chow, Benjamin; Freeman, Michael; Provost, Yves; Dennie, Carole; Cohen, Eric; Marcuzzi, Dan; Iwanochko, Robert; Moody, Alan; Paul, Narinder; Parker, John D

2013-10-01

Conventional coronary angiography (CCA) is the standard diagnostic for coronary artery disease (CAD), but multi-detector computed tomography coronary angiography (CTCA) is a non-invasive alternative. A multi-center coverage with evidence development study was undertaken and combined with an economic model to estimate the cost-effectiveness of CTCA followed by CCA vs CCA alone. Alternative assumptions were tested in patient scenario and sensitivity analyses. CCA was found to dominate CTCA, however, CTCA was relatively more cost-effective in females, in advancing age, in patients with lower pre-test probabilities of CAD, the higher the sensitivity of CTCA and the lower the probability of undergoing a confirmatory CCA following a positive CTCA. RESULTS were very sensitive to alternative patient populations and modeling assumptions. Careful consideration of patient characteristics, procedures to improve the diagnostic yield of CTCA and selective use of CCA following CTCA will impact whether CTCA is cost-effective or dominates CCA.

a Portable Pixel Detector Operating as AN Active Nuclear Emulsion and its Application for X-Ray and Neutron Tomography

NASA Astrophysics Data System (ADS)

Vykydal, Z.; Jakubek, J.; Holy, T.; Pospisil, S.

2006-04-01

This work is devoted to the development of a USB1.1 (Universal Serial Bus) based read out system for the Medipix2 detector to achieve maximum portability of this position sensitive detecting device. All necessary detector support is integrated into one compact system (80 × 50 × 20 mm3) including the detector bias source (up to 100 V). The read out interface can control external I2C based devices, so in case of tomography it is easy to synchronize detector shutter with stepper motor control. An additional significant advantage of the USB interface is the support of back side pulse processing. This feature enables to determine the energy additionally to the position of a heavy charged particle hitting the sensor. Due to the small pixel dimensions it is also possible to distinguish the type of single quanta of radiation from the track created in the pixel detector as in case of an active nuclear emulsion.

Factors Associated with Shooting Accuracy and Wounding Rate of Four Managed Wild Deer Species in the UK, Based on Anonymous Field Records from Deer Stalkers

PubMed Central

Aebischer, Nicholas J.; Wheatley, Christopher J.; Rose, Hugh R.

2014-01-01

The amount of wounding during routine culling is an important factor in the welfare of wild deer. Little information exists on factors determining shooting accuracy and wounding rates under field conditions in the UK. In this study, 102 anonymous stalkers collected data on the outcomes and circumstances of 2281 shots. Using hot-deck imputation and generalised linear mixed modelling, we related the probability that a shot hit its target, and the probability that the shot killed the deer if it was hit, to 28 variables describing the circumstances of the shot. Overall, 96% of deer were hit, of which 93% were killed outright. A reduced probability of hitting the target was associated with an uncomfortable firing position, too little time available, shooting off elbows or freehand, taking the head or upper neck as point of aim, a heavily obscured target, a distant target, shooting at females, lack of shooting practice and a basic (or no) stalker qualification. An increase in the likelihood of wounding was associated with an uncomfortable firing position, shooting with insufficient time, a distant target (only when time was not sufficient), a bullet weight below 75 grains, a target concealed in thicket or on the move and an area rarely stalked. To maximise stalking success and deer welfare, we recommend that stalkers ensure a comfortable firing position, use a gun rest, aim at the chest, use bullets heavier than 75 grains, avoid taking a rushed shot, shoot a distant animal only if there is plenty of time, fire only when the target is stationary, avoid shooting at an obscured animal, take care when the ground is unfamiliar, and do shooting practice at least once a month. The high miss rate of basic-level stalkers suggests that training should include additional firing practice under realistic shooting conditions. PMID:25334012

The importance of accurate muscle modelling for biomechanical analyses: a case study with a lizard skull

PubMed Central

Gröning, Flora; Jones, Marc E. H.; Curtis, Neil; Herrel, Anthony; O'Higgins, Paul; Evans, Susan E.; Fagan, Michael J.

2013-01-01

Computer-based simulation techniques such as multi-body dynamics analysis are becoming increasingly popular in the field of skull mechanics. Multi-body models can be used for studying the relationships between skull architecture, muscle morphology and feeding performance. However, to be confident in the modelling results, models need to be validated against experimental data, and the effects of uncertainties or inaccuracies in the chosen model attributes need to be assessed with sensitivity analyses. Here, we compare the bite forces predicted by a multi-body model of a lizard (Tupinambis merianae) with in vivo measurements, using anatomical data collected from the same specimen. This subject-specific model predicts bite forces that are very close to the in vivo measurements and also shows a consistent increase in bite force as the bite position is moved posteriorly on the jaw. However, the model is very sensitive to changes in muscle attributes such as fibre length, intrinsic muscle strength and force orientation, with bite force predictions varying considerably when these three variables are altered. We conclude that accurate muscle measurements are crucial to building realistic multi-body models and that subject-specific data should be used whenever possible. PMID:23614944

Implementation of Complex Signal Processing Algorithms for Position-Sensitive Microcalorimeters

NASA Technical Reports Server (NTRS)

Smith, Stephen J.

2008-01-01

We have recently reported on a theoretical digital signal-processing algorithm for improved energy and position resolution in position-sensitive, transition-edge sensor (POST) X-ray detectors [Smith et al., Nucl, lnstr and Meth. A 556 (2006) 2371. PoST's consists of one or more transition-edge sensors (TES's) on a large continuous or pixellated X-ray absorber and are under development as an alternative to arrays of single pixel TES's. PoST's provide a means to increase the field-of-view for the fewest number of read-out channels. In this contribution we extend the theoretical correlated energy position optimal filter (CEPOF) algorithm (originally developed for 2-TES continuous absorber PoST's) to investigate the practical implementation on multi-pixel single TES PoST's or Hydras. We use numerically simulated data for a nine absorber device, which includes realistic detector noise, to demonstrate an iterative scheme that enables convergence on the correct photon absorption position and energy without any a priori assumptions. The position sensitivity of the CEPOF implemented on simulated data agrees very well with the theoretically predicted resolution. We discuss practical issues such as the impact of random arrival phase of the measured data on the performance of the CEPOF. The CEPOF algorithm demonstrates that full-width-at- half-maximum energy resolution of < 8 eV coupled with position-sensitivity down to a few 100 eV should be achievable for a fully optimized device.

Molecular cloning of a putative divalent-cation transporter gene as a new genetic marker for the identification of Lactobacillus brevis strains capable of growing in beer.

PubMed

Hayashi, N; Ito, M; Horiike, S; Taguchi, H

2001-05-01

Random amplified polymorphic DNA (RAPD) PCR analysis of Lactobacillus brevis isolates from breweries revealed that one of the random primers could distinguish beer-spoilage strains of L. brevis from nonspoilage strains. The 1.1-kb DNA fragment amplified from all beer-spoilers included one open reading frame, termed hitA (hop-inducible cation transporter), which encodes an integral membrane protein with 11 putative trans-membrane domains and a binding protein-dependent transport signature of a non-ATP binding membrane transporter common to several prokaryotic and eukaryotic transporters. The hitA polypeptide is homologous to the natural resistance-associated macrophage protein (Nramp) family characterized as divalent-cation transport proteins in many prokaryotic and eukaryotic organisms. Northern blot analysis indicated that the hitA transcripts are expressed in cells cultivated in MRS broth supplemented with hop bitter compounds, which act as mobile-carrier ionophores, dissipating the trans-membrane pH gradient in bacteria sensitive to the hop bitter compounds by exchanging H+ for cellular divalent cations such as Mn2+. This suggests that the hitA gene products may play an important role in making the bacteria resistant to hop bitter compounds in beer by transporting metal ions such as Mn2+ into cells that no longer maintain the proton gradient.

A Practical and Time-Efficient High-Intensity Interval Training Program Modifies Cardio-Metabolic Risk Factors in Adults with Risk Factors for Type II Diabetes.

PubMed

Phillips, Bethan E; Kelly, Benjamin M; Lilja, Mats; Ponce-González, Jesús Gustavo; Brogan, Robert J; Morris, David L; Gustafsson, Thomas; Kraus, William E; Atherton, Philip J; Vollaard, Niels B J; Rooyackers, Olav; Timmons, James A

2017-01-01

Regular physical activity (PA) can reduce the risk of developing type 2 diabetes, but adherence to time-orientated (150 min week -1 or more) PA guidelines is very poor. A practical and time-efficient PA regime that was equally efficacious at controlling risk factors for cardio-metabolic disease is one solution to this problem. Herein, we evaluate a new time-efficient and genuinely practical high-intensity interval training (HIT) protocol in men and women with pre-existing risk factors for type 2 diabetes. One hundred eighty-nine sedentary women ( n  = 101) and men ( n  = 88) with impaired glucose tolerance and/or a body mass index >27 kg m -2 [mean (range) age: 36 (18-53) years] participated in this multi-center study. Each completed a fully supervised 6-week HIT protocol at work-loads equivalent to ~100 or ~125% [Formula: see text]. Change in [Formula: see text] was used to monitor protocol efficacy, while Actiheart™ monitors were used to determine PA during four, weeklong, periods. Mean arterial (blood) pressure (MAP) and fasting insulin resistance [homeostatic model assessment (HOMA)-IR] represent key health biomarker outcomes. The higher intensity bouts (~125% [Formula: see text]) used during a 5-by-1 min HIT protocol resulted in a robust increase in [Formula: see text] (136 participants, +10.0%, p  < 0.001; large size effect). 5-by-1 HIT reduced MAP (~3%; p  < 0.001) and HOMA-IR (~16%; p  < 0.01). Physiological responses were similar in men and women while a sizeable proportion of the training-induced changes in [Formula: see text], MAP, and HOMA-IR was retained 3 weeks after cessation of training. The supervised HIT sessions accounted for the entire quantifiable increase in PA, and this equated to 400 metabolic equivalent (MET) min week -1 . Meta-analysis indicated that 5-by-1 HIT matched the efficacy and variability of a time-consuming 30-week PA program on [Formula: see text], MAP, and HOMA-IR. With a total time-commitment of <15 min per session and reliance on a practical ergometer protocol, 5-by-1 HIT offers a new solution to modulate cardio-metabolic risk factors in adults with pre-existing risk factors for type 2 diabetes while approximately meeting the MET min week -1 PA guidelines. Long-term randomized controlled studies will be required to quantify the ability for 5-by-1 HIT to reduce the incidence of type 2 diabetes, while strategies are required to harmonize the adaptations to exercise across individuals.

Integration of multi-scale molecular modeling approaches with experiments for the in silico guided design and discovery of novel hERG-Neutral antihypertensive oxazalone and imidazolone derivatives and analysis of their potential restrictive effects on cell proliferation.

PubMed

Durdagi, Serdar; Aksoydan, Busecan; Erol, Ismail; Kantarcioglu, Isik; Ergun, Yavuz; Bulut, Gulay; Acar, Melih; Avsar, Timucin; Liapakis, George; Karageorgos, Vlasios; Salmas, Ramin E; Sergi, Barış; Alkhatib, Sara; Turan, Gizem; Yigit, Berfu Nur; Cantasir, Kutay; Kurt, Bahar; Kilic, Turker

2018-02-10

AT1 antagonists is the most recent drug class of molecules against hypertension and they mediate their actions through blocking detrimental effects of angiotensin II (A-II) when acts on type I (AT1) A-II receptor. The effects of AT1 antagonists are not limited to cardiovascular diseases. AT1 receptor blockers may be used as potential anti-cancer agents - due to the inhibition of cell proliferation stimulated by A-II. Therefore, AT1 receptors and the A-II biosynthesis mechanisms are targets for the development of new synthetic drugs and therapeutic treatment of various cardiovascular and other diseases. In this work, multi-scale molecular modeling approaches were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor. In silico-guided designed hit molecules were then synthesized and tested for their binding affinities to human AT1 receptor in radioligand binding studies, using [ 125 I-Sar 1 -Ile 8 ] AngII. Among the compounds tested, 19d and 9j molecules bound to receptor in a dose response manner and with relatively high affinities. Next, cytotoxicity and wound healing assays were performed for these hit molecules. Since hit molecule 19d led to deceleration of cell motility in all three cell lines (NIH3T3, A549, and H358) tested in this study, this molecule is investigated in further tests. In two cell lines (HUVEC and MCF-7) tested, 19d induced G2/M cell cycle arrest in a concentration dependent manner. Adherent cells detached from the plates and underwent cell death possibly due to apoptosis at 19d concentrations that induced cell cycle arrest. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Mississippi Scale for Combat-Related Posttraumatic Stress Disorder: Three Studies in Reliabilty and Validity.

ERIC Educational Resources Information Center

Keane, Terence M.; And Others

1988-01-01

Explored the psychometric properties of the Mississippi Scale for Combat-Related Posttraumatic Stress Disorder to assess its internal consistency and factor structure. Administered the test to Vietnam veterans seeking help at Veteran Centers. Demonstrated high test-retest reliability, sensitivity of .93, specificity .89, and overall hit rate .90…

Autism Prevalence Following Prenatal Exposure to Hurricanes and Tropical Storms in Louisiana

ERIC Educational Resources Information Center

Kinney, Dennis K.; Miller, Andrea M.; Crowley, David J.; Huang, Emerald; Gerber, Erika

2008-01-01

Hurricanes and tropical storms served as natural experiments for investigating whether autism is associated with exposure to stressful events during sensitive periods of gestation. Weather service data identified severe storms in Louisiana from 1980 to 1995 and parishes hit by storm centers during this period. Autism prevalences in different…

A Luciferase Reporter Gene System for High-Throughput Screening of γ-Globin Gene Activators.

PubMed

Xie, Wensheng; Silvers, Robert; Ouellette, Michael; Wu, Zining; Lu, Quinn; Li, Hu; Gallagher, Kathleen; Johnson, Kathy; Montoute, Monica

2016-01-01

Luciferase reporter gene assays have long been used for drug discovery due to their high sensitivity and robust signal. A dual reporter gene system contains a gene of interest and a control gene to monitor non-specific effects on gene expression. In our dual luciferase reporter gene system, a synthetic promoter of γ-globin gene was constructed immediately upstream of the firefly luciferase gene, followed downstream by a synthetic β-globin gene promoter in front of the Renilla luciferase gene. A stable cell line with the dual reporter gene was cloned and used for all assay development and HTS work. Due to the low activity of the control Renilla luciferase, only the firefly luciferase activity was further optimized for HTS. Several critical factors, such as cell density, serum concentration, and miniaturization, were optimized using tool compounds to achieve maximum robustness and sensitivity. Using the optimized reporter assay, the HTS campaign was successfully completed and approximately 1000 hits were identified. In this chapter, we also describe strategies to triage hits that non-specifically interfere with firefly luciferase.

Application of activity sensors for estimating behavioral patterns

USGS Publications Warehouse

Roberts, Caleb P.; Cain, James W.; Cox, Robert D.

2016-01-01

The increasing use of Global Positioning System (GPS) collars in habitat selection studies provides large numbers of precise location data points with reduced field effort. However, inclusion of activity sensors in many GPS collars also grants the potential to remotely estimate behavioral state. Thus, only using GPS collars to collect location data belies their full capabilities. Coupling behavioral state with location data would allow researchers and managers to refine habitat selection models by using diel behavioral state changes to partition fine-scale temporal shifts in habitat selection. We tested the capability of relatively unsophisticated GPS-collar activity sensors to estimate behavior throughout diel periods using free-ranging female elk (Cervus canadensis) in the Jemez Mountains of north-central New Mexico, USA, 2013–2014. Collars recorded cumulative number of movements (hits) per 15-min recording period immediately preceding GPS fixes at 0000, 0600, 1200, and 1800 hr. We measured diel behavioral patterns of focal elk, categorizing active (i.e., foraging, traveling, vigilant, grooming) and inactive (i.e., resting) states. Active behaviors (foraging, traveling) produced more average hits (0.87 ± 0.69 hits/min, 4.0 ± 2.2 hits/min, respectively; 95% CI) and inactive (resting) behavior fewer hits (−1.1 ± 0.61 95% CI). We differentiated active and inactive behavioral states with a bootstrapped threshold of 5.9 ± 3.9 hits/15-min recording period. Mean cumulative activity-sensor hits corresponded with observed diel behavioral patterns: hits increased during crepuscular (0600, 1800 hr) observations when elk were most active (0000–0600 hr: d = 0.19; 1200–1800 hr: d = 0.64) and decreased during midday and night (0000 hr, 1200 hr) when elk were least active (1800–0000 hr: d = −0.39; 0600–1200 hr: d = −0.43). Even using relatively unsophisticated GPS-collar activity sensors, managers can remotely estimate behavioral states, approximate diel behavioral patterns, and potentially complement location data in developing habitat selection models.

Development of an LC-MS based enzyme activity assay for MurC: application to evaluation of inhibitors and kinetic analysis.

PubMed

Deng, Gejing; Gu, Rong-Fang; Marmor, Stephen; Fisher, Stewart L; Jahic, Haris; Sanyal, Gautam

2004-06-29

An enzyme activity assay, based on mass spectrometric (MS) detection of specific reaction product following HPLC separation, has been developed to evaluate pharmaceutical hits identified from primary high throughput screening (HTS) against target enzyme Escherichia coli UDP-N-acetyl-muramyl-L-alanine ligase (MurC), an essential enzyme in the bacterial peptidoglycan biosynthetic pathway, and to study the kinetics of the enzyme. A comparative analysis of this new liquid chromatographic-MS (LC-MS) based assay with a conventional spectrophotometric Malachite Green (MG) assay, which detects phosphate produced in the reaction, was performed. The results demonstrated that the LC-MS assay, which determines specific ligase activity of MurC, offers several advantages including a lower background (0.2% versus 26%), higher sensitivity (> or = 10 fold), lower limit of quantitation (LOQ) (0.02 microM versus 1 microM) and wider linear dynamic range (> or = 4 fold) than the MG assay. Good precision for the LC-MS assay was demonstrated by the low intraday and interday coefficient of variation (CV) values (3 and 6%, respectively). The LC-MS assay, free of the artifacts often seen in the Malachite Green assay, offers a valuable secondary assay for hit evaluation in which the false positives from the primary high throughput screening can be eliminated. In addition, the applicability of this assay to the study of enzyme kinetics has also been demonstrated. Copyright 2004 Elsevier B.V.

Effect of health information technology interventions on lipid management in clinical practice: a systematic review of randomized controlled trials.

PubMed

Aspry, Karen E; Furman, Roy; Karalis, Dean G; Jacobson, Terry A; Zhang, Audrey M; Liptak, Gregory S; Cohen, Jerome D

2013-01-01

Large gaps in lipid treatment and medication adherence persist in high-risk outpatients in the United States. Health information technology (HIT) is being applied to close quality gaps in chronic illness care, but its utility for lipid management has not been widely studied. To perform a qualitative review of the impact of HIT interventions on lipid management processes of care (screening or testing; drug initiation, titration or adherence; or referrals) or clinical outcomes (percent at low density lipoprotein cholesterol goal; absolute lipid levels; absolute risk scores; or cardiac hospitalizations) in outpatients with coronary heart disease or at increased risk. PubMed and Google Scholar databases were searched using Medical Subject Headings related to clinical informatics and cholesterol or lipid management. English language articles that described a randomized controlled design, tested at least one HIT tool in high risk outpatients, and reported at least 1 lipid management process measure or clinical outcome, were included. Thirty-four studies that enrolled 87,874 persons were identified. Study ratings, outcomes, and magnitude of effects varied widely. Twenty-three trials reported a significant positive effect from a HIT tool on lipid management, but only 14 showed evidence that HIT interventions improve clinical outcomes. There was mixed evidence that provider-level computerized decision support improves outcomes. There was more evidence in support of patient-level tools that provide connectivity to the healthcare system, as well as system-level interventions that involve database monitoring and outreach by centralized care teams. Randomized controlled trials show wide variability in the effects of HIT on lipid management outcomes. Evidence suggests that multilevel HIT approaches that target not only providers but include patients and systems approaches will be needed to improve lipid treatment, adherence and quality. Copyright © 2013 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Health Information Technology Coordination to Support Patient-centered Care Coordination.

PubMed

Steichen, O; Gregg, W

2015-08-13

To select papers published in 2014, illustrating how information technology can contribute to and improve patient-centered care coordination. The two section editors performed a literature review from Medline and Web of Science to select a list of candidate best papers on the use of information technology for patient-centered care coordination. These papers were peer-reviewed by external reviewers and three of them were selected as "best papers". The first selected paper reports a qualitative study exploring the gap between current practices of care coordination in various settings and idealized longitudinal care plans. The second selected paper illustrates several unintended consequences of HIT designed to improve care coordination. The third selected paper shows that advanced analytic techniques in medical informatics can be instrumental in studying patient-centered care coordination. The realization of true patient-centered care coordination is dependent upon a number of factors. Standardization of clinical documentation and HIT interoperability across organization and settings is a critical prerequisite for HIT to support patient-centered care coordination. Enabling patient involvement is an efficient means for goal setting and health information sharing. Additionally, unintended consequences of HIT tools (both positive and negative) must be measured and taken into account for quality improvement.

Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review.

PubMed

Poudel, Dilli Ram; Ghimire, Sushil; Dhital, Rashmi; Forman, Daniel A; Warkentin, Theodore E

2017-09-01

Recently published reports have established a heparin-induced thrombocytopenia (HIT)-mimicking thromboembolic disorder without proximate heparin exposure, called spontaneous HIT syndrome. Although the pathophysiology remains unclear, anti-platelet factor 4 (PF4)/heparin antibodies possibly triggered by exposure to knee cartilage glycosaminoglycans or other non-heparin polyanions found on bacterial surfaces and nucleic acids have been postulated. We present a 53-year-old female receiving antithrombotic prophylaxis with aspirin following right total knee replacement surgery (without perioperative or any previous lifetime heparin exposure) who acutely presented with high-risk pulmonary embolism (PE) and right great saphenous vein thrombophlebitis on postoperative day (POD) 14; her platelet count at presentation was 13 × 10 9 /L. Prior to diagnostic consideration of spontaneous HIT syndrome, the patient briefly received unfractionated heparin (UFH) and one dose of enoxaparin. The patient's serum tested strongly positive for anti-PF4/heparin antibodies by two different PF4-dependent enzyme-linked immunosorbent assays (ELISAs) and by serotonin release assay (SRA). Failure of fondaparinux anticoagulation (persisting HIT-associated disseminated intravascular coagulation) prompted switching to argatroban. Severe thrombocytopenia persisted (platelet count nadir, 12 × 10 9 /L, on POD21), and 9 days after starting argatroban symptomatic right leg deep-vein thrombosis (DVT) occurred, prompting switch to rivaroxaban. Thereafter, her course was uneventful, although platelet count recovery was prolonged, reaching 99 × 10 9 /L by POD45 and 199 × 10 9 /L by POD79. The patient's serum elicited strong serotonin release in the absence of heparin (seen even with 1/32 serum dilution) that was enhanced by pharmacological concentrations of UFH (0.1 and 0.3 IU/mL) and fondaparinux (0.1-1.2 μg/mL, i.e., in vitro fondaparinux "cross-reactivity"). Ultimately, platelet count recovery was associated with seroreversion to a negative SRA (documented at POD151). Our literature review identified joint replacement surgery, specifically knee replacement, to be a relatively common trigger of spontaneous HIT syndrome. Further, including our patient case, 5 of 7 patients with spontaneous HIT syndrome post-orthopedic surgery who received treatment with argatroban developed new and/or progressive lower-limb DVT or recurrent PE despite anticoagulation with this parenteral direct thrombin inhibitor, suggesting that this patient population is at high risk of breakthrough thrombotic events despite treatment with this HIT treatment-approved anticoagulant. Our case also illustrates successful outcome with rivaroxaban for treatment of spontaneous HIT syndrome, consistent with emerging literature supporting safety and efficacy of direct oral anticoagulant therapy for treatment of acute HIT.

Simulation study of pixel detector charge digitization

NASA Astrophysics Data System (ADS)

Wang, Fuyue; Nachman, Benjamin; Sciveres, Maurice; Lawrence Berkeley National Laboratory Team

2017-01-01

Reconstruction of tracks from nearly overlapping particles, called Tracking in Dense Environments (TIDE), is an increasingly important component of many physics analyses at the Large Hadron Collider as signatures involving highly boosted jets are investigated. TIDE makes use of the charge distribution inside a pixel cluster to resolve tracks that share one of more of their pixel detector hits. In practice, the pixel charge is discretized using the Time-over-Threshold (ToT) technique. More charge information is better for discrimination, but more challenging for designing and operating the detector. A model of the silicon pixels has been developed in order to study the impact of the precision of the digitized charge distribution on distinguishing multi-particle clusters. The output of the GEANT4-based simulation is used to train neutral networks that predict the multiplicity and location of particles depositing energy inside one cluster of pixels. By studying the multi-particle cluster identification efficiency and position resolution, we quantify the trade-off between the number of ToT bits and low-level tracking inputs. As both ATLAS and CMS are designing upgraded detectors, this work provides guidance for the pixel module designs to meet TIDE needs. Work funded by the China Scholarship Council and the Office of High Energy Physics of the U.S. Department of Energy under contract DE-AC02-05CH11231.

Direct Position Determination of Unknown Signals in the Presence of Multipath Propagation

PubMed Central

Yu, Hongyi

2018-01-01

A novel geolocation architecture, termed “Multiple Transponders and Multiple Receivers for Multiple Emitters Positioning System (MTRE)” is proposed in this paper. Existing Direct Position Determination (DPD) methods take advantage of a rather simple channel assumption (line of sight channels with complex path attenuations) and a simplified MUltiple SIgnal Classification (MUSIC) algorithm cost function to avoid the high dimension searching. We point out that the simplified assumption and cost function reduce the positioning accuracy because of the singularity of the array manifold in a multi-path environment. We present a DPD model for unknown signals in the presence of Multi-path Propagation (MP-DPD) in this paper. MP-DPD adds non-negative real path attenuation constraints to avoid the mistake caused by the singularity of the array manifold. The Multi-path Propagation MUSIC (MP-MUSIC) method and the Active Set Algorithm (ASA) are designed to reduce the dimension of searching. A Multi-path Propagation Maximum Likelihood (MP-ML) method is proposed in addition to overcome the limitation of MP-MUSIC in the sense of a time-sensitive application. An iterative algorithm and an approach of initial value setting are given to make the MP-ML time consumption acceptable. Numerical results validate the performances improvement of MP-MUSIC and MP-ML. A closed form of the Cramér–Rao Lower Bound (CRLB) is derived as a benchmark to evaluate the performances of MP-MUSIC and MP-ML. PMID:29562601

Direct Position Determination of Unknown Signals in the Presence of Multipath Propagation.

PubMed

Du, Jianping; Wang, Ding; Yu, Wanting; Yu, Hongyi

2018-03-17

A novel geolocation architecture, termed "Multiple Transponders and Multiple Receivers for Multiple Emitters Positioning System (MTRE)" is proposed in this paper. Existing Direct Position Determination (DPD) methods take advantage of a rather simple channel assumption (line of sight channels with complex path attenuations) and a simplified MUltiple SIgnal Classification (MUSIC) algorithm cost function to avoid the high dimension searching. We point out that the simplified assumption and cost function reduce the positioning accuracy because of the singularity of the array manifold in a multi-path environment. We present a DPD model for unknown signals in the presence of Multi-path Propagation (MP-DPD) in this paper. MP-DPD adds non-negative real path attenuation constraints to avoid the mistake caused by the singularity of the array manifold. The Multi-path Propagation MUSIC (MP-MUSIC) method and the Active Set Algorithm (ASA) are designed to reduce the dimension of searching. A Multi-path Propagation Maximum Likelihood (MP-ML) method is proposed in addition to overcome the limitation of MP-MUSIC in the sense of a time-sensitive application. An iterative algorithm and an approach of initial value setting are given to make the MP-ML time consumption acceptable. Numerical results validate the performances improvement of MP-MUSIC and MP-ML. A closed form of the Cramér-Rao Lower Bound (CRLB) is derived as a benchmark to evaluate the performances of MP-MUSIC and MP-ML.

Multi-wavelength emissivity measurement of stainless steel substrate

NASA Astrophysics Data System (ADS)

Zhang, Y. F. F.; Dai, J. M. M.; Zhang, L.; Pan, W. D. D.

2013-01-01

The emissivity is a key parameter to measure the surface temperature of materials in the radiation thermometry. In this paper, the surface emissivity of metallic substrates is measured by the multi-wavelength emissivity measurement apparatus developed by the Harbin Institute of Technology (HIT). The measuring principle of this apparatus is based on the energy comparison. Several radiation thermometers, whose emissivity coefficients corrected by the measured emissivity from this apparatus, are used to measure the surface temperature of stainless steel substrates. The temperature values measured by means of radiation thermometry are compared to those measured by means of contact thermometry. The relative error between the two means is less than 2% at temperatures from 700K to 1300K, it suggests that the emissivity of stainless steel substrate measured by the multi-wavelength emissivity measurement apparatus are accurate and reliable. Emissivity measurements performed with this apparatus present an uncertainty of 5.9% (cover factor=2).

The impact of health information technology on cancer care across the continuum: a systematic review and meta-analysis.

PubMed

Tarver, Will L; Menachemi, Nir

2016-03-01

Health information technology (HIT) has the potential to play a significant role in the management of cancer. The purpose of this review is to identify and examine empirical studies that investigate the impact of HIT in cancer care on different levels of the care continuum. Electronic searches were performed in four academic databases. The authors used a three-step search process to identify 122 studies that met specific inclusion criteria. Next, a coding sheet was used to extract information from each included article to use in an analysis. Logistic regression was used to determine study-specific characteristics that were associated with positive findings. Overall, 72.4% of published analyses reported a beneficial effect of HIT. Multivariate analysis found that the impact of HIT differs across the cancer continuum with studies targeting diagnosis and treatment being, respectively, 77 (P = .001) and 39 (P = .039) percentage points less likely to report a beneficial effect when compared to those targeting prevention. In addition, studies targeting HIT to patients were 31 percentage points less likely to find a beneficial effect than those targeting providers (P = .030). Lastly, studies assessing behavior change as an outcome were 41 percentage points less likely to find a beneficial effect (P = .006), while studies targeting decision making were 27 percentage points more likely to find a beneficial effect (P = .034). Based on current evidence, HIT interventions seem to be more successful when targeting physicians, care in the prevention phase of the cancer continuum, and/or decision making. An agenda for future research is discussed. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Identification of a self-paced hitting task in freely moving rats based on adaptive spike detection from multi-unit M1 cortical signals

PubMed Central

Hammad, Sofyan H. H.; Farina, Dario; Kamavuako, Ernest N.; Jensen, Winnie

2013-01-01

Invasive brain–computer interfaces (BCIs) may prove to be a useful rehabilitation tool for severely disabled patients. Although some systems have shown to work well in restricted laboratory settings, their usefulness must be tested in less controlled environments. Our objective was to investigate if a specific motor task could reliably be detected from multi-unit intra-cortical signals from freely moving animals. Four rats were trained to hit a retractable paddle (defined as a “hit”). Intra-cortical signals were obtained from electrodes placed in the primary motor cortex. First, the signal-to-noise ratio was increased by wavelet denoising. Action potentials were then detected using an adaptive threshold, counted in three consecutive time intervals and were used as features to classify either a “hit” or a “no-hit” (defined as an interval between two “hits”). We found that a “hit” could be detected with an accuracy of 75 ± 6% when wavelet denoising was applied whereas the accuracy dropped to 62 ± 5% without prior denoising. We compared our approach with the common daily practice in BCI that consists of using a fixed, manually selected threshold for spike detection without denoising. The results showed the feasibility of detecting a motor task in a less restricted environment than commonly applied within invasive BCI research. PMID:24298254

Automated Tests for Telephone Telepathy Using Mobile Phones.

PubMed

Sheldrake, Rupert; Smart, Pamela; Avraamides, Leonidas

2015-01-01

To carry out automated experiments on mobile phones to test for telepathy in connection with telephone calls. Subjects, aged from 10 to 83, registered online with the names and mobile telephone numbers of three or two senders. A computer selected a sender at random, and asked him to call the subject via the computer. The computer then asked the subject to guess the caller׳s name, and connected the caller and the subject after receiving the guess. A test consisted of six trials. The effects of subjects׳ sex and age and the effects of time delays on guesses. The proportion of correct guesses of the caller׳s name, compared with the 33.3% or 50% mean chance expectations. In 2080 trials with three callers there were 869 hits (41.8%), above the 33.3% chance level (P < 1 × 10(-15)). The hit rate in incomplete tests was 43.8% (P = .00003) showing that optional stopping could not explain the positive results. In 745 trials with two callers, there were 411 hits (55.2%), above the 50% chance level (P = .003). An analysis of the data made it very unlikely that cheating could explain the positive results. These experiments showed that automated tests for telephone telepathy can be carried out using mobile phones. Copyright © 2015 Elsevier Inc. All rights reserved.

Translations on Eastern Europe Political, Sociological, and Military Affairs No. 1575

DTIC Science & Technology

1978-08-08

Developments in European Communist Movement Assessed (Alfred Marter; HORIZONT, No 27, 1978) 49 Position of Churches, CDU on Military Training Stated...Editorial; FRANKFURTER RUNDSCHAU, 29 Jun 78) 58 Protestant League Guidelines CDU Position Paper West German Comment: GDR Church Hits School...conspicuously aggravated external economic conditions, the balance of the party’s economic policy is positive . Thus, the recent years are honorably linked with

Combinatorial phenotypic screen uncovers unrecognized family of extended thiourea inhibitors with copper-dependent anti-staphylococcal activity.

PubMed

Dalecki, Alex G; Malalasekera, Aruni P; Schaaf, Kaitlyn; Kutsch, Olaf; Bossmann, Stefan H; Wolschendorf, Frank

2016-04-01

The continuous rise of multi-drug resistant pathogenic bacteria has become a significant challenge for the health care system. In particular, novel drugs to treat infections of methicillin-resistant Staphylococcus aureus strains (MRSA) are needed, but traditional drug discovery campaigns have largely failed to deliver clinically suitable antibiotics. More than simply new drugs, new drug discovery approaches are needed to combat bacterial resistance. The recently described phenomenon of copper-dependent inhibitors has galvanized research exploring the use of metal-coordinating molecules to harness copper's natural antibacterial properties for therapeutic purposes. Here, we describe the results of the first concerted screening effort to identify copper-dependent inhibitors of Staphylococcus aureus. A standard library of 10 000 compounds was assayed for anti-staphylococcal activity, with hits defined as those compounds with a strict copper-dependent inhibitory activity. A total of 53 copper-dependent hit molecules were uncovered, similar to the copper independent hit rate of a traditionally executed campaign conducted in parallel on the same library. Most prominent was a hit family with an extended thiourea core structure, termed the NNSN motif. This motif resulted in copper-dependent and copper-specific S. aureus inhibition, while simultaneously being well tolerated by eukaryotic cells. Importantly, we could demonstrate that copper binding by the NNSN motif is highly unusual and likely responsible for the promising biological qualities of these compounds. A subsequent chemoinformatic meta-analysis of the ChEMBL chemical database confirmed the NNSNs as an unrecognized staphylococcal inhibitor, despite the family's presence in many chemical screening libraries. Thus, our copper-biased screen has proven able to discover inhibitors within previously screened libraries, offering a mechanism to reinvigorate exhausted molecular collections.

Development and experimental test of support vector machines virtual screening method for searching Src inhibitors from large compound libraries.

PubMed

Han, Bucong; Ma, Xiaohua; Zhao, Ruiying; Zhang, Jingxian; Wei, Xiaona; Liu, Xianghui; Liu, Xin; Zhang, Cunlong; Tan, Chunyan; Jiang, Yuyang; Chen, Yuzong

2012-11-23

Src plays various roles in tumour progression, invasion, metastasis, angiogenesis and survival. It is one of the multiple targets of multi-target kinase inhibitors in clinical uses and trials for the treatment of leukemia and other cancers. These successes and appearances of drug resistance in some patients have raised significant interest and efforts in discovering new Src inhibitors. Various in-silico methods have been used in some of these efforts. It is desirable to explore additional in-silico methods, particularly those capable of searching large compound libraries at high yields and reduced false-hit rates. We evaluated support vector machines (SVM) as virtual screening tools for searching Src inhibitors from large compound libraries. SVM trained and tested by 1,703 inhibitors and 63,318 putative non-inhibitors correctly identified 93.53%~ 95.01% inhibitors and 99.81%~ 99.90% non-inhibitors in 5-fold cross validation studies. SVM trained by 1,703 inhibitors reported before 2011 and 63,318 putative non-inhibitors correctly identified 70.45% of the 44 inhibitors reported since 2011, and predicted as inhibitors 44,843 (0.33%) of 13.56M PubChem, 1,496 (0.89%) of 168 K MDDR, and 719 (7.73%) of 9,305 MDDR compounds similar to the known inhibitors. SVM showed comparable yield and reduced false hit rates in searching large compound libraries compared to the similarity-based and other machine-learning VS methods developed from the same set of training compounds and molecular descriptors. We tested three virtual hits of the same novel scaffold from in-house chemical libraries not reported as Src inhibitor, one of which showed moderate activity. SVM may be potentially explored for searching Src inhibitors from large compound libraries at low false-hit rates.

Psychological and social factors affecting Internet searches on suicide in Korea: a big data analysis of Google search trends.

PubMed

Song, Tae Min; Song, Juyoung; An, Ji-Young; Hayman, Laura L; Woo, Jong-Min

2014-01-01

The average mortality rate for death by suicide among OECD countries is 12.8 per 100000, and 33.5 for Korea. The present study analyzed big data extracted from Google to identify factors related to searches on suicide in Korea. Google search trends for the search words of suicide, stress, exercise, and drinking were obtained for 2004-2010. Analyzing data by month, the relationship between the actual number of suicides and search words per year was examined using multi-level models. Both suicide rates and Google searches on suicide in Korea increased since 2007. An unconditional slope model indicated stress and suicide-related searches were positively related. A conditional model showed that factors associated with suicide by year directly affected suicide-related searches. The interaction between stress-related searches and the actual number of suicides was significant. A positive relationship between stress- and suicide-related searches further confirmed that stress affects suicide. Taken together and viewed in context of the big data analysis, our results point to the need for a tailored prevention program. Real-time big data can be of use in indicating increases in suicidality when search words such as stress and suicide generate greater numbers of hits on portals and social network sites.

Microbiology of tunnelled catheter-related infections in a multi-ethnic South-east Asian patient population.

PubMed

Teo, Boon Wee; Sau, Po Yi; Xu, Hui; Ma, Valerie; Vathsala, A; Lee, Evan J C

2011-01-01

Clinical practice guidelines recommend empiric antibiotic therapy for suspected tunnelled haemodialysis catheter-related infections (CRI), and the choice of antibiotics should be adjusted according to the local microbiological profile and antimicrobial sensitivities. We aim to describe the microbiology, antibiotic sensitivities, and clinical outcomes of CRI with tunnelled haemodialysis catheters in a multi-ethnic South-East Asian population. Using a prospective vascular access registry, we identified 99 patients who had catheters removed for suspected or confirmed CRI (50.5% male, mean age 56.9 years) from January 1, 2007, till May 2009. We retrospectively retrieved microbiology, mortality and echocardiography data from the hospital electronic databases. There were 115 removal-unique cultures that yielded 75.7% Gram-positive and 24.3% Gram-negative isolates (15 removals were polymicrobial). Organisms isolated were methicillin-resistant Staphylococcus aureus (MRSA) 28.6%, methicillin-sensitive S. aureus 26.5%, coagulase-negative staphylococci 21.4%, Pseudomonas aeruginosa 10.2%, and others. Out of 8 patients who died, 7 had MRSA. Risk factors associated with mortality were Chinese race (p = 0.03), MRSA infection (p < 0.001), and older age (p < 0.001). Gram-positive isolates accounted for most tunnelled CRI and MRSA was highly associated with death. In sick patients presenting with suspected CRI, the preferred empiric antibiotic regimen should include agents active against both MRSA and P. aeruginosa. Copyright © 2010 S. Karger AG, Basel.

Development of slew-rate-limited time-over-threshold (ToT) ASIC for a multi-channel silicon-based ion detector

NASA Astrophysics Data System (ADS)

Uenomachi, M.; Orita, T.; Shimazoe, K.; Takahashi, H.; Ikeda, H.; Tsujita, K.; Sekiba, D.

2018-01-01

High-resolution Elastic Recoil Detection Analysis (HERDA), which consists of a 90o sector magnetic spectrometer and a position-sensitive detector (PSD), is a method of quantitative hydrogen analysis. In order to increase sensitivity, a HERDA system using a multi-channel silicon-based ion detector has been developed. Here, as a parallel and fast readout circuit from a multi-channel silicon-based ion detector, a slew-rate-limited time-over-threshold (ToT) application-specific integrated circuit (ASIC) was designed, and a new slew-rate-limited ToT method is proposed. The designed ASIC has 48 channels and each channel consists of a preamplifier, a slew-rate-limited shaping amplifier, which makes ToT response linear, and a comparator. The measured equivalent noise charges (ENCs) of the preamplifier, the shaper, and the ToT on no detector capacitance were 253±21, 343±46, and 560±56 electrons RMS, respectively. The spectra from a 241Am source measured using a slew-rate-limited ToT ASIC are also reported.

Lessons from the Canadian national health information technology plan for the United States: opinions of key Canadian experts.

PubMed

Zimlichman, Eyal; Rozenblum, Ronen; Salzberg, Claudia A; Jang, Yeona; Tamblyn, Melissa; Tamblyn, Robyn; Bates, David W

2012-01-01

To summarize the Canadian health information technology (HIT) policy experience and impart lessons learned to the US as it determines its policy in this area. Qualitative analysis of interviews with identified key stakeholders followed by an electronic survey. We conducted semi-structured interviews with 29 key Canadian HIT policy and opinion leaders and used a grounded theory approach to analyze the results. The informant sample was chosen to provide views from different stakeholder groups including national representatives and regional representatives from three Canadian provinces. Canadian informants believed that much of the current US direction is positive, especially regarding incentives and meaningful use, but that there are key opportunities for the US to emphasize direct engagement with providers, define a clear business case for them, sponsor large scale evaluations to assess HIT impact in a broad array of settings, determine standards but also enable access to resources needed for mid-course corrections of standards when issues are identified, and, finally, leverage implementation of digital imaging systems. Not all stakeholder groups were included, such as providers or patients. In addition, as in all qualitative research, a selection bias could be present due to the relatively small sample size. Based on Canadian experience with HIT policy, stakeholders identified as lessons for the US the need to increase direct engagement with providers and the importance of defining the business case for HIT, which can be achieved through large scale evaluations, and of recognizing and leveraging successes as they emerge.

Prospective performance evaluation of selected common virtual screening tools. Case study: Cyclooxygenase (COX) 1 and 2.

PubMed

Kaserer, Teresa; Temml, Veronika; Kutil, Zsofia; Vanek, Tomas; Landa, Premysl; Schuster, Daniela

2015-01-01

Computational methods can be applied in drug development for the identification of novel lead candidates, but also for the prediction of pharmacokinetic properties and potential adverse effects, thereby aiding to prioritize and identify the most promising compounds. In principle, several techniques are available for this purpose, however, which one is the most suitable for a specific research objective still requires further investigation. Within this study, the performance of several programs, representing common virtual screening methods, was compared in a prospective manner. First, we selected top-ranked virtual screening hits from the three methods pharmacophore modeling, shape-based modeling, and docking. For comparison, these hits were then additionally predicted by external pharmacophore- and 2D similarity-based bioactivity profiling tools. Subsequently, the biological activities of the selected hits were assessed in vitro, which allowed for evaluating and comparing the prospective performance of the applied tools. Although all methods performed well, considerable differences were observed concerning hit rates, true positive and true negative hits, and hitlist composition. Our results suggest that a rational selection of the applied method represents a powerful strategy to maximize the success of a research project, tightly linked to its aims. We employed cyclooxygenase as application example, however, the focus of this study lied on highlighting the differences in the virtual screening tool performances and not in the identification of novel COX-inhibitors. Copyright © 2015 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Registration of central paths and colonic polyps between supine and prone scans in computed tomography colonography: Pilot study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li Ping; Napel, Sandy; Acar, Burak

2004-10-01

Computed tomography colonography (CTC) is a minimally invasive method that allows the evaluation of the colon wall from CT sections of the abdomen/pelvis. The primary goal of CTC is to detect colonic polyps, precursors to colorectal cancer. Because imperfect cleansing and distension can cause portions of the colon wall to be collapsed, covered with water, and/or covered with retained stool, patients are scanned in both prone and supine positions. We believe that both reading efficiency and computer aided detection (CAD) of CTC images can be improved by accurate registration of data from the supine and prone positions. We developed amore » two-stage approach that first registers the colonic central paths using a heuristic and automated algorithm and then matches polyps or polyp candidates (CAD hits) by a statistical approach. We evaluated the registration algorithm on 24 patient cases. After path registration, the mean misalignment distance between prone and supine identical anatomic landmarks was reduced from 47.08 to 12.66 mm, a 73% improvement. The polyp registration algorithm was specifically evaluated using eight patient cases for which radiologists identified polyps separately for both supine and prone data sets, and then manually registered corresponding pairs. The algorithm correctly matched 78% of these pairs without user input. The algorithm was also applied to the 30 highest-scoring CAD hits in the prone and supine scans and showed a success rate of 50% in automatically registering corresponding polyp pairs. Finally, we computed the average number of CAD hits that need to be manually compared in order to find the correct matches among the top 30 CAD hits. With polyp registration, the average number of comparisons was 1.78 per polyp, as opposed to 4.28 comparisons without polyp registration.« less

Double-hit follicular lymphoma with MYC and BCL2 translocations: a study of 7 cases with a review of literature.

PubMed

Miao, Yuan; Hu, Shimin; Lu, Xinyan; Li, Shaoying; Wang, Wei; Medeiros, L Jeffrey; Lin, Pei

2016-12-01

Follicular lymphoma with MYC and BCL2 translocations, so-called double-hit follicular lymphoma (DH-FL), is rare. Here, we report the clinicopathological features of 7 cases of DH-FL. All neoplasms had a follicular pattern (1 partially diffuse). Five cases were predominantly low grade, 4 of which had focal (≤20%) grade 3A areas, and 2 cases were of grade 3. All cases were positive for pan-B-cell antigens, CD10, and BCL6; 6 cases were positive for BCL2. Ki-67 was less than or equal to 50% in 6 cases and 90% in 1 grade 3 case. Three patients presented with stage IV disease and 3 had a Follicular Lymphoma International Prognostic Index score of greater than 2. Six patients received immunochemotherapy, and 1 is still under induction therapy with rituximab, ibrutinib, and lenalidomide. Four achieved complete remission and two had a partial response with persistent or refractory disease. The median follow-up time was 25 months (range, 8.5-53.7 months). Two patients treated with standard regimen for follicular lymphoma had relapsed or refractory disease, and 1 died from complications of allogeneic stem cell transplant administered for relapse. In contrast, all 4 patients treated with more intensive regimen for double-hit lymphoma achieved complete remission. In summary, despite predominantly low-grade histology, cases of DH-FL in this study were aggressive and responded better to more intensive than standard treatment regimens, suggesting DH-FL is part of the spectrum of double-hit high-grade lymphoma. Copyright © 2016 Elsevier Inc. All rights reserved.

The effect of training on the use of tobacco-use cessation guidelines in dental settings

PubMed Central

Walsh, Margaret M.; Belek, Marilyn; Prakash, Preeti; Grimes, Barbara; Heckman, Barbara; Kaufman, Nathan; Meckstroth, Richard; Kavanagh, Ms. Catherine; Murray, Jana; Weintraub, Jane A.; Silverstein, Steven; Gansky, Stuart A.

2014-01-01

Background An increase in the number of dentists conducting tobacco-use cessation treatment is needed. The authors assessed the effects of high-intensity training (HIT) or low-intensity training (LIT) and reimbursement on general dentists’ tobacco-use–related attitudes and treatment behaviors. Methods The authors randomly selected 265 dentists in three states and assigned them to one of five groups: HIT workshop groups with and without tobacco-use cessation counseling reimbursement, LIT mailed self-study groups with and without reimbursement or a control group. Outcomes at follow-up were dentists’ self-reported tobacco-use–related attitudes and behaviors and patients’ reports of dentists’ behaviors. Results Significantly more dentists in the intervention groups reported having positive attitudes and behaviors at follow-up than did dentists in the control group. Dentists in the HIT groups, however, reported assessing patients’ willingness to quit and assisting them with the quitting process significantly more often than did dentists in the LIT groups. Significantly more patients of dentists in the intervention groups who used tobacco reported receiving advice and assistance from their dentists than did patients of dentists in the control group. Adding reimbursement to HIT or LIT conditions did not provide additional intervention effect. Conclusion Dentists trained by means of a workshop or self-study program used components of a recommended guideline more frequently and felt more positive toward tobacco-use cessation counseling than did dentists in the control group. Clinical Implications Although the workshop training was more successful than the self-study training, the latter’s reach among dentists could have a more significant public health impact. The effect of reimbursement needs further study. PMID:22653940

Chronic inflammation and impaired development of the preterm brain.

PubMed

Bennet, Laura; Dhillon, Simerdeep; Lear, Chris A; van den Heuij, Lotte; King, Victoria; Dean, Justin M; Wassink, Guido; Davidson, Joanne O; Gunn, Alistair Jan

2018-02-01

The preterm newborn is at significant risk of neural injury and impaired neurodevelopment. Infants with mild or no evidence of injury may also be at risk of altered brain development, with evidence impaired cell maturation. The underlying causes are multifactorial and include exposure of both the fetus and newborn to hypoxia-ischemia, inflammation (chorioamnionitis) and infection, adverse maternal lifestyle choices (smoking, drug and alcohol use, diet) and obesity, as well as the significant demand that adaptation to post-natal life places on immature organs. Further, many fetuses and infants may have combinations of these events, and repeated (multi-hit) events that may induce tolerance to injury or sensitize to greater injury. Currently there are no treatments to prevent preterm injury or impaired neurodevelopment. However, inflammation is a common pathway for many of these insults, and clinical and experimental evidence demonstrates that acute and chronic inflammation is associated with impaired brain development. This review examines our current knowledge about the relationship between inflammation and preterm brain development, and the potential for stem cell therapy to provide neuroprotection and neurorepair through reducing inflammation and release of trophic factors, which promote cell maturation and repair. Copyright © 2017 Elsevier B.V. All rights reserved.

Heparin-induced thrombocytopenia

PubMed Central

2017-01-01

Heparin-induced thrombocytopenia (HIT) is an immune complication of heparin therapy caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. Pathogenic antibodies to PF4/heparin bind and activate cellular FcγRIIA on platelets and monocytes to propagate a hypercoagulable state culminating in life-threatening thrombosis. It is now recognized that anti-PF4/heparin antibodies develop commonly after heparin exposure, but only a subset of sensitized patients progress to life-threatening complications of thrombocytopenia and thrombosis. Recent scientific developments have clarified mechanisms underlying PF4/heparin immunogenicity, disease susceptibility, and clinical manifestations of disease. Insights from clinical and laboratory findings have also been recently harnessed for disease prevention. This review will summarize our current understanding of HIT by reviewing pathogenesis, essential clinical and laboratory features, and management. PMID:28416511

Positioning a Paediatric Compounded Non-Sterile Product Electronic Repository (pCNPeRx) within the Health Information Technology Infrastructure

PubMed Central

Parrish, Richard H.

2015-01-01

Numerous gaps in the current medication use system impede complete transmission of electronically identifiable and standardized extemporaneous formulations as well as a uniform approach to medication therapy management (MTM) for paediatric patients. The Pharmacy Health Information Technology Collaborative (Pharmacy HIT) identified six components that may have direct importance for pharmacy related to medication use in children. This paper will discuss key positions within the information technology infrastructure (HIT) where an electronic repository for the medication management of paediatric patients’ compounded non-sterile products (pCNP) and care provision could be housed optimally to facilitate and maintain transmission of e-prescriptions (eRx) from initiation to fulfillment. Further, the paper will propose key placement requirements to provide for maximal interoperability of electronic medication management systems to minimize disruptions across the continuum of care. PMID:28970375

Roles of effective helical ripple rates in nonlinear stability of externally induced magnetic islands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishimura, Seiya, E-mail: n-seiya@kobe-kosen.ac.jp

Magnetic islands are externally produced by resonant magnetic perturbations (RMPs) in toroidal plasmas. Spontaneous annihilation of RMP-induced magnetic islands called self-healing has been observed in helical systems. A possible mechanism of the self-healing is shielding of RMP penetration by helical ripple-induced neoclassical flows, which give rise to neoclassical viscous torques. In this study, effective helical ripple rates in multi-helicity helical systems are revisited, and a multi-helicity effect on the self-healing is investigated, based on a theoretical model of rotating magnetic islands. It is confirmed that effective helical ripple rates are sensitive to magnetic axis positions. It is newly found thatmore » self-healing thresholds also strongly depend on magnetic axis positions, which is due to dependence of neoclassical viscous torques on effective helical ripple rates.« less

Design and Optimization of Multi-Pixel Transition-Edge Sensors for X-Ray Astronomy Applications

NASA Technical Reports Server (NTRS)

Smith, Stephen J.; Adams, Joseph S.; Bandler, Simon R.; Chervenak, James A.; Datesman, Aaron Michael; Eckart, Megan E.; Ewin, Audrey J.; Finkbeiner, Fred M.; Kelley, Richard L.; Kilbourne, Caroline A.;

Using MASHA+TIMEPIX Setup for Registration Beta Decay Isotopes Produced in Heavy Ion Induced Reactions

NASA Astrophysics Data System (ADS)

Rodin, A. M.; Belozerov, A. V.; Chernysheva, E. V.; Dmitriev, S. N.; Gulyaev, A. V.; Gulyaeva, A. V.; Itkis, M. G.; Novoselov, A. S.; Oganessian, Yu. Ts.; Salamatin, V. S.; Stepantsov, S. V.; Vedeneev, V. Yu.; Yukhimchuk, S. A.; Krupa, L.; Granja, C.; Pospisil, S.; Kliman, J.; Motycak, S.; Sivacek, I.

2015-06-01

Radon and mercury isotopes were produced in multi nucleon transfer (48Ca + 232Th) and complete fusion (48Ca + naturalNd) reactions, respectively. The isotopes with given masses were detected using two detectors: a multi-strip detector of the well-type (made in CANBERRA) and a position-sensitive quantum counting hybrid pixel detector of the TIMEPIX type. The isotopes implanted into the detectors then emit alpha- and betaparticles until reaching the long lived isotopes. The position of the isotopes, the tracks, the time and energy of beta-particles were measured and analyzed. A new software for the particle recognition and data analysis of experimental results was developed and used. It was shown that MASHA+ TIMEPIX setup is a powerful instrument for investigation of neutron-rich isotopes far from stability limits.

Real-time track-less Cherenkov ring fitting trigger system based on Graphics Processing Units

NASA Astrophysics Data System (ADS)

Ammendola, R.; Biagioni, A.; Chiozzi, S.; Cretaro, P.; Cotta Ramusino, A.; Di Lorenzo, S.; Fantechi, R.; Fiorini, M.; Frezza, O.; Gianoli, A.; Lamanna, G.; Lo Cicero, F.; Lonardo, A.; Martinelli, M.; Neri, I.; Paolucci, P. S.; Pastorelli, E.; Piandani, R.; Piccini, M.; Pontisso, L.; Rossetti, D.; Simula, F.; Sozzi, M.; Vicini, P.

2017-12-01

The parallel computing power of commercial Graphics Processing Units (GPUs) is exploited to perform real-time ring fitting at the lowest trigger level using information coming from the Ring Imaging Cherenkov (RICH) detector of the NA62 experiment at CERN. To this purpose, direct GPU communication with a custom FPGA-based board has been used to reduce the data transmission latency. The GPU-based trigger system is currently integrated in the experimental setup of the RICH detector of the NA62 experiment, in order to reconstruct ring-shaped hit patterns. The ring-fitting algorithm running on GPU is fed with raw RICH data only, with no information coming from other detectors, and is able to provide more complex trigger primitives with respect to the simple photodetector hit multiplicity, resulting in a higher selection efficiency. The performance of the system for multi-ring Cherenkov online reconstruction obtained during the NA62 physics run is presented.

Virus Neutralisation: New Insights from Kinetic Neutralisation Curves

PubMed Central

Magnus, Carsten

2013-01-01

Antibodies binding to the surface of virions can lead to virus neutralisation. Different theories have been proposed to determine the number of antibodies that must bind to a virion for neutralisation. Early models are based on chemical binding kinetics. Applying these models lead to very low estimates of the number of antibodies needed for neutralisation. In contrast, according to the more conceptual approach of stoichiometries in virology a much higher number of antibodies is required for virus neutralisation by antibodies. Here, we combine chemical binding kinetics with (virological) stoichiometries to better explain virus neutralisation by antibody binding. This framework is in agreement with published data on the neutralisation of the human immunodeficiency virus. Knowing antibody reaction constants, our model allows us to estimate stoichiometrical parameters from kinetic neutralisation curves. In addition, we can identify important parameters that will make further analysis of kinetic neutralisation curves more valuable in the context of estimating stoichiometries. Our model gives a more subtle explanation of kinetic neutralisation curves in terms of single-hit and multi-hit kinetics. PMID:23468602

Multi-arm multilateral haptics-based immersive tele-robotic system (HITS) for improvised explosive device disposal

NASA Astrophysics Data System (ADS)

Erickson, David; Lacheray, Hervé; Lai, Gilbert; Haddadi, Amir

2014-06-01

This paper presents the latest advancements of the Haptics-based Immersive Tele-robotic System (HITS) project, a next generation Improvised Explosive Device (IED) disposal (IEDD) robotic interface containing an immersive telepresence environment for a remotely-controlled three-articulated-robotic-arm system. While the haptic feedback enhances the operator's perception of the remote environment, a third teleoperated dexterous arm, equipped with multiple vision sensors and cameras, provides stereo vision with proper visual cues, and a 3D photo-realistic model of the potential IED. This decentralized system combines various capabilities including stable and scaled motion, singularity avoidance, cross-coupled hybrid control, active collision detection and avoidance, compliance control and constrained motion to provide a safe and intuitive control environment for the operators. Experimental results and validation of the current system are presented through various essential IEDD tasks. This project demonstrates that a two-armed anthropomorphic Explosive Ordnance Disposal (EOD) robot interface can achieve complex neutralization techniques against realistic IEDs without the operator approaching at any time.

Discovery of wt RET and V804M RET Inhibitors: From Hit to Lead.

PubMed

Mologni, Luca; Dalla Via, Martina; Chilin, Adriana; Palumbo, Manlio; Marzaro, Giovanni

2017-08-22

Oncogenic activation of RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma, and non-small-cell lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors, and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wild-type RET ( wt RET) and its mutants (e.g., V804M RET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar wt RET/ V804M RET inhibitor, N-(2-fluoro-5-trifluoromethylphenyl)-N'-{4'-[(2''-benzamido)pyridin-4''-ylamino]phenyl}urea (69), endowed with a 4-anilinopyridine structure, starting from our previously identified 4-anilinopyrimidine hit compound. Profiling against a panel of kinases indicated 69 as a multi cKIT/ wt RET/ V804M RET inhibitor. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Combined multi-pharmacophore, molecular docking and molecular dynamic study for discovery of promising MTH1 inhibitors

NASA Astrophysics Data System (ADS)

Dai, Duoqian; Zhou, Lu; Zhu, Xiaohong; You, Rong; Zhong, Liangliang

2017-06-01

MutT homolog 1 (MTH1), a nudix phosphohydrolase enzyme participates in the process of repairing of DNA damage by hydrolyzing oxidized deoxy-ribonucleoside triphosphate in cancer cells, is regarded as a potential target for anticancer therapy. In order to seek for promising inhibitor of MTH1, structured-based pharmacophore and 3D-QSAR pharmacophore hypotheses combine with the ADMET analysis and Lipinski's rule of five were used for screening the public molecules libraries (Asinex, Ibscreen and Natural). Then molecular docking studies were performed on screened hits via various docking programs (Glide SP, GOLD and Glide XP), five molecules with three scaffolds were picked out as potential inhibitors against MTH1. Eventually, 20 ns molecular dynamics simulation was implemented on the potential inhibitors. The RMSD (Root Mean Square Deviation) values were used to illustrate bind stability between potential molecules and MTH1. Therefore, the five hits may be considered as promising MTH1 inhibitors by all above studies.

Performance Comparison of Two Gene Set Analysis Methods for Genome-wide Association Study Results: GSA-SNP vs i-GSEA4GWAS.

PubMed

Kwon, Ji-Sun; Kim, Jihye; Nam, Dougu; Kim, Sangsoo

2012-06-01

Gene set analysis (GSA) is useful in interpreting a genome-wide association study (GWAS) result in terms of biological mechanism. We compared the performance of two different GSA implementations that accept GWAS p-values of single nucleotide polymorphisms (SNPs) or gene-by-gene summaries thereof, GSA-SNP and i-GSEA4GWAS, under the same settings of inputs and parameters. GSA runs were made with two sets of p-values from a Korean type 2 diabetes mellitus GWAS study: 259,188 and 1,152,947 SNPs of the original and imputed genotype datasets, respectively. When Gene Ontology terms were used as gene sets, i-GSEA4GWAS produced 283 and 1,070 hits for the unimputed and imputed datasets, respectively. On the other hand, GSA-SNP reported 94 and 38 hits, respectively, for both datasets. Similar, but to a lesser degree, trends were observed with Kyoto Encyclopedia of Genes and Genomes (KEGG) gene sets as well. The huge number of hits by i-GSEA4GWAS for the imputed dataset was probably an artifact due to the scaling step in the algorithm. The decrease in hits by GSA-SNP for the imputed dataset may be due to the fact that it relies on Z-statistics, which is sensitive to variations in the background level of associations. Judicious evaluation of the GSA outcomes, perhaps based on multiple programs, is recommended.

Electronics for a prototype variable field of view PET camera using the PMT-quadrant-sharing detector array

NASA Astrophysics Data System (ADS)

Li, H.; Wong, Wai-Hoi; Zhang, N.; Wang, J.; Uribe, J.; Baghaei, H.; Yokoyama, S.

1999-06-01

Electronics for a prototype high-resolution PET camera with eight position-sensitive detector modules has been developed. Each module has 16 BGO (Bi/sub 4/Ge/sub 3/O/sub 12/) blocks (each block is composed of 49 crystals). The design goals are component and space reduction. The electronics is composed of five parts: front-end analog processing, digital position decoding, fast timing, coincidence processing and master data acquisition. The front-end analog circuit is a zone-based structure (each zone has 3/spl times/3 PMTs). Nine ADCs digitize integration signals of an active zone identified by eight trigger clusters; each cluster is composed of six photomultiplier tubes (PMTs). A trigger corresponding to a gamma ray is sent to a fast timing board to obtain a time-mark, and the nine digitized signals are passed to the position decoding board, where a real block (four PMTs) can be picked out from the zone for position decoding. Lookup tables are used for energy discrimination and to identify the gamma-hit crystal location. The coincidence board opens a 70-ns initial timing window, followed by two 20-ns true/accidental time-mark lookup table windows. The data output from the coincidence board can be acquired either in sinogram mode or in list mode with a Motorola/IRONICS VME-based system.

Real-Time Motion Planning and Safe Navigation in Dynamic Multi-Robot Environments

DTIC Science & Technology

2006-12-15

referee against a robot for pushing or hitting an opponent excessively, as well as for a non- goalie robot entering the team’s own defense area. The DSS... pulling ” a search graph by choosing random samples and then trying to connect a path to those points, some planners “push” samples by first choosing...implement the various roles (attacker, goalie , defender), which in turn build on sub-tactics known as skills [16]. One primitive skill used by almost all

What Websites Are Patients Using: Results of a Tracking Study Exploring Patients Use of Websites at a Multi-Media Patient Education Center

PubMed Central

Ravitch, Stephanie; Fleisher, Linda; Torres, Stephen

2005-01-01

An exploratory study utilized computer tracking software at a hospital based patient education center was conducted to access use of the Web. During six months, 625 hits were tracked with 1/3 to www.cancer.gov one of the recommended websites, while over half of the sites were not on the recommended list. Here we report the challenges and results of this tracking study. PMID:16779379

Novel active principles from spider venom.

PubMed

Vassilevski, Alexander A; Grishin, Eugene V

2011-12-01

Spiders are one of the most intriguing groups of venomous animals. Substances found in their venom vary from simple inorganic compounds to large multi-domain proteins. In this article, we review some of the latest work presenting active principles that add to the known spider toxin universe. Two aspects of novelty are addressed in particular, structural (novel types of molecules in terms of structure) and functional (novel types of biological targets hit by substances from spider venom and novel mechanisms of action).

14C autoradiography with an energy-sensitive silicon pixel detector.

PubMed

Esposito, M; Mettivier, G; Russo, P

2011-04-07

The first performance tests are presented of a carbon-14 ((14)C) beta-particle digital autoradiography system with an energy-sensitive hybrid silicon pixel detector based on the Timepix readout circuit. Timepix was developed by the Medipix2 Collaboration and it is similar to the photon-counting Medipix2 circuit, except for an added time-based synchronization logic which allows derivation of energy information from the time-over-threshold signal. This feature permits direct energy measurements in each pixel of the detector array. Timepix is bump-bonded to a 300 µm thick silicon detector with 256 × 256 pixels of 55 µm pitch. Since an energetic beta-particle could release its kinetic energy in more than one detector pixel as it slows down in the semiconductor detector, an off-line image analysis procedure was adopted in which the single-particle cluster of hit pixels is recognized; its total energy is calculated and the position of interaction on the detector surface is attributed to the centre of the charge cluster. Measurements reported are detector sensitivity, (4.11 ± 0.03) × 10(-3) cps mm(-2) kBq(-1) g, background level, (3.59 ± 0.01) × 10(-5) cps mm(-2), and minimum detectable activity, 0.0077 Bq. The spatial resolution is 76.9 µm full-width at half-maximum. These figures are compared with several digital imaging detectors for (14)C beta-particle digital autoradiography.

Improving multi-objective reservoir operation optimization with sensitivity-informed dimension reduction

NASA Astrophysics Data System (ADS)

Chu, J.; Zhang, C.; Fu, G.; Li, Y.; Zhou, H.

2015-08-01

This study investigates the effectiveness of a sensitivity-informed method for multi-objective operation of reservoir systems, which uses global sensitivity analysis as a screening tool to reduce computational demands. Sobol's method is used to screen insensitive decision variables and guide the formulation of the optimization problems with a significantly reduced number of decision variables. This sensitivity-informed method dramatically reduces the computational demands required for attaining high-quality approximations of optimal trade-off relationships between conflicting design objectives. The search results obtained from the reduced complexity multi-objective reservoir operation problems are then used to pre-condition the full search of the original optimization problem. In two case studies, the Dahuofang reservoir and the inter-basin multi-reservoir system in Liaoning province, China, sensitivity analysis results show that reservoir performance is strongly controlled by a small proportion of decision variables. Sensitivity-informed dimension reduction and pre-conditioning are evaluated in their ability to improve the efficiency and effectiveness of multi-objective evolutionary optimization. Overall, this study illustrates the efficiency and effectiveness of the sensitivity-informed method and the use of global sensitivity analysis to inform dimension reduction of optimization problems when solving complex multi-objective reservoir operation problems.

Improving multi-objective reservoir operation optimization with sensitivity-informed problem decomposition

NASA Astrophysics Data System (ADS)

Chu, J. G.; Zhang, C.; Fu, G. T.; Li, Y.; Zhou, H. C.

2015-04-01

This study investigates the effectiveness of a sensitivity-informed method for multi-objective operation of reservoir systems, which uses global sensitivity analysis as a screening tool to reduce the computational demands. Sobol's method is used to screen insensitive decision variables and guide the formulation of the optimization problems with a significantly reduced number of decision variables. This sensitivity-informed problem decomposition dramatically reduces the computational demands required for attaining high quality approximations of optimal tradeoff relationships between conflicting design objectives. The search results obtained from the reduced complexity multi-objective reservoir operation problems are then used to pre-condition the full search of the original optimization problem. In two case studies, the Dahuofang reservoir and the inter-basin multi-reservoir system in Liaoning province, China, sensitivity analysis results show that reservoir performance is strongly controlled by a small proportion of decision variables. Sensitivity-informed problem decomposition and pre-conditioning are evaluated in their ability to improve the efficiency and effectiveness of multi-objective evolutionary optimization. Overall, this study illustrates the efficiency and effectiveness of the sensitivity-informed method and the use of global sensitivity analysis to inform problem decomposition when solving the complex multi-objective reservoir operation problems.

[Identification and drug susceptibility testing of Mycobacterium thermoresistibile and Mycobacterium elephantis isolated from a cow with mastitis].

PubMed

Li, W B; Ji, L Y; Xu, D L; Liu, H C; Zhao, X Q; Wu, Y M; Wan, K L

2018-05-10

Objective: To understand the etiological characteristics and drug susceptibility of Mycobacterium thermoresistibile and Mycobacterium elephantis isolated from a cow with mastitis and provide evidence for the prevention and control of infectious mastitis in cows. Methods: The milk sample was collected from a cow with mastitis, which was pretreated with 4 % NaOH and inoculated with L-J medium for Mycobacterium isolation. The positive cultures were initially identified by acid-fast staining and multi-loci PCR, then Mycobacterium species was identified by the multiple loci sequence analysis (MLSA) with 16S rRNA , hsp65 , ITS and SodA genes. The drug sensitivity of the isolates to 27 antibiotics was tested by alamar blue assay. Results: Two anti-acid stain positive strains were isolated from the milk of a cow with mastitis, which were identified as non- tuberculosis mycobacterium by multi-loci PCR, and multi-loci nucleic acid sequence analysis indicated that one strain was Mycobacterium thermoresistibile and another one was Mycobacterium elephantis . The results of the drug susceptibility test showed that the two strains were resistant to most antibiotics, including rifampicin and isoniazid, but they were sensitive to amikacin, moxifloxacin, levofloxacin, ethambutol, streptomycin, tobramycin, ciprofloxacin and linezolid. Conclusions: Mycobacterium thermoresistibile and Mycobacterium elephantis were isolated in a cow with mastitis and the drug susceptibility spectrum of the pathogens were unique. The results of the study can be used as reference for the prevention and control the infection in cows.

Real­-Time Ensemble Forecasting of Coronal Mass Ejections Using the Wsa-Enlil+Cone Model

NASA Astrophysics Data System (ADS)

Mays, M. L.; Taktakishvili, A.; Pulkkinen, A. A.; Odstrcil, D.; MacNeice, P. J.; Rastaetter, L.; LaSota, J. A.

2014-12-01

Ensemble forecasting of coronal mass ejections (CMEs) provides significant information in that it provides an estimation of the spread or uncertainty in CME arrival time predictions. Real-time ensemble modeling of CME propagation is performed by forecasters at the Space Weather Research Center (SWRC) using the WSA-ENLIL+cone model available at the Community Coordinated Modeling Center (CCMC). To estimate the effect of uncertainties in determining CME input parameters on arrival time predictions, a distribution of n (routinely n=48) CME input parameter sets are generated using the CCMC Stereo CME Analysis Tool (StereoCAT) which employs geometrical triangulation techniques. These input parameters are used to perform n different simulations yielding an ensemble of solar wind parameters at various locations of interest, including a probability distribution of CME arrival times (for hits), and geomagnetic storm strength (for Earth-directed hits). We present the results of ensemble simulations for a total of 38 CME events in 2013-2014. For 28 of the ensemble runs containing hits, the observed CME arrival was within the range of ensemble arrival time predictions for 14 runs (half). The average arrival time prediction was computed for each of the 28 ensembles predicting hits and using the actual arrival time, an average absolute error of 10.0 hours (RMSE=11.4 hours) was found for all 28 ensembles, which is comparable to current forecasting errors. Some considerations for the accuracy of ensemble CME arrival time predictions include the importance of the initial distribution of CME input parameters, particularly the mean and spread. When the observed arrivals are not within the predicted range, this still allows the ruling out of prediction errors caused by tested CME input parameters. Prediction errors can also arise from ambient model parameters such as the accuracy of the solar wind background, and other limitations. Additionally the ensemble modeling sysem was used to complete a parametric event case study of the sensitivity of the CME arrival time prediction to free parameters for ambient solar wind model and CME. The parameter sensitivity study suggests future directions for the system, such as running ensembles using various magnetogram inputs to the WSA model.

Sensitivity of the two-dimensional shearless mixing layer to the initial turbulent kinetic energy and integral length scale

NASA Astrophysics Data System (ADS)

Fathali, M.; Deshiri, M. Khoshnami

2016-04-01

The shearless mixing layer is generated from the interaction of two homogeneous isotropic turbulence (HIT) fields with different integral scales ℓ1 and ℓ2 and different turbulent kinetic energies E1 and E2. In this study, the sensitivity of temporal evolutions of two-dimensional, incompressible shearless mixing layers to the parametric variations of ℓ1/ℓ2 and E1/E2 is investigated. The sensitivity methodology is based on the nonintrusive approach; using direct numerical simulation and generalized polynomial chaos expansion. The analysis is carried out at Reℓ 1=90 for the high-energy HIT region and different integral length scale ratios 1 /4 ≤ℓ1/ℓ2≤4 and turbulent kinetic energy ratios 1 ≤E1/E2≤30 . It is found that the most influential parameter on the variability of the mixing layer evolution is the turbulent kinetic energy while variations of the integral length scale show a negligible influence on the flow field variability. A significant level of anisotropy and intermittency is observed in both large and small scales. In particular, it is found that large scales have higher levels of intermittency and sensitivity to the variations of ℓ1/ℓ2 and E1/E2 compared to the small scales. Reconstructed response surfaces of the flow field intermittency and the turbulent penetration depth show monotonic dependence on ℓ1/ℓ2 and E1/E2 . The mixing layer growth rate and the mixing efficiency both show sensitive dependence on the initial condition parameters. However, the probability density function of these quantities shows relatively small solution variations in response to the variations of the initial condition parameters.

Demand spillovers of smash-hit papers: evidence from the 'Male Organ Incident'.

PubMed

Kässi, Otto; Westling, Tatu

2013-12-01

This study explores the short-run spillover effects of popular research papers. We consider the publicity of 'Male Organ and Economic Growth: Does Size Matter?' as an exogenous shock to economics discussion paper demand, a natural experiment of a sort. In particular, we analyze how the very substantial visibility influenced the downloads of Helsinki Center of Economic Research discussion papers. Difference in differences and regression discontinuity analysis are conducted to elicit the spillover patterns. This study finds that the spillover effect to average economics paper demand is positive and statistically significant. It seems that hit papers increase the exposure of previously less downloaded papers. We find that part of the spillover effect could be attributable to Internet search engines' influence on browsing behavior. Conforming to expected patterns, papers residing on the same web page as the hit paper evidence very significant increases in downloads which also supports the spillover thesis. A11, C21. 97K80.

An interactive web-based application for Comprehensive Analysis of RNAi-screen Data.

PubMed

Dutta, Bhaskar; Azhir, Alaleh; Merino, Louis-Henri; Guo, Yongjian; Revanur, Swetha; Madhamshettiwar, Piyush B; Germain, Ronald N; Smith, Jennifer A; Simpson, Kaylene J; Martin, Scott E; Buehler, Eugen; Beuhler, Eugen; Fraser, Iain D C

2016-02-23

RNAi screens are widely used in functional genomics. Although the screen data can be susceptible to a number of experimental biases, many of these can be corrected by computational analysis. For this purpose, here we have developed a web-based platform for integrated analysis and visualization of RNAi screen data named CARD (for Comprehensive Analysis of RNAi Data; available at https://card.niaid.nih.gov). CARD allows the user to seamlessly carry out sequential steps in a rigorous data analysis workflow, including normalization, off-target analysis, integration of gene expression data, optimal thresholds for hit selection and network/pathway analysis. To evaluate the utility of CARD, we describe analysis of three genome-scale siRNA screens and demonstrate: (i) a significant increase both in selection of subsequently validated hits and in rejection of false positives, (ii) an increased overlap of hits from independent screens of the same biology and (iii) insight to microRNA (miRNA) activity based on siRNA seed enrichment.

An Automatic Quality Control Pipeline for High-Throughput Screening Hit Identification.

PubMed

Zhai, Yufeng; Chen, Kaisheng; Zhong, Yang; Zhou, Bin; Ainscow, Edward; Wu, Ying-Ta; Zhou, Yingyao

2016-09-01

The correction or removal of signal errors in high-throughput screening (HTS) data is critical to the identification of high-quality lead candidates. Although a number of strategies have been previously developed to correct systematic errors and to remove screening artifacts, they are not universally effective and still require fair amount of human intervention. We introduce a fully automated quality control (QC) pipeline that can correct generic interplate systematic errors and remove intraplate random artifacts. The new pipeline was first applied to ~100 large-scale historical HTS assays; in silico analysis showed auto-QC led to a noticeably stronger structure-activity relationship. The method was further tested in several independent HTS runs, where QC results were sampled for experimental validation. Significantly increased hit confirmation rates were obtained after the QC steps, confirming that the proposed method was effective in enriching true-positive hits. An implementation of the algorithm is available to the screening community. © 2016 Society for Laboratory Automation and Screening.

An interactive web-based application for Comprehensive Analysis of RNAi-screen Data

PubMed Central

Dutta, Bhaskar; Azhir, Alaleh; Merino, Louis-Henri; Guo, Yongjian; Revanur, Swetha; Madhamshettiwar, Piyush B.; Germain, Ronald N.; Smith, Jennifer A.; Simpson, Kaylene J.; Martin, Scott E.; Beuhler, Eugen; Fraser, Iain D. C.

2016-01-01

RNAi screens are widely used in functional genomics. Although the screen data can be susceptible to a number of experimental biases, many of these can be corrected by computational analysis. For this purpose, here we have developed a web-based platform for integrated analysis and visualization of RNAi screen data named CARD (for Comprehensive Analysis of RNAi Data; available at https://card.niaid.nih.gov). CARD allows the user to seamlessly carry out sequential steps in a rigorous data analysis workflow, including normalization, off-target analysis, integration of gene expression data, optimal thresholds for hit selection and network/pathway analysis. To evaluate the utility of CARD, we describe analysis of three genome-scale siRNA screens and demonstrate: (i) a significant increase both in selection of subsequently validated hits and in rejection of false positives, (ii) an increased overlap of hits from independent screens of the same biology and (iii) insight to microRNA (miRNA) activity based on siRNA seed enrichment. PMID:26902267

Novel small molecule inhibitors targeting the "switch region" of bacterial RNAP: structure-based optimization of a virtual screening hit.

PubMed

Sahner, J Henning; Groh, Matthias; Negri, Matthias; Haupenthal, Jörg; Hartmann, Rolf W

2013-07-01

Rising resistance against current antibiotics necessitates the development of antibacterial agents with alternative targets. The "switch region" of RNA polymerase (RNAP), addressed by the myxopyronins, could be such a novel target site. Based on a hit candidate discovered by virtual screening, a small library of 5-phenyl-3-ureidothiophene-2-carboxylic acids was synthesized resulting in compounds with increased RNAP inhibition. Hansch analysis revealed π (lipophilicity constant) and σ (Hammet substituent constant) of the substituents at the 5-phenyl moiety to be crucial for activity. The binding mode was proven by the targeted introduction of a moiety mimicking the enecarbamate side chain of myxopyronin into the hit compound, accompanied by enhanced RNAP inhibitory potency. The new compounds displayed good antibacterial activities against Gram positive bacteria and Gram negative Escherichia coli TolC and a reduced resistance frequency compared to the established antibiotic rifampicin. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Non-alcoholic steatohepatitis: review of a growing medical problem.

PubMed

Te Sligte, K.; Bourass, I.; Sels, J.P.; Driessen, A.; Stockbrugger, R.W.; Koek, G.H.

2004-02-01

Non-alcoholic steatohepatitis (NASH) is a metabolic liver disorder that is seen in 2-6% of the general population. It manifests itself by elevated liver enzymes, frequently without symptoms. The histological findings include steatosis, inflammation, fibrosis, and cirrhosis. Three case reports are presented to illustrate features of NASH. A two-hit model has been proposed in the pathogenesis of NASH. The first hit is hepatic steatosis. A hypercaloric diet with high levels of carbohydrates and saturated fatty acids results in elevated plasma free fatty acids (FFA) and expands the adipose tissue. Insulin resistance develops and augments steatosis. Oxidation of FFA yields toxic free radicals, resulting in lipid peroxidation. They cause the second hits: increased oxidative stress on hepatocytes and induction of pro-inflammatory cytokines. When the antioxidant capacities of the liver are insufficient, mitochondrial dysfunction and tumor necrosis factor alpha (TNF-alpha) cause inflammation and fibrosis. Treatment consists of life style modifications, particularly weight loss and exercise. Many drugs have been tried in the treatment of NASH. The insulin-sensitizing drugs metformin, rosiglitazone, and pioglitazone, and the antioxidant vitamin E show promising results. Further investigation of therapeutic options is needed to direct the choice of therapy in the future.

Discovery and structure-guided fragment-linking of 4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxamide as a pyruvate kinase M2 activator.

PubMed

Matsui, Yumi; Yasumatsu, Isao; Asahi, Takashi; Kitamura, Takahiro; Kanai, Kazuo; Ubukata, Osamu; Hayasaka, Hitoshi; Takaishi, Sachiko; Hanzawa, Hiroyuki; Katakura, Shinichi

2017-07-01

Tumor cells switch glucose metabolism to aerobic glycolysis by expressing the pyruvate kinase M2 isoform (PKM2) in a low active form, providing glycolytic intermediates as building blocks for biosynthetic processes, and thereby supporting cell proliferation. Activation of PKM2 should invert aerobic glycolysis to an oxidative metabolism and prevent cancer growth. Thus, PKM2 has gained attention as a promising cancer therapy target. To obtain novel PKM2 activators, we conducted a high-throughput screening (HTS). Among several hit compounds, a fragment-like hit compound with low potency but high ligand efficiency was identified. Two molecules of the hit compound bound at one activator binding site, and the molecules were linked based on the crystal structure. Since this linkage succeeded in maintaining the original position of the hit compound, the obtained compound exhibited highly improved potency in an in vitro assay. The linked compound also showed PKM2 activating activity in a cell based assay, and cellular growth inhibition of the A549 cancer cell line. Discovery of this novel scaffold and binding mode of the linked compound provides a valuable platform for the structure-guided design of PKM2 activators. Copyright © 2017 Elsevier Ltd. All rights reserved.

GPU-based low-level trigger system for the standalone reconstruction of the ring-shaped hit patterns in the RICH Cherenkov detector of NA62 experiment

NASA Astrophysics Data System (ADS)

Ammendola, R.; Biagioni, A.; Chiozzi, S.; Cretaro, P.; Cotta Ramusino, A.; Di Lorenzo, S.; Fantechi, R.; Fiorini, M.; Frezza, O.; Gianoli, A.; Lamanna, G.; Lo Cicero, F.; Lonardo, A.; Martinelli, M.; Neri, I.; Paolucci, P. S.; Pastorelli, E.; Piandani, R.; Piccini, M.; Pontisso, L.; Rossetti, D.; Simula, F.; Sozzi, M.; Vicini, P.

2017-03-01

This project aims to exploit the parallel computing power of a commercial Graphics Processing Unit (GPU) to implement fast pattern matching in the Ring Imaging Cherenkov (RICH) detector for the level 0 (L0) trigger of the NA62 experiment. In this approach, the ring-fitting algorithm is seedless, being fed with raw RICH data, with no previous information on the ring position from other detectors. Moreover, since the L0 trigger is provided with a more elaborated information than a simple multiplicity number, it results in a higher selection power. Two methods have been studied in order to reduce the data transfer latency from the readout boards of the detector to the GPU, i.e., the use of a dedicated NIC device driver with very low latency and a direct data transfer protocol from a custom FPGA-based NIC to the GPU. The performance of the system, developed through the FPGA approach, for multi-ring Cherenkov online reconstruction obtained during the NA62 physics runs is presented.

Study of sub-pixel position resolution with time-correlated transient signals in 3D pixelated CdZnTe detectors with varying pixel sizes

NASA Astrophysics Data System (ADS)

Ocampo Giraldo, L.; Bolotnikov, A. E.; Camarda, G. S.; De Geronimo, G.; Fried, J.; Gul, R.; Hodges, D.; Hossain, A.; Ünlü, K.; Vernon, E.; Yang, G.; James, R. B.

2018-03-01

We evaluated the sub-pixel position resolution achievable in large-volume CdZnTe pixelated detectors with conventional pixel patterns and for several different pixel sizes: 2.8 mm, 1.72 mm, 1.4 mm and 0.8 mm. Achieving position resolution below the physical dimensions of pixels (sub-pixel resolution) is a practical path for making high-granularity position-sensitive detectors, <100 μm, using a limited number of pixels dictated by the mechanical constraints and multi-channel readout electronics. High position sensitivity is important for improving the imaging capability of CZT gamma cameras. It also allows for making more accurate corrections of response non-uniformities caused by crystal defects, thus enabling use of standard-grade (unselected) and less expensive CZT crystals for producing large-volume position-sensitive CZT detectors feasible for many practical applications. We analyzed the digitized charge signals from a representative 9 pixels and the cathode, generated using a pulsed-laser light beam focused down to 10 μm (650 nm) to scan over a selected 3 × 3 pixel area. We applied our digital pulse processing technique to the time-correlated signals captured from adjacent pixels to achieve and evaluate the capability for sub-pixel position resolution. As an example, we also demonstrated an application of 3D corrections to improve the energy resolution and positional information of the events for the tested detectors.

Study of sub-pixel position resolution with time-correlated transient signals in 3D pixelated CdZnTe detectors with varying pixel sizes

DOE PAGES

Giraldo, L. Ocampo; Bolotnikov, A. E.; Camarda, G. S.; ...

2017-12-18

Here, we evaluated the sub-pixel position resolution achievable in large-volume CdZnTe pixelated detectors with conventional pixel patterns and for several different pixel sizes: 2.8 mm, 1.72 mm, 1.4 mm and 0.8 mm. Achieving position resolution below the physical dimensions of pixels (sub-pixel resolution) is a practical path for making high-granularity position-sensitive detectors, <100 μμm, using a limited number of pixels dictated by the mechanical constraints and multi-channel readout electronics. High position sensitivity is important for improving the imaging capability of CZT gamma cameras. It also allows for making more accurate corrections of response non-uniformities caused by crystal defects, thus enablingmore » use of standard-grade (unselected) and less expensive CZT crystals for producing large-volume position-sensitive CZT detectors feasible for many practical applications. We analyzed the digitized charge signals from a representative 9 pixels and the cathode, generated using a pulsed-laser light beam focused down to 10 m (650 nm) to scan over a selected 3×3 pixel area. We applied our digital pulse processing technique to the time-correlated signals captured from adjacent pixels to achieve and evaluate the capability for sub-pixel position resolution. As an example, we also demonstrated an application of 3D corrections to improve the energy resolution and positional information of the events for the tested detectors.« less

Study of sub-pixel position resolution with time-correlated transient signals in 3D pixelated CdZnTe detectors with varying pixel sizes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giraldo, L. Ocampo; Bolotnikov, A. E.; Camarda, G. S.

Here, we evaluated the sub-pixel position resolution achievable in large-volume CdZnTe pixelated detectors with conventional pixel patterns and for several different pixel sizes: 2.8 mm, 1.72 mm, 1.4 mm and 0.8 mm. Achieving position resolution below the physical dimensions of pixels (sub-pixel resolution) is a practical path for making high-granularity position-sensitive detectors, <100 μμm, using a limited number of pixels dictated by the mechanical constraints and multi-channel readout electronics. High position sensitivity is important for improving the imaging capability of CZT gamma cameras. It also allows for making more accurate corrections of response non-uniformities caused by crystal defects, thus enablingmore » use of standard-grade (unselected) and less expensive CZT crystals for producing large-volume position-sensitive CZT detectors feasible for many practical applications. We analyzed the digitized charge signals from a representative 9 pixels and the cathode, generated using a pulsed-laser light beam focused down to 10 m (650 nm) to scan over a selected 3×3 pixel area. We applied our digital pulse processing technique to the time-correlated signals captured from adjacent pixels to achieve and evaluate the capability for sub-pixel position resolution. As an example, we also demonstrated an application of 3D corrections to improve the energy resolution and positional information of the events for the tested detectors.« less

Hit discovery and hit-to-lead approaches.

PubMed

Keseru, György M; Makara, Gergely M

2006-08-01

Hit discovery technologies range from traditional high-throughput screening to affinity selection of large libraries, fragment-based techniques and computer-aided de novo design, many of which have been extensively reviewed. Development of quality leads using hit confirmation and hit-to-lead approaches present their own challenges, depending on the hit discovery method used to identify the initial hits. In this paper, we summarize common industry practices adopted to tackle hit-to-lead challenges and review how the advantages and drawbacks of different hit discovery techniques could affect the various issues hit-to-lead groups face.

GALAXY CLUSTERS IN THE LINE OF SIGHT TO BACKGROUND QUASARS. III. MULTI-OBJECT SPECTROSCOPY

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andrews, H.; Barrientos, L. F.; Padilla, N.

2013-09-01

We present Gemini/GMOS-S multi-object spectroscopy of 31 galaxy cluster candidates at redshifts between 0.2 and 1.0 and centered on QSO sight lines taken from Lopez et al. The targets were selected based on the presence of an intervening Mg II absorption system at a similar redshift to that of a galaxy cluster candidate lying at a projected distance <2 h{sub 71}{sup -1} Mpc from the QSO sight line (a {sup p}hotometric hit{sup )}. The absorption systems span rest-frame equivalent widths between 0.015 and 2.028 A. Our aim was three-fold: (1) to identify the absorbing galaxies and determine their impact parameters,more » (2) to confirm the galaxy cluster candidates in the vicinity of each quasar sightline, and (3) to determine whether the absorbing galaxies reside in galaxy clusters. In this way, we are able to characterize the absorption systems associated with cluster members. Our main findings are as follows. (1) We identified 10 out of 24 absorbing galaxies with redshifts between 0.2509 {<=} z{sub gal} {<=} 1.0955, up to an impact parameter of 142 h{sub 71}{sup -1} kpc and a maximum velocity difference of 280 km s{sup -1}. (2) We spectroscopically confirmed 20 out of 31 cluster/group candidates, with most of the confirmed clusters/groups at z < 0.7. This relatively low efficiency results from the fact that we centered our observations on the QSO location, and thus occasionally some of the cluster centers were outside the instrument field of view. (3) Following from the results above, we spectroscopically confirmed of 10 out of 14 photometric hits within {approx}650 km s{sup -1} from galaxy clusters/groups, in addition to two new ones related to galaxy group environments. These numbers imply efficiencies of 71% in finding such systems with MOS spectroscopy. This is a remarkable result since we defined a photometric hit as those cluster-absorber pairs having a redshift difference {Delta}z = 0.1. The general population of our confirmed absorbing galaxies have luminosities L{sub B}{approx}L{sub B}{sup *} and mean rest-frame colors (R{sub c} - z') typical of S{sub cd} galaxies. From this sample, absorbing cluster galaxies hosting weak absorbers are consistent with lower star formation activity than the rest, which produce strong absorption and agree with typical Mg II absorbing galaxies found in the literature. Our spectroscopic confirmations lend support to the selection of photometric hits made in Lopez et al.« less

Investigating Team Coordination in Baseball Using a Novel Joint Decision Making Paradigm

PubMed Central

Gray, Rob; Cooke, Nancy J.; McNeese, Nathan J.; McNabb, Jaimie

2017-01-01

A novel joint decision making paradigm for assessing team coordination was developed and tested using baseball infielders. Balls launched onto an infield at different trajectories were filmed using four video cameras that were each placed at one of the typical positions of the four infielders. Each participant viewed temporally occluded videos for one of the four positions and were asked to say either “ball” if they would attempt to field it or the name of the bag that they would cover. The evaluation of two experienced coaches was used to assign a group coordination score for each trajectory and group decision times were calculated. Thirty groups of 4 current college baseball players were: (i) teammates (players from same team/view from own position), (ii) non-teammates (players from different teams/view from own position), or (iii) scrambled teammates (players from same team/view not from own position). Teammates performed significantly better (i.e., faster and more coordinated decisions) than the other two groups, whereas scrambled teammates performed significantly better than non-teammates. These findings suggest that team coordination is achieved through both experience with one’s teammates’ responses to particular events (e.g., a ball hit up the middle) and one’s own general action capabilities (e.g., running speed). The sensitivity of our joint decision making paradigm to group makeup provides support for its use as a method for studying team coordination. PMID:28638354

Clinical picture of heparin-induced thrombocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia.

PubMed

Warkentin, Theodore E

2016-10-28

HIT is an acquired antibody-mediated disorder strongly associated with thrombosis, including microthrombosis secondary to disseminated intravascular dissemination (DIC). The clinical features of HIT are reviewed from the perspective of the 4Ts scoring system for HIT, which emphasises its characteristic timing of onset of thrombocytopenia. HIT antibodies recognize multimolecular complexes of platelet factor 4 (PF4)/heparin. However, a subset of HIT sera recognise PF4 bound to platelet chondroitin sulfate; these antibodies activate platelets in vitro and in vivo even in the absence of heparin, thus explaining: delayed-onset HIT (where HIT begins or worsens after stopping heparin); persisting HIT (where HIT takes several weeks to recover); spontaneous HIT syndrome (a disorder clinically and serologically resembling HIT but without proximate heparin exposure); and fondaparinux-associated HIT (four distinct syndromes featuring thrombocytopenia that begins or worsens during treatment with fondaparinux), with a new patient case presented with ongoing thrombocytopenia (and fatal haemorrhage) during treatment of HIT with fondaparinux, with fondaparinux-dependent platelet activation induced by patient serum ("fondaparinux cross-reactivity"). Ironically, despite existence of fondaparinux-associated HIT, this pentasaccharide anticoagulant is a frequent treatment for HIT (including one used by the author). HIT can be confused with other disorders, including those with a) timing similar to HIT (e. g. abciximab-associated thrombocytopenia of delayed-onset); b) combined thrombocytopenia/thrombosis (e. g. symmetrical peripheral gangrene secondary to acute DIC and shock liver); and c) both timing of onset and thrombosis (e. g. warfarin-associated venous limb gangrene complicating cancer-associated DIC). By understanding clinical and pathophysiological similarities and differences between HIT and non-HIT mimicking disorders, the clinician is better able to make the correct diagnosis.

The utility of pre-test clinical scoring for clinical diagnosis of heparin-induced thrombocytopenia in cardiac surgery patients of a tertiary care centre in north India.

PubMed

Sachan, D; Gupta, N; Agarwal, P; Chaudhary, R

2011-08-01

Heparin-induced thrombocytopenia (HIT) should be diagnosed clinically as well as by laboratory assays for timely recognition, prevention and management of complications. To evaluate the clinical utility of pre-test clinical scoring system in combination with two immunoassays for the diagnosis of HIT in cardiac surgery patients. A total of 100 consecutive patients undergoing cardiac surgery were studied. Pre-test clinical scoring was carried out in patients with thrombocytopenia and further tested by two immunoassays, i.e., Heparin platelet factor 4 (H-PF4) enzyme-linked immunosorbent assay (ELISA) and particle gel immunoassay (PaGIA). Of the 100 patients studied, 42 patients developed thrombocytopenia post-operatively. On pre-test clinical scoring, low T-score was observed in 6 patients, intermediate in 28 and high score in 8 patients, whereas 19 patients (45.2%) were positive by H-PF4 ELISA and 10 (23.8%) by PaGIA for H-PF4 antibody. The difference in the incidence of clinically significant HIT antibodies in the three categories was statistically significant. A good correlation was also observed with ELISA optical density, T-scoring and PaGIA. Pre-test clinical scoring correlates well with the development of H-PF4 antibodies which are incriminated in the causation of thrombotic complications in patients with HIT. We also propose a protocol for diagnosing patients with clinical suspicion of HIT using pre-test clinical scoring and immunoassay. © 2011 The Authors. Transfusion Medicine © 2011 British Blood Transfusion Society.

Design, synthesis and screening studies of potent thiazol-2-amine derivatives as fibroblast growth factor receptor 1 inhibitors.

PubMed

Kumar, B V S Suneel; Lakshmi, Narasu; Kumar, M Ravi; Rambabu, Gundla; Manjashetty, Thimmappa H; Arunasree, Kalle M; Sriram, Dharmarajan; Ramkumar, Kavya; Neamati, Nouri; Dayam, Raveendra; Sarma, J A R P

2014-01-01

Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing. The FGFR isoforms and their receptors (FGFRs) considered as a potential targets and under intense research to design potential anticancer agents. Fibroblast growth factors (FGF's) and its growth factor receptors (FGFR) plays vital role in one of the critical pathway in monitoring angiogenesis. In the current study, quantitative pharmacophore models were generated and validated using known FGFR1 inhibitors. The pharmacophore models were generated using a set of 28 compounds (training). The top pharmacophore model was selected and validated using a set of 126 compounds (test set) and also using external validation. The validated pharmacophore was considered as a virtual screening query to screen a database of 400,000 virtual molecules and pharmacophore model retrieved 2800 hits. The retrieved hits were subsequently filtered based on the fit value. The selected hits were subjected for docking studies to observe the binding modes of the retrieved hits and also to reduce the false positives. One of the potential hits (thiazole-2-amine derivative) was selected based the pharmacophore fit value, dock score, and synthetic feasibility. A few analogues of the thiazole-2-amine derivative were synthesized. These compounds were screened for FGFR1 activity and anti-proliferative studies. The top active compound showed 56.87% inhibition of FGFR1 activity at 50 µM and also showed good cellular activity. Further optimization of thiazole-2-amine derivatives is in progress.

Voltage-sensitive dye imaging of mouse neocortex during a whisker detection task

PubMed Central

Kyriakatos, Alexandros; Sadashivaiah, Vijay; Zhang, Yifei; Motta, Alessandro; Auffret, Matthieu; Petersen, Carl C. H.

2016-01-01

Abstract. Sensorimotor processing occurs in a highly distributed manner in the mammalian neocortex. The spatiotemporal dynamics of electrical activity in the dorsal mouse neocortex can be imaged using voltage-sensitive dyes (VSDs) with near-millisecond temporal resolution and ∼100-μm spatial resolution. Here, we trained mice to lick a water reward spout after a 1-ms deflection of the C2 whisker, and we imaged cortical dynamics during task execution with VSD RH1691. Responses to whisker deflection were highly dynamic and spatially highly distributed, exhibiting high variability from trial to trial in amplitude and spatiotemporal dynamics. We differentiated trials based on licking and whisking behavior. Hit trials, in which the mouse licked after the whisker stimulus, were accompanied by overall greater depolarization compared to miss trials, with the strongest hit versus miss differences being found in frontal cortex. Prestimulus whisking decreased behavioral performance by increasing the fraction of miss trials, and these miss trials had attenuated cortical sensorimotor responses. Our data suggest that the spatiotemporal dynamics of depolarization in mouse sensorimotor cortex evoked by a single brief whisker deflection are subject to important behavioral modulation during the execution of a simple, learned, goal-directed sensorimotor transformation. PMID:27921068

In-depth comparison of somatic point mutation callers based on different tumor next-generation sequencing depth data

NASA Astrophysics Data System (ADS)

Cai, Lei; Yuan, Wei; Zhang, Zhou; He, Lin; Chou, Kuo-Chen

2016-11-01

Four popular somatic single nucleotide variant (SNV) calling methods (Varscan, SomaticSniper, Strelka and MuTect2) were carefully evaluated on the real whole exome sequencing (WES, depth of ~50X) and ultra-deep targeted sequencing (UDT-Seq, depth of ~370X) data. The four tools returned poor consensus on candidates (only 20% of calls were with multiple hits by the callers). For both WES and UDT-Seq, MuTect2 and Strelka obtained the largest proportion of COSMIC entries as well as the lowest rate of dbSNP presence and high-alternative-alleles-in-control calls, demonstrating their superior sensitivity and accuracy. Combining different callers does increase reliability of candidates, but narrows the list down to very limited range of tumor read depth and variant allele frequency. Calling SNV on UDT-Seq data, which were of much higher read-depth, discovered additional true-positive variations, despite an even more tremendous growth in false positive predictions. Our findings not only provide valuable benchmark for state-of-the-art SNV calling methods, but also shed light on the access to more accurate SNV identification in the future.

First Generation Korean American Parents’ Perceptions of Discipline

PubMed Central

Kim, Eunjung; Hong, Seunghye

2007-01-01

Nurses not only need to be familiar with the professional guidelines of discipline and but also be aware of variances in styles of acceptable discipline across cultural groups. The goal of this study was to explore cultural influences in relation to (1) first generation Korean American parents’ perceptions of common discipline strategies in the United States and (2) discipline strategies commonly used among first generation Korean American parents. Inductive content analysis was used to analyze interview data from seven first generation Korean American parents. Derived themes indicated that parents considered spanking/hitting and less hugging/kissing as Korean style and time out, using a sticker chart, hugging/kissing, removing/adding privileges, and giving chores as American style. Recent immigrant parents were not familiar with common positive discipline strategies in the United States. As they adapted to the mainstream society, they discontinued what they perceived to be negative aspects of Korean style and adopted positive aspects of American style. They were sensitive to children’s views on discipline and they experienced communication difficulties with children. These findings indicated that Korean American parents’ perceptions on discipline strategies were shaped by living in two cultures and were different from the western viewpoints. PMID:17292135

First-generation Korean-American parents' perceptions of discipline.

PubMed

Kim, Eunjung; Hong, Seunghye

2007-01-01

Nurses not only need to be familiar with professional guidelines of discipline and but also need to be aware of variances in styles of acceptable discipline across cultural groups. The goal of this study was to explore cultural influences in relation to (1) first-generation Korean-American parents' perceptions of common discipline strategies in the United States, and (2) discipline strategies commonly used among first-generation Korean-American parents. Inductive content analysis was used to analyze interview data from seven first-generation Korean-American parents. Derived themes indicated that parents considered spanking/hitting and less hugging/kissing as Korean style, and time-out, use of sticker charts, hugging/kissing, removing/adding privileges, and giving chores as American style. Recent immigrant parents were not familiar with common positive discipline strategies in the United States. As they adapted to mainstream society, they discontinued what they perceived to be negative aspects of Korean style and adopted positive aspects of American style. They were sensitive to children's views on discipline, and they experienced communication difficulties with children. These findings indicated that Korean-American parents' perceptions of discipline strategies were shaped by living in two cultures and were different from western viewpoints.

Improving pairwise comparison of protein sequences with domain co-occurrence

PubMed Central

Gascuel, Olivier

2018-01-01

Comparing and aligning protein sequences is an essential task in bioinformatics. More specifically, local alignment tools like BLAST are widely used for identifying conserved protein sub-sequences, which likely correspond to protein domains or functional motifs. However, to limit the number of false positives, these tools are used with stringent sequence-similarity thresholds and hence can miss several hits, especially for species that are phylogenetically distant from reference organisms. A solution to this problem is then to integrate additional contextual information to the procedure. Here, we propose to use domain co-occurrence to increase the sensitivity of pairwise sequence comparisons. Domain co-occurrence is a strong feature of proteins, since most protein domains tend to appear with a limited number of other domains on the same protein. We propose a method to take this information into account in a typical BLAST analysis and to construct new domain families on the basis of these results. We used Plasmodium falciparum as a case study to evaluate our method. The experimental findings showed an increase of 14% of the number of significant BLAST hits and an increase of 25% of the proteome area that can be covered with a domain. Our method identified 2240 new domains for which, in most cases, no model of the Pfam database could be linked. Moreover, our study of the quality of the new domains in terms of alignment and physicochemical properties show that they are close to that of standard Pfam domains. Source code of the proposed approach and supplementary data are available at: https://gite.lirmm.fr/menichelli/pairwise-comparison-with-cooccurrence PMID:29293498

From benchmarking HITS-CLIP peak detection programs to a new method for identification of miRNA-binding sites from Ago2-CLIP data.

PubMed

Bottini, Silvia; Hamouda-Tekaya, Nedra; Tanasa, Bogdan; Zaragosi, Laure-Emmanuelle; Grandjean, Valerie; Repetto, Emanuela; Trabucchi, Michele

2017-05-19

Experimental evidence indicates that about 60% of miRNA-binding activity does not follow the canonical rule about the seed matching between miRNA and target mRNAs, but rather a non-canonical miRNA targeting activity outside the seed or with a seed-like motifs. Here, we propose a new unbiased method to identify canonical and non-canonical miRNA-binding sites from peaks identified by Ago2 Cross-Linked ImmunoPrecipitation associated to high-throughput sequencing (CLIP-seq). Since the quality of peaks is of pivotal importance for the final output of the proposed method, we provide a comprehensive benchmarking of four peak detection programs, namely CIMS, PIPE-CLIP, Piranha and Pyicoclip, on four publicly available Ago2-HITS-CLIP datasets and one unpublished in-house Ago2-dataset in stem cells. We measured the sensitivity, the specificity and the position accuracy toward miRNA binding sites identification, and the agreement with TargetScan. Secondly, we developed a new pipeline, called miRBShunter, to identify canonical and non-canonical miRNA-binding sites based on de novo motif identification from Ago2 peaks and prediction of miRNA::RNA heteroduplexes. miRBShunter was tested and experimentally validated on the in-house Ago2-dataset and on an Ago2-PAR-CLIP dataset in human stem cells. Overall, we provide guidelines to choose a suitable peak detection program and a new method for miRNA-target identification. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

From benchmarking HITS-CLIP peak detection programs to a new method for identification of miRNA-binding sites from Ago2-CLIP data

PubMed Central

Bottini, Silvia; Hamouda-Tekaya, Nedra; Tanasa, Bogdan; Zaragosi, Laure-Emmanuelle; Grandjean, Valerie; Repetto, Emanuela

2017-01-01

Abstract Experimental evidence indicates that about 60% of miRNA-binding activity does not follow the canonical rule about the seed matching between miRNA and target mRNAs, but rather a non-canonical miRNA targeting activity outside the seed or with a seed-like motifs. Here, we propose a new unbiased method to identify canonical and non-canonical miRNA-binding sites from peaks identified by Ago2 Cross-Linked ImmunoPrecipitation associated to high-throughput sequencing (CLIP-seq). Since the quality of peaks is of pivotal importance for the final output of the proposed method, we provide a comprehensive benchmarking of four peak detection programs, namely CIMS, PIPE-CLIP, Piranha and Pyicoclip, on four publicly available Ago2-HITS-CLIP datasets and one unpublished in-house Ago2-dataset in stem cells. We measured the sensitivity, the specificity and the position accuracy toward miRNA binding sites identification, and the agreement with TargetScan. Secondly, we developed a new pipeline, called miRBShunter, to identify canonical and non-canonical miRNA-binding sites based on de novo motif identification from Ago2 peaks and prediction of miRNA::RNA heteroduplexes. miRBShunter was tested and experimentally validated on the in-house Ago2-dataset and on an Ago2-PAR-CLIP dataset in human stem cells. Overall, we provide guidelines to choose a suitable peak detection program and a new method for miRNA-target identification. PMID:28108660

Target size matters: target errors contribute to the generalization of implicit visuomotor learning.

PubMed

Reichenthal, Maayan; Avraham, Guy; Karniel, Amir; Shmuelof, Lior

2016-08-01

The process of sensorimotor adaptation is considered to be driven by errors. While sensory prediction errors, defined as the difference between the planned and the actual movement of the cursor, drive implicit learning processes, target errors (e.g., the distance of the cursor from the target) are thought to drive explicit learning mechanisms. This distinction was mainly studied in the context of arm reaching tasks where the position and the size of the target were constant. We hypothesize that in a dynamic reaching environment, where subjects have to hit moving targets and the targets' dynamic characteristics affect task success, implicit processes will benefit from target errors as well. We examine the effect of target errors on learning of an unnoticed perturbation during unconstrained reaching movements. Subjects played a Pong game, in which they had to hit a moving ball by moving a paddle controlled by their hand. During the game, the movement of the paddle was gradually rotated with respect to the hand, reaching a final rotation of 25°. Subjects were assigned to one of two groups: The high-target error group played the Pong with a small ball, and the low-target error group played with a big ball. Before and after the Pong game, subjects performed open-loop reaching movements toward static targets with no visual feedback. While both groups adapted to the rotation, the postrotation reaching movements were directionally biased only in the small-ball group. This result provides evidence that implicit adaptation is sensitive to target errors. Copyright © 2016 the American Physiological Society.

Evaluation of a human neurite growth assay as specific screen for developmental neurotoxicants.

PubMed

Krug, Anne K; Balmer, Nina V; Matt, Florian; Schönenberger, Felix; Merhof, Dorit; Leist, Marcel

2013-12-01

Organ-specific in vitro toxicity assays are often highly sensitive, but they lack specificity. We evaluated here examples of assay features that can affect test specificity, and some general procedures are suggested on how positive hits in complex biological assays may be defined. Differentiating human LUHMES cells were used as potential model for developmental neurotoxicity testing. Forty candidate toxicants were screened, and several hits were obtained and confirmed. Although the cells had a definitive neuronal phenotype, the use of a general cell death endpoint in these cultures did not allow specific identification of neurotoxicants. As alternative approach, neurite growth was measured as an organ-specific functional endpoint. We found that neurite extension of developing LUHMES was specifically inhibited by diverse compounds such as colchicine, vincristine, narciclasine, rotenone, cycloheximide, or diquat. These compounds reduced neurite growth at concentrations that did not compromise cell viability, and neurite growth was affected more potently than the integrity of developed neurites of mature neurons. A ratio of the EC50 values of neurite growth inhibition and cell death of >4 provided a robust classifier for compounds associated with a developmental neurotoxic hazard. Screening of unspecific toxicants in the test system always yielded ratios <4. The assay identified also compounds that accelerated neurite growth, such as the rho kinase pathway modifiers blebbistatin or thiazovivin. The negative effects of colchicine or rotenone were completely inhibited by a rho kinase inhibitor. In summary, we suggest that assays using functional endpoints (neurite growth) can specifically identify and characterize (developmental) neurotoxicants.

Immunoglobulin A Nephropathy: Advances in Understanding of Pathogenesis and Treatment.

PubMed

Lafayette, Richard A; Kelepouris, Ellie

2018-05-31

Immunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis and has clinical associations with a wide range of inflammatory and infectious diseases. There is a substantial variation in clinical course and outcomes, with many patients not diagnosed until they present with sequelae, which may include gross hematuria, hypertension, renal insufficiency, and/or significant proteinuria. Treatment options are currently limited and directed mainly toward control of these sequelae and have limited ability to reduce the incidence of end-stage renal disease or treat the primary IgA defect. Growing knowledge about the pathogenesis of IgA nephropathy and research into its genetic basis are helping to elucidate the course of this widely variable disease. IgA accumulation in the kidneys is thought to be the result of a number of different pathways in a "multi-hit" process that includes an initial traumatic trigger (often infection related) and subsequent memory responses that are amplified in those with a genetic predisposition to the disease and lead to an inflammatory response in susceptible individuals. Genome-wide association studies are providing new insights into the genetic variance of this autoimmune disease and are yielding information that may address both its causes and consequences. Key Messages: New treatment approaches are urgently required for the management of patients with IgA nephropathy. Novel interventions based around its inflammatory nature and "multi-hit" pathogenesis are being investigated to potentially limit disease progression. © 2018 S. Karger AG, Basel.

Masticatory mechanosensitivity, mouth opening and impact of headache in subjects with a history of orthodontics use: a cross-sectional study.

PubMed

Heredia-Rizo, A M; Rodríguez-Blanco, C; Oliva-Pascual-Vaca, Á; Torres-Lagares, D; Albornoz-Cabello, M; Piña-Pozo, F; Luque-Carrasco, A

2014-08-01

The correlation between orthodontics and the development of signs and symptoms of temporomandibular disorders (TMD) is a major concern in the physical rehabilitation field. The aim of the study was to observe whether subjects with a history of orthodontics use show differences from subjects who have never used orthodontics in: 1) masseter and temporalis muscle mechanosensitivity; 2) maximal vertical mouth opening (VMO); and 3) the impact of headache on their quality of life. Cross-sectional study. The study was carried out in the Faculty of Nursing, Physiotherapy and Podiatry of the University of Sevilla, Spain. All participants were pre graduate students from the University of Sevilla, Spain. The final sample comprised 65 subjects (N.=65) with a mean age of 21 ± 2.46 years (18-29) divided into two groups; orthodontics group (N.=31) and non-orthodontics group (N.=34). All students followed the same testing protocol. Measurements were taken of the pressure pain threshold (PPT) in two locations of the masseter (M1, M2) and temporalis (T1, T2) muscles, the maximal VMO, and the incidence of headache (Headache Impact Test-6; HIT-6, Spanish version). The measured values of the masticatory muscle PPTs were lower in the non-orthodontics group. Besides, the maximal VMO and HIT-6 scores were better in the orthodontics group. Nevertheless, none of these intergroup differences were statistically significant (ANOVA test): (M1 P=0.790); (M2 P=0.329); (T1 P=0.249); (T2 P=0.440); (HIT-6 P=0.443); (VMO P=0.626). A previous history of orthodontics use does not seem to lead to any greater sensitivity of the masticatory muscles, limitations of vertical mouth opening, or greater impact of headache on the subject's quality of life. There is no evidence enough to support either a positive or negative correlation between orthodontics and signs and symptoms of TMD. Pain is a subjective perception and it is influenced by several factors. It remains uncertain if the use of orthodontics might be one of them.

Multi-class biological tissue classification based on a multi-classifier: Preliminary study of an automatic output power control for ultrasonic surgical units.

PubMed

Youn, Su Hyun; Sim, Taeyong; Choi, Ahnryul; Song, Jinsung; Shin, Ki Young; Lee, Il Kwon; Heo, Hyun Mu; Lee, Daeweon; Mun, Joung Hwan

2015-06-01

Ultrasonic surgical units (USUs) have the advantage of minimizing tissue damage during surgeries that require tissue dissection by reducing problems such as coagulation and unwanted carbonization, but the disadvantage of requiring manual adjustment of power output according to the target tissue. In order to overcome this limitation, it is necessary to determine the properties of in vivo tissues automatically. We propose a multi-classifier that can accurately classify tissues based on the unique impedance of each tissue. For this purpose, a multi-classifier was built based on single classifiers with high classification rates, and the classification accuracy of the proposed model was compared with that of single classifiers for various electrode types (Type-I: 6 mm invasive; Type-II: 3 mm invasive; Type-III: surface). The sensitivity and positive predictive value (PPV) of the multi-classifier by cross checks were determined. According to the 10-fold cross validation results, the classification accuracy of the proposed model was significantly higher (p<0.05 or <0.01) than that of existing single classifiers for all electrode types. In particular, the classification accuracy of the proposed model was highest when the 3mm invasive electrode (Type-II) was used (sensitivity=97.33-100.00%; PPV=96.71-100.00%). The results of this study are an important contribution to achieving automatic optimal output power adjustment of USUs according to the properties of individual tissues. Copyright © 2015 Elsevier Ltd. All rights reserved.

Multi-site evaluation of the LN34 pan-lyssavirus real-time RT-PCR assay for post-mortem rabies diagnostics

PubMed Central

Dettinger, Lisa; Powell, James W.; Seiders, Melanie; Condori, Rene Edgar Condori; Griesser, Richard; Okogi, Kenneth; Carlos, Maria; Pesko, Kendra; Breckenridge, Mike; Simon, Edson Michael M.; Chu, Maria Yna Joyce V.; Davis, April D.; Brunt, Scott J.; Orciari, Lillian; Yager, Pamela; Carson, William C.; Hartloge, Claire; Saliki, Jeremiah T.; Deldari, Mojgan; Hsieh, Kristina; Wadhwa, Ashutosh; Wilkins, Kimberly; Rabideau, Patricia; Gruhn, Nina; Cadet, Rolain; Isloor, Shrikrishna; Nath, Sujith S.; Joseph, Tomy; Gao, Jinxin; Wallace, Ryan; Reynolds, Mary; Olson, Victoria A.

2018-01-01

Rabies is a fatal zoonotic disease that requires fast, accurate diagnosis to prevent disease in an exposed individual. The current gold standard for post-mortem diagnosis of human and animal rabies is the direct fluorescent antibody (DFA) test. While the DFA test has proven sensitive and reliable, it requires high quality antibody conjugates, a skilled technician, a fluorescence microscope and diagnostic specimen of sufficient quality. The LN34 pan-lyssavirus real-time RT-PCR assay represents a strong candidate for rabies post-mortem diagnostics due to its ability to detect RNA across the diverse Lyssavirus genus, its high sensitivity, its potential for use with deteriorated tissues, and its simple, easy to implement design. Here, we present data from a multi-site evaluation of the LN34 assay in 14 laboratories. A total of 2,978 samples (1,049 DFA positive) from Africa, the Americas, Asia, Europe, and the Middle East were tested. The LN34 assay exhibited low variability in repeatability and reproducibility studies and was capable of detecting viral RNA in fresh, frozen, archived, deteriorated and formalin-fixed brain tissue. The LN34 assay displayed high diagnostic specificity (99.68%) and sensitivity (99.90%) when compared to the DFA test, and no DFA positive samples were negative by the LN34 assay. The LN34 assay produced definitive findings for 80 samples that were inconclusive or untestable by DFA; 29 were positive. Five samples were inconclusive by the LN34 assay, and only one sample was inconclusive by both tests. Furthermore, use of the LN34 assay led to the identification of one false negative and 11 false positive DFA results. Together, these results demonstrate the reliability and robustness of the LN34 assay and support a role for the LN34 assay in improving rabies diagnostics and surveillance. PMID:29768505

Stochastic von Bertalanffy models, with applications to fish recruitment.

PubMed

Lv, Qiming; Pitchford, Jonathan W

2007-02-21

We consider three individual-based models describing growth in stochastic environments. Stochastic differential equations (SDEs) with identical von Bertalanffy deterministic parts are formulated, with a stochastic term which decreases, remains constant, or increases with organism size, respectively. Probability density functions for hitting times are evaluated in the context of fish growth and mortality. Solving the hitting time problem analytically or numerically shows that stochasticity can have a large positive impact on fish recruitment probability. It is also demonstrated that the observed mean growth rate of surviving individuals always exceeds the mean population growth rate, which itself exceeds the growth rate of the equivalent deterministic model. The consequences of these results in more general biological situations are discussed.

An investigation of the 'von Restorff' phenomenon in post-test workload ratings

NASA Technical Reports Server (NTRS)

Thornton, D. C.

1985-01-01

The von Restorff effect in post-task ratings of task difficulty is examined. Nine subjects performed a hovercraft simulation task which combined elements of skill-based tracking and rule- and knowledge-based process control for five days of one hour sessions. The effects of isolated increases in workload on rating of task performance, and on the number of command errors and river band hits are analyzed. It is observed that the position of the workload increase affects the number of bank hits and command errors. The data reveal that factors not directly related to the task performance influence subjective rating, and post-task ratings of workload are biased.

Inhibitors of acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). Part 1: Hit to lead evaluation of a novel arylsulfonamide series.

PubMed

Green, Oluyinka M; McKenzie, Andrew R; Shapiro, Adam B; Otterbein, Ludovic; Ni, Haihong; Patten, Arthur; Stokes, Suzanne; Albert, Robert; Kawatkar, Sameer; Breed, Jason

2012-02-15

A novel arylsulfonamide-containing series of compounds represented by 1, discovered by highthroughput screening, inhibit the acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). X-ray structure determination confirmed that inhibitor binds at the site occupied by acetyl-CoA, indicating that series is competitive with this substrate. This letter documents our early hit-to-lead evaluation of the chemical series and some of the findings that led to improvement in in-vitro potency against Gram-negative and Gram-positive bacterial isozymes, exemplified by compound 40. Copyright © 2012 Elsevier Ltd. All rights reserved.

Brightness and uniformity measurements of plastic scintillator tiles at the CERN H2 test beam

NASA Astrophysics Data System (ADS)

Chatrchyan, S.; Sirunyan, A. M.; Tumasyan, A.; Litomin, A.; Mossolov, V.; Shumeiko, N.; Van De Klundert, M.; Van Haevermaet, H.; Van Mechelen, P.; Van Spilbeeck, A.; Alves, G. A.; Aldá Júnior, W. L.; Hensel, C.; Carvalho, W.; Chinellato, J.; De Oliveira Martins, C.; Matos Figueiredo, D.; Mora Herrera, C.; Nogima, H.; Prado Da Silva, W. L.; Tonelli Manganote, E. J.; Vilela Pereira, A.; Finger, M.; Finger, M., Jr.; Kveton, A.; Tomsa, J.; Adamov, G.; Tsamalaidze, Z.; Behrens, U.; Borras, K.; Campbell, A.; Costanza, F.; Gunnellini, P.; Lobanov, A.; Melzer-Pellmann, I.-A.; Muhl, C.; Roland, B.; Sahin, M.; Saxena, P.; Hegde, V.; Kothekar, K.; Pandey, S.; Sharma, S.; Beri, S. B.; Bhawandeep, B.; Chawla, R.; Kalsi, A.; Kaur, A.; Kaur, M.; Walia, G.; Bhattacharya, S.; Ghosh, S.; Nandan, S.; Purohit, A.; Sharan, M.; Banerjee, S.; Bhattacharya, S.; Chatterjee, S.; Das, P.; Guchait, M.; Jain, S.; Kumar, S.; Maity, M.; Majumder, G.; Mazumdar, K.; Patil, M.; Sarkar, T.; Juodagalvis, A.; Afanasiev, S.; Bunin, P.; Ershov, Y.; Golutvin, I.; Malakhov, A.; Moisenz, P.; Smirnov, V.; Zarubin, A.; Chadeeva, M.; Chistov, R.; Danilov, M.; Popova, E.; Rusinov, V.; Andreev, Yu.; Dermenev, A.; Karneyeu, A.; Krasnikov, N.; Tlisov, D.; Toropin, A.; Epshteyn, V.; Gavrilov, V.; Lychkovskaya, N.; Popov, V.; Pozdnyakov, I.; Safronov, G.; Toms, M.; Zhokin, A.; Baskakov, A.; Belyaev, A.; Boos, E.; Dubinin, M.; Dudko, L.; Ershov, A.; Gribushin, A.; Kaminskiy, A.; Klyukhin, V.; Kodolova, O.; Lokhtin, I.; Miagkov, I.; Obraztsov, S.; Petrushanko, S.; Savrin, V.; Snigirev, A.; Andreev, V.; Azarkin, M.; Dremin, I.; Kirakosyan, M.; Leonidov, A.; Terkulov, A.; Bitioukov, S.; Elumakhov, D.; Kalinin, A.; Krychkine, V.; Mandrik, P.; Petrov, V.; Ryutin, R.; Sobol, A.; Troshin, S.; Volkov, A.; Sekmen, S.; Medvedeva, T.; Rumerio, P.; Adiguzel, A.; Bakirci, N.; Boran, F.; Cerci, S.; Damarseckin, S.; Demiroglu, Z. S.; Dölek, F.; Dozen, C.; Dumanoglu, I.; Eskut, E.; Girgis, S.; Gokbulut, G.; Guler, Y.; Hos, I.; Kangal, E. E.; Kara, O.; Kayis Topaksu, A.; Işik, C.; Kiminsu, U.; Oglakci, M.; Onengut, G.; Ozdemir, K.; Ozturk, S.; Polatoz, A.; Sunar Cerci, D.; Tali, B.; Tok, U. G.; Topakli, H.; Turkcapar, S.; Zorbakir, I. S.; Zorbilmez, C.; Bilin, B.; Isildak, B.; Karapinar, G.; Murat Guler, A.; Ocalan, K.; Yalvac, M.; Zeyrek, M.; Atakisi, I. O.; Gülmez, E.; Kaya, M.; Kaya, O.; Koseyan, O. K.; Ozcelik, O.; Ozkorucuklu, S.; Tekten, S.; Yetkin, E. A.; Yetkin, T.; Cankocak, K.; Sen, S.; Boyarintsev, A.; Grynyov, B.; Levchuk, L.; Popov, V.; Sorokin, P.; Flacher, H.; Borzou, A.; Call, K.; Dittmann, J.; Hatakeyama, K.; Liu, H.; Pastika, N.; Buccilli, A.; Cooper, S. I.; Henderson, C.; West, C.; Arcaro, D.; Gastler, D.; Hazen, E.; Rohlf, J.; Sulak, L.; Wu, S.; Zou, D.; Hakala, J.; Heintz, U.; Kwok, K. H. M.; Laird, E.; Landsberg, G.; Mao, Z.; Yu, D. R.; Gary, J. W.; Ghiasi Shirazi, S. M.; Lacroix, F.; Long, O. R.; Wei, H.; Bhandari, R.; Heller, R.; Stuart, D.; Yoo, J. H.; Chen, Y.; Duarte, J.; Lawhorn, J. M.; Nguyen, T.; Spiropulu, M.; Winn, D.; Abdullin, S.; Apresyan, A.; Apyan, A.; Banerjee, S.; Chlebana, F.; Freeman, J.; Green, D.; Hare, D.; Hirschauer, J.; Joshi, U.; Lincoln, D.; Los, S.; Pedro, K.; Spalding, W. J.; Strobbe, N.; Tkaczyk, S.; Whitbeck, A.; Linn, S.; Markowitz, P.; Martinez, G.; Bertoldi, M.; Hagopian, S.; Hagopian, V.; Kolberg, T.; Baarmand, M. M.; Noonan, D.; Roy, T.; Yumiceva, F.; Bilki, B.; Clarida, W.; Debbins, P.; Dilsiz, K.; Durgut, S.; Gandrajula, R. P.; Haytmyradov, M.; Khristenko, V.; Merlo, J.-P.; Mermerkaya, H.; Mestvirishvili, A.; Miller, M.; Moeller, A.; Nachtman, J.; Ogul, H.; Onel, Y.; Ozok, F.; Penzo, A.; Schmidt, I.; Snyder, C.; Southwick, D.; Tiras, E.; Yi, K.; Al-bataineh, A.; Bowen, J.; Castle, J.; McBrayer, W.; Murray, M.; Wang, Q.; Kaadze, K.; Maravin, Y.; Mohammadi, A.; Saini, L. K.; Baden, A.; Belloni, A.; Calderon, J. D.; Eno, S. C.; Feng, Y. B.; Ferraioli, C.; Grassi, T.; Hadley, N. J.; Jeng, G.-Y.; Kellogg, R. G.; Kunkle, J.; Mignerey, A.; Ricci-Tam, F.; Shin, Y. H.; Skuja, A.; Yang, Z. S.; Yao, Y.; Brandt, S.; D'Alfonso, M.; Hu, M.; Klute, M.; Niu, X.; Chatterjee, R. M.; Evans, A.; Frahm, E.; Kubota, Y.; Lesko, Z.; Mans, J.; Ruckstuhl, N.; Heering, A.; Karmgard, D. J.; Musienko, Y.; Ruchti, R.; Wayne, M.; Benaglia, A. D.; Mei, K.; Tully, C.; Bodek, A.; de Barbaro, P.; Galanti, M.; Garcia-Bellido, A.; Khukhunaishvili, A.; Lo, K. H.; Vishnevskiy, D.; Zielinski, M.; Agapitos, A.; Amouzegar, M.; Chou, J. P.; Hughes, E.; Saka, H.; Sheffield, D.; Akchurin, N.; Damgov, J.; De Guio, F.; Dudero, P. R.; Faulkner, J.; Gurpinar, E.; Kunori, S.; Lamichhane, K.; Lee, S. W.; Libeiro, T.; Mengke, T.; Muthumuni, S.; Undleeb, S.; Volobouev, I.; Wang, Z.; Goadhouse, S.; Hirosky, R.; Wang, Y.

2018-01-01

We study the light output, light collection efficiency and signal timing of a variety of organic scintillators that are being considered for the upgrade of the hadronic calorimeter of the CMS detector. The experimental data are collected at the H2 test-beam area at CERN, using a 150 GeV muon beam. In particular, we investigate the usage of over-doped and green-emitting plastic scintillators, two solutions that have not been extensively considered. We present a study of the energy distribution in plastic-scintillator tiles, the hit efficiency as a function of the hit position, and a study of the signal timing for blue and green scintillators.

Power of Orbitrap-based LC-high resolution-MS/MS for comprehensive drug testing in urine with or without conjugate cleavage or using dried urine spots after on-spot cleavage in comparison to established LC-MSn or GC-MS procedures.

PubMed

Michely, Julian A; Meyer, Markus R; Maurer, Hans H

2018-01-01

Reliable, sensitive, and comprehensive urine screening procedures by gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS) with low or high resolution (HR) are of high importance for drug testing, adherence monitoring, or detection of toxic compounds. Besides conventional urine sampling, dried urine spots are of increasing interest. In the present study, the power of LC-HR-MS/MS was investigated for comprehensive drug testing in urine with or without conjugate cleavage or using dried urine spots after on-spot cleavage in comparison to established LC-MS n or GC-MS procedures. Authentic human urine samples (n = 103) were split in 4 parts. One aliquot was prepared by precipitation (UP), one by UP with conjugate cleavage (UglucP), one spot on filter paper cards and prepared by on-spot cleavage followed by liquid extraction (DUSglucE), and one worked-up by acid hydrolysis, liquid-liquid extraction, and acetylation for GC-MS analysis. The 3 series of LC-HR-MS/MS results were compared among themselves, to corresponding published LC-MS n data, and to screening results obtained by conventional GC-MS. The reference libraries used for the 3 techniques contained over 4500 spectra of parent compounds and their metabolites. The number of all detected hits (770 drug intakes) was set to 100%. The LC-HR-MS/MS approach detected 80% of the hits after UP, 89% after UglucP, and 77% after DUSglucE, which meant over one-third more hits in comparison to the corresponding published LC-MS n results with ≤49% detected hits. The GC-MS approach identified 56% of all detected hits. In conclusion, LC-HR-MS/MS provided the best screening results after conjugate cleavage and precipitation. Copyright © 2017 John Wiley & Sons, Ltd.

Confocal nanoscanning, bead picking (CONA): PickoScreen microscopes for automated and quantitative screening of one-bead one-compound libraries.

PubMed

Hintersteiner, Martin; Buehler, Christof; Uhl, Volker; Schmied, Mario; Müller, Jürgen; Kottig, Karsten; Auer, Manfred

2009-01-01

Solid phase combinatorial chemistry provides fast and cost-effective access to large bead based libraries with compound numbers easily exceeding tens of thousands of compounds. Incubating one-bead one-compound library beads with fluorescently labeled target proteins and identifying and isolating the beads which contain a bound target protein, potentially represents one of the most powerful generic primary high throughput screening formats. On-bead screening (OBS) based on this detection principle can be carried out with limited automation. Often hit bead detection, i.e. recognizing beads with a fluorescently labeled protein bound to the compound on the bead, relies on eye-inspection under a wide-field microscope. Using low resolution detection techniques, the identification of hit beads and their ranking is limited by a low fluorescence signal intensity and varying levels of the library beads' autofluorescence. To exploit the full potential of an OBS process, reliable methods for both automated quantitative detection of hit beads and their subsequent isolation are needed. In a joint collaborative effort with Evotec Technologies (now Perkin-Elmer Cellular Technologies Germany GmbH), we have built two confocal bead scanner and picker platforms PS02 and a high-speed variant PS04 dedicated to automated high resolution OBS. The PS0X instruments combine fully automated confocal large area scanning of a bead monolayer at the bottom of standard MTP plates with semiautomated isolation of individual hit beads via hydraulic-driven picker capillaries. The quantification of fluorescence intensities with high spatial resolution in the equatorial plane of each bead allows for a reliable discrimination between entirely bright autofluorescent beads and real hit beads which exhibit an increased fluorescence signal at the outer few micrometers of the bead. The achieved screening speed of up to 200,000 bead assayed in less than 7 h and the picking time of approximately 1 bead/min allow exploitation of one-bead one-compound libraries with high sensitivity, accuracy, and speed.

Prospects for observing and localizing gravitational-wave transients with Advanced LIGO, Advanced Virgo and KAGRA

NASA Astrophysics Data System (ADS)

Abbott, B. P.; Abbott, R.; Abbott, T. D.; Abernathy, M. R.; Acernese, F.; Ackley, K.; Adams, C.; Adams, T.; Addesso, P.; Adhikari, R. X.; Adya, V. B.; Affeldt, C.; Agathos, M.; Agatsuma, K.; Aggarwal, N.; Aguiar, O. D.; Aiello, L.; Ain, A.; Ajith, P.; Akutsu, T.; Allen, B.; Allocca, A.; Altin, P. A.; Ananyeva, A.; Anderson, S. B.; Anderson, W. G.; Ando, M.; Appert, S.; Arai, K.; Araya, A.; Araya, M. C.; Areeda, J. S.; Arnaud, N.; Arun, K. G.; Asada, H.; Ascenzi, S.; Ashton, G.; Aso, Y.; Ast, M.; Aston, S. M.; Astone, P.; Atsuta, S.; Aufmuth, P.; Aulbert, C.; Avila-Alvarez, A.; Awai, K.; Babak, S.; Bacon, P.; Bader, M. K. M.; Baiotti, L.; Baker, P. T.; Baldaccini, F.; Ballardin, G.; Ballmer, S. W.; Barayoga, J. C.; Barclay, S. E.; Barish, B. C.; Barker, D.; Barone, F.; Barr, B.; Barsotti, L.; Barsuglia, M.; Barta, D.; Bartlett, J.; Barton, M. A.; Bartos, I.; Bassiri, R.; Basti, A.; Batch, J. C.; Baune, C.; Bavigadda, V.; Bazzan, M.; Bécsy, B.; Beer, C.; Bejger, M.; Belahcene, I.; Belgin, M.; Bell, A. S.; Berger, B. K.; Bergmann, G.; Berry, C. P. L.; Bersanetti, D.; Bertolini, A.; Betzwieser, J.; Bhagwat, S.; Bhandare, R.; Bilenko, I. A.; Billingsley, G.; Billman, C. R.; Birch, J.; Birney, R.; Birnholtz, O.; Biscans, S.; Bisht, A.; Bitossi, M.; Biwer, C.; Bizouard, M. A.; Blackburn, J. K.; Blackman, J.; Blair, C. D.; Blair, D. G.; Blair, R. M.; Bloemen, S.; Bock, O.; Boer, M.; Bogaert, G.; Bohe, A.; Bondu, F.; Bonnand, R.; Boom, B. A.; Bork, R.; Boschi, V.; Bose, S.; Bouffanais, Y.; Bozzi, A.; Bradaschia, C.; Brady, P. R.; Braginsky, V. B.; Branchesi, M.; Brau, J. E.; Briant, T.; Brillet, A.; Brinkmann, M.; Brisson, V.; Brockill, P.; Broida, J. E.; Brooks, A. F.; Brown, D. A.; Brown, D. D.; Brown, N. M.; Brunett, S.; Buchanan, C. C.; Buikema, A.; Bulik, T.; Bulten, H. J.; Buonanno, A.; Buskulic, D.; Buy, C.; Byer, R. L.; Cabero, M.; Cadonati, L.; Cagnoli, G.; Cahillane, C.; Calderón Bustillo, J.; Callister, T. A.; Calloni, E.; Camp, J. B.; Cannon, K. C.; Cao, H.; Cao, J.; Capano, C. D.; Capocasa, E.; Carbognani, F.; Caride, S.; Casanueva Diaz, J.; Casentini, C.; Caudill, S.; Cavaglià, M.; Cavalier, F.; Cavalieri, R.; Cella, G.; Cepeda, C. B.; Cerboni Baiardi, L.; Cerretani, G.; Cesarini, E.; Chamberlin, S. J.; Chan, M.; Chao, S.; Charlton, P.; Chassande-Mottin, E.; Cheeseboro, B. D.; Chen, H. Y.; Chen, Y.; Cheng, H.-P.; Chincarini, A.; Chiummo, A.; Chmiel, T.; Cho, H. S.; Cho, M.; Chow, J. H.; Christensen, N.; Chu, Q.; Chua, A. J. K.; Chua, S.; Chung, S.; Ciani, G.; Clara, F.; Clark, J. A.; Cleva, F.; Cocchieri, C.; Coccia, E.; Cohadon, P.-F.; Colla, A.; Collette, C. G.; Cominsky, L.; Constancio, M.; Conti, L.; Cooper, S. J.; Corbitt, T. R.; Cornish, N.; Corsi, A.; Cortese, S.; Costa, C. A.; Coughlin, M. W.; Coughlin, S. B.; Coulon, J.-P.; Countryman, S. T.; Couvares, P.; Covas, P. B.; Cowan, E. E.; Coward, D. M.; Cowart, M. J.; Coyne, D. C.; Coyne, R.; Creighton, J. D. E.; Creighton, T. D.; Cripe, J.; Crowder, S. G.; Cullen, T. J.; Cumming, A.; Cunningham, L.; Cuoco, E.; Canton, T. Dal; Danilishin, S. L.; D'Antonio, S.; Danzmann, K.; Dasgupta, A.; Da Silva Costa, C. F.; Dattilo, V.; Dave, I.; Davier, M.; Davies, G. S.; Davis, D.; Daw, E. J.; Day, B.; Day, R.; De, S.; DeBra, D.; Debreczeni, G.; Degallaix, J.; De Laurentis, M.; Deléglise, S.; Del Pozzo, W.; Denker, T.; Dent, T.; Dergachev, V.; De Rosa, R.; DeRosa, R. T.; DeSalvo, R.; Devine, R. C.; Dhurandhar, S.; Díaz, M. C.; Fiore, L. Di; Giovanni, M. Di; Girolamo, T. Di; Lieto, A. Di; Pace, S. Di; Palma, I. Di; Virgilio, A. Di; Doctor, Z.; Doi, K.; Dolique, V.; Donovan, F.; Dooley, K. L.; Doravari, S.; Dorrington, I.; Douglas, R.; Dovale Álvarez, M.; Downes, T. P.; Drago, M.; Drever, R. W. P.; Driggers, J. C.; Du, Z.; Ducrot, M.; Dwyer, S. E.; Eda, K.; Edo, T. B.; Edwards, M. C.; Effler, A.; Eggenstein, H.-B.; Ehrens, P.; Eichholz, J.; Eikenberry, S. S.; Eisenstein, R. A.; Essick, R. C.; Etienne, Z.; Etzel, T.; Evans, M.; Evans, T. M.; Everett, R.; Factourovich, M.; Fafone, V.; Fair, H.; Fairhurst, S.; Fan, X.; Farinon, S.; Farr, B.; Farr, W. M.; Fauchon-Jones, E. J.; Favata, M.; Fays, M.; Fehrmann, H.; Fejer, M. M.; Fernández Galiana, A.; Ferrante, I.; Ferreira, E. C.; Ferrini, F.; Fidecaro, F.; Fiori, I.; Fiorucci, D.; Fisher, R. P.; Flaminio, R.; Fletcher, M.; Fong, H.; Forsyth, S. S.; Fournier, J.-D.; Frasca, S.; Frasconi, F.; Frei, Z.; Freise, A.; Frey, R.; Frey, V.; Fries, E. M.; Fritschel, P.; Frolov, V. V.; Fujii, Y.; Fujimoto, M.-K.; Fulda, P.; Fyffe, M.; Gabbard, H.; Gadre, B. U.; Gaebel, S. M.; Gair, J. R.; Gammaitoni, L.; Gaonkar, S. G.; Garufi, F.; Gaur, G.; Gayathri, V.; Gehrels, N.; Gemme, G.; Genin, E.; Gennai, A.; George, J.; Gergely, L.; Germain, V.; Ghonge, S.; Ghosh, Abhirup; Ghosh, Archisman; Ghosh, S.; Giaime, J. A.; Giardina, K. D.; Giazotto, A.; Gill, K.; Glaefke, A.; Goetz, E.; Goetz, R.; Gondan, L.; González, G.; Gonzalez Castro, J. M.; Gopakumar, A.; Gorodetsky, M. L.; Gossan, S. E.; Gosselin, M.; Gouaty, R.; Grado, A.; Graef, C.; Granata, M.; Grant, A.; Gras, S.; Gray, C.; Greco, G.; Green, A. C.; Groot, P.; Grote, H.; Grunewald, S.; Guidi, G. M.; Guo, X.; Gupta, A.; Gupta, M. K.; Gushwa, K. E.; Gustafson, E. K.; Gustafson, R.; Hacker, J. J.; Hagiwara, A.; Hall, B. R.; Hall, E. D.; Hammond, G.; Haney, M.; Hanke, M. M.; Hanks, J.; Hanna, C.; Hannam, M. D.; Hanson, J.; Hardwick, T.; Harms, J.; Harry, G. M.; Harry, I. W.; Hart, M. J.; Hartman, M. T.; Haster, C.-J.; Haughian, K.; Hayama, K.; Healy, J.; Heidmann, A.; Heintze, M. C.; Heitmann, H.; Hello, P.; Hemming, G.; Hendry, M.; Heng, I. S.; Hennig, J.; Henry, J.; Heptonstall, A. W.; Heurs, M.; Hild, S.; Hirose, E.; Hoak, D.; Hofman, D.; Holt, K.; Holz, D. E.; Hopkins, P.; Hough, J.; Houston, E. A.; Howell, E. J.; Hu, Y. M.; Huerta, E. A.; Huet, D.; Hughey, B.; Husa, S.; Huttner, S. H.; Huynh-Dinh, T.; Indik, N.; Ingram, D. R.; Inta, R.; Ioka, K.; Isa, H. N.; Isac, J.-M.; Isi, M.; Isogai, T.; Itoh, Y.; Iyer, B. R.; Izumi, K.; Jacqmin, T.; Jani, K.; Jaranowski, P.; Jawahar, S.; Jiménez-Forteza, F.; Johnson, W. W.; Jones, D. I.; Jones, R.; Jonker, R. J. G.; Ju, L.; Junker, J.; Kagawa, T.; Kajita, T.; Kakizaki, M.; Kalaghatgi, C. V.; Kalogera, V.; Kamiizumi, M.; Kanda, N.; Kandhasamy, S.; Kanemura, S.; Kaneyama, M.; Kang, G.; Kanner, J. B.; Karki, S.; Karvinen, K. S.; Kasprzack, M.; Kataoka, Y.; Katsavounidis, E.; Katzman, W.; Kaufer, S.; Kaur, T.; Kawabe, K.; Kawai, N.; Kawamura, S.; Kéfélian, F.; Keitel, D.; Kelley, D. B.; Kennedy, R.; Key, J. S.; Khalili, F. Y.; Khan, I.; Khan, S.; Khan, Z.; Khazanov, E. A.; Kijbunchoo, N.; Kim, C.; Kim, H.; Kim, J. C.; Kim, J.; Kim, W.; Kim, Y.-M.; Kimbrell, S. J.; Kimura, N.; King, E. J.; King, P. J.; Kirchhoff, R.; Kissel, J. S.; Klein, B.; Kleybolte, L.; Klimenko, S.; Koch, P.; Koehlenbeck, S. M.; Kojima, Y.; Kokeyama, K.; Koley, S.; Komori, K.; Kondrashov, V.; Kontos, A.; Korobko, M.; Korth, W. Z.; Kotake, K.; Kowalska, I.; Kozak, D. B.; Krämer, C.; Kringel, V.; Krishnan, B.; Królak, A.; Kuehn, G.; Kumar, P.; Kumar, Rahul; Kumar, Rakesh; Kuo, L.; Kuroda, K.; Kutynia, A.; Kuwahara, Y.; Lackey, B. D.; Landry, M.; Lang, R. N.; Lange, J.; Lantz, B.; Lanza, R. K.; Lartaux-Vollard, A.; Lasky, P. D.; Laxen, M.; Lazzarini, A.; Lazzaro, C.; Leaci, P.; Leavey, S.; Lebigot, E. O.; Lee, C. H.; Lee, H. K.; Lee, H. M.; Lee, H. W.; Lee, K.; Lehmann, J.; Lenon, A.; Leonardi, M.; Leong, J. R.; Leroy, N.; Letendre, N.; Levin, Y.; Li, T. G. F.; Libson, A.; Littenberg, T. B.; Liu, J.; Lockerbie, N. A.; Lombardi, A. L.; London, L. T.; Lord, J. E.; Lorenzini, M.; Loriette, V.; Lormand, M.; Losurdo, G.; Lough, J. D.; Lousto, C. O.; Lovelace, G.; Lück, H.; Lundgren, A. P.; Lynch, R.; Ma, Y.; Macfoy, S.; Machenschalk, B.; MacInnis, M.; Macleod, D. M.; Magaña-Sandoval, F.; Majorana, E.; Maksimovic, I.; Malvezzi, V.; Man, N.; Mandic, V.; Mangano, V.; Mano, S.; Mansell, G. L.; Manske, M.; Mantovani, M.; Marchesoni, F.; Marchio, M.; Marion, F.; Márka, S.; Márka, Z.; Markosyan, A. S.; Maros, E.; Martelli, F.; Martellini, L.; Martin, I. W.; Martynov, D. V.; Mason, K.; Masserot, A.; Massinger, T. J.; Masso-Reid, M.; Mastrogiovanni, S.; Matichard, F.; Matone, L.; Matsumoto, N.; Matsushima, F.; Mavalvala, N.; Mazumder, N.; McCarthy, R.; McClelland, D. E.; McCormick, S.; McGrath, C.; McGuire, S. C.; McIntyre, G.; McIver, J.; McManus, D. J.; McRae, T.; McWilliams, S. T.; Meacher, D.; Meadors, G. D.; Meidam, J.; Melatos, A.; Mendell, G.; Mendoza-Gandara, D.; Mercer, R. A.; Merilh, E. L.; Merzougui, M.; Meshkov, S.; Messenger, C.; Messick, C.; Metzdorff, R.; Meyers, P. M.; Mezzani, F.; Miao, H.; Michel, C.; Michimura, Y.; Middleton, H.; Mikhailov, E. E.; Milano, L.; Miller, A. L.; Miller, A.; Miller, B. B.; Miller, J.; Millhouse, M.; Minenkov, Y.; Ming, J.; Mirshekari, S.; Mishra, C.; Mitrofanov, V. P.; Mitselmakher, G.; Mittleman, R.; Miyakawa, O.; Miyamoto, A.; Miyamoto, T.; Miyoki, S.; Moggi, A.; Mohan, M.; Mohapatra, S. R. P.; Montani, M.; Moore, B. C.; Moore, C. J.; Moraru, D.; Moreno, G.; Morii, W.; Morisaki, S.; Moriwaki, Y.; Morriss, S. R.; Mours, B.; Mow-Lowry, C. M.; Mueller, G.; Muir, A. W.; Mukherjee, Arunava; Mukherjee, D.; Mukherjee, S.; Mukund, N.; Mullavey, A.; Munch, J.; Muniz, E. A. M.; Murray, P. G.; Mytidis, A.; Nagano, S.; Nakamura, K.; Nakamura, T.; Nakano, H.; Nakano, Masaya; Nakano, Masayuki; Nakao, K.; Napier, K.; Nardecchia, I.; Narikawa, T.; Naticchioni, L.; Nelemans, G.; Nelson, T. J. N.; Neri, M.; Nery, M.; Neunzert, A.; Newport, J. M.; Newton, G.; Nguyen, T. T.; Ni, W.-T.; Nielsen, A. B.; Nissanke, S.; Nitz, A.; Noack, A.; Nocera, F.; Nolting, D.; Normandin, M. E. N.; Nuttall, L. K.; Oberling, J.; Ochsner, E.; Oelker, E.; Ogin, G. H.; Oh, J. J.; Oh, S. H.; Ohashi, M.; Ohishi, N.; Ohkawa, M.; Ohme, F.; Okutomi, K.; Oliver, M.; Ono, K.; Ono, Y.; Oohara, K.; Oppermann, P.; Oram, Richard J.; O'Reilly, B.; O'Shaughnessy, R.; Ottaway, D. J.; Overmier, H.; Owen, B. J.; Pace, A. E.; Page, J.; Pai, A.; Pai, S. A.; Palamos, J. R.; Palashov, O.; Palomba, C.; Pal-Singh, A.; Pan, H.; Pankow, C.; Pannarale, F.; Pant, B. C.; Paoletti, F.; Paoli, A.; Papa, M. A.; Paris, H. R.; Parker, W.; Pascucci, D.; Pasqualetti, A.; Passaquieti, R.; Passuello, D.; Patricelli, B.; Pearlstone, B. L.; Pedraza, M.; Pedurand, R.; Pekowsky, L.; Pele, A.; Peña Arellano, F. E.; Penn, S.; Perez, C. J.; Perreca, A.; Perri, L. M.; Pfeiffer, H. P.; Phelps, M.; Piccinni, O. J.; Pichot, M.; Piergiovanni, F.; Pierro, V.; Pillant, G.; Pinard, L.; Pinto, I. M.; Pitkin, M.; Poe, M.; Poggiani, R.; Popolizio, P.; Post, A.; Powell, J.; Prasad, J.; Pratt, J. W. W.; Predoi, V.; Prestegard, T.; Prijatelj, M.; Principe, M.; Privitera, S.; Prodi, G. A.; Prokhorov, L. G.; Puncken, O.; Punturo, M.; Puppo, P.; Pürrer, M.; Qi, H.; Qin, J.; Qiu, S.; Quetschke, V.; Quintero, E. A.; Quitzow-James, R.; Raab, F. J.; Rabeling, D. S.; Radkins, H.; Raffai, P.; Raja, S.; Rajan, C.; Rakhmanov, M.; Rapagnani, P.; Raymond, V.; Razzano, M.; Re, V.; Read, J.; Regimbau, T.; Rei, L.; Reid, S.; Reitze, D. H.; Rew, H.; Reyes, S. D.; Rhoades, E.; Ricci, F.; Riles, K.; Rizzo, M.; Robertson, N. A.; Robie, R.; Robinet, F.; Rocchi, A.; Rolland, L.; Rollins, J. G.; Roma, V. J.; Romano, R.; Romie, J. H.; Rosińska, D.; Rowan, S.; Rüdiger, A.; Ruggi, P.; Ryan, K.; Sachdev, S.; Sadecki, T.; Sadeghian, L.; Sago, N.; Saijo, M.; Saito, Y.; Sakai, K.; Sakellariadou, M.; Salconi, L.; Saleem, M.; Salemi, F.; Samajdar, A.; Sammut, L.; Sampson, L. M.; Sanchez, E. J.; Sandberg, V.; Sanders, J. R.; Sasaki, Y.; Sassolas, B.; Sathyaprakash, B. S.; Sato, S.; Sato, T.; Saulson, P. R.; Sauter, O.; Savage, R. L.; Sawadsky, A.; Schale, P.; Scheuer, J.; Schmidt, E.; Schmidt, J.; Schmidt, P.; Schnabel, R.; Schofield, R. M. S.; Schönbeck, A.; Schreiber, E.; Schuette, D.; Schutz, B. F.; Schwalbe, S. G.; Scott, J.; Scott, S. M.; Sekiguchi, T.; Sekiguchi, Y.; Sellers, D.; Sengupta, A. S.; Sentenac, D.; Sequino, V.; Sergeev, A.; Setyawati, Y.; Shaddock, D. A.; Shaffer, T. J.; Shahriar, M. S.; Shapiro, B.; Shawhan, P.; Sheperd, A.; Shibata, M.; Shikano, Y.; Shimoda, T.; Shoda, A.; Shoemaker, D. H.; Shoemaker, D. M.; Siellez, K.; Siemens, X.; Sieniawska, M.; Sigg, D.; Silva, A. D.; Singer, A.; Singer, L. P.; Singh, A.; Singh, R.; Singhal, A.; Sintes, A. M.; Slagmolen, B. J. J.; Smith, B.; Smith, J. R.; Smith, R. J. E.; Somiya, K.; Son, E. J.; Sorazu, B.; Sorrentino, F.; Souradeep, T.; Spencer, A. P.; Srivastava, A. K.; Staley, A.; Steinke, M.; Steinlechner, J.; Steinlechner, S.; Steinmeyer, D.; Stephens, B. C.; Stevenson, S. P.; Stone, R.; Strain, K. A.; Straniero, N.; Stratta, G.; Strigin, S. E.; Sturani, R.; Stuver, A. L.; Sugimoto, Y.; Summerscales, T. Z.; Sun, L.; Sunil, S.; Sutton, P. J.; Suzuki, T.; Swinkels, B. L.; Szczepańczyk, M. J.; Tacca, M.; Tagoshi, H.; Takada, S.; Takahashi, H.; Takahashi, R.; Takamori, A.; Talukder, D.; Tanaka, H.; Tanaka, K.; Tanaka, T.; Tanner, D. B.; Tápai, M.; Taracchini, A.; Tatsumi, D.; Taylor, R.; Telada, S.; Theeg, T.; Thomas, E. G.; Thomas, M.; Thomas, P.; Thorne, K. A.; Thrane, E.; Tippens, T.; Tiwari, S.; Tiwari, V.; Tokmakov, K. V.; Toland, K.; Tomaru, T.; Tomlinson, C.; Tonelli, M.; Tornasi, Z.; Torrie, C. I.; Töyrä, D.; Travasso, F.; Traylor, G.; Trifirò, D.; Trinastic, J.; Tringali, M. C.; Trozzo, L.; Tse, M.; Tso, R.; Tsubono, K.; Tsuzuki, T.; Turconi, M.; Tuyenbayev, D.; Uchiyama, T.; Uehara, T.; Ueki, S.; Ueno, K.; Ugolini, D.; Unnikrishnan, C. S.; Urban, A. L.; Ushiba, T.; Usman, S. A.; Vahlbruch, H.; Vajente, G.; Valdes, G.; van Bakel, N.; van Beuzekom, M.; van den Brand, J. F. J.; Van Den Broeck, C.; Vander-Hyde, D. C.; van der Schaaf, L.; van Heijningen, J. V.; van Putten, M. H. P. M.; van Veggel, A. A.; Vardaro, M.; Varma, V.; Vass, S.; Vasúth, M.; Vecchio, A.; Vedovato, G.; Veitch, J.; Veitch, P. J.; Venkateswara, K.; Venugopalan, G.; Verkindt, D.; Vetrano, F.; Viceré, A.; Viets, A. D.; Vinciguerra, S.; Vine, D. J.; Vinet, J.-Y.; Vitale, S.; Vo, T.; Vocca, H.; Vorvick, C.; Voss, D. V.; Vousden, W. D.; Vyatchanin, S. P.; Wade, A. R.; Wade, L. E.; Wade, M.; Wakamatsu, T.; Walker, M.; Wallace, L.; Walsh, S.; Wang, G.; Wang, H.; Wang, M.; Wang, Y.; Ward, R. L.; Warner, J.; Was, M.; Watchi, J.; Weaver, B.; Wei, L.-W.; Weinert, M.; Weinstein, A. J.; Weiss, R.; Wen, L.; Weßels, P.; Westphal, T.; Wette, K.; Whelan, J. T.; Whiting, B. F.; Whittle, C.; Williams, D.; Williams, R. D.; Williamson, A. R.; Willis, J. L.; Willke, B.; Wimmer, M. H.; Winkler, W.; Wipf, C. C.; Wittel, H.; Woan, G.; Woehler, J.; Worden, J.; Wright, J. L.; Wu, D. S.; Wu, G.; Yam, W.; Yamamoto, H.; Yamamoto, K.; Yamamoto, T.; Yancey, C. C.; Yano, K.; Yap, M. J.; Yokoyama, J.; Yokozawa, T.; Yoon, T. H.; Yu, Hang; Yu, Haocun; Yuzurihara, H.; Yvert, M.; Zadrożny, A.; Zangrando, L.; Zanolin, M.; Zeidler, S.; Zendri, J.-P.; Zevin, M.; Zhang, L.; Zhang, M.; Zhang, T.; Zhang, Y.; Zhao, C.; Zhou, M.; Zhou, Z.; Zhu, S. J.; Zhu, X. J.; Zucker, M. E.; Zweizig, J.

2018-04-01

We present possible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves. We estimate the sensitivity of the network to transient gravitational-wave signals, and study the capability of the network to determine the sky location of the source. We report our findings for gravitational-wave transients, with particular focus on gravitational-wave signals from the inspiral of binary neutron star systems, which are the most promising targets for multi-messenger astronomy. The ability to localize the sources of the detected signals depends on the geographical distribution of the detectors and their relative sensitivity, and 90% credible regions can be as large as thousands of square degrees when only two sensitive detectors are operational. Determining the sky position of a significant fraction of detected signals to areas of 5-20 deg^2 requires at least three detectors of sensitivity within a factor of ˜ 2 of each other and with a broad frequency bandwidth. When all detectors, including KAGRA and the third LIGO detector in India, reach design sensitivity, a significant fraction of gravitational-wave signals will be localized to a few square degrees by gravitational-wave observations alone.

Prospects for observing and localizing gravitational-wave transients with Advanced LIGO, Advanced Virgo and KAGRA.

PubMed

Abbott, B P; Abbott, R; Abbott, T D; Abernathy, M R; Acernese, F; Ackley, K; Adams, C; Adams, T; Addesso, P; Adhikari, R X; Adya, V B; Affeldt, C; Agathos, M; Agatsuma, K; Aggarwal, N; Aguiar, O D; Aiello, L; Ain, A; Ajith, P; Akutsu, T; Allen, B; Allocca, A; Altin, P A; Ananyeva, A; Anderson, S B; Anderson, W G; Ando, M; Appert, S; Arai, K; Araya, A; Araya, M C; Areeda, J S; Arnaud, N; Arun, K G; Asada, H; Ascenzi, S; Ashton, G; Aso, Y; Ast, M; Aston, S M; Astone, P; Atsuta, S; Aufmuth, P; Aulbert, C; Avila-Alvarez, A; Awai, K; Babak, S; Bacon, P; Bader, M K M; Baiotti, L; Baker, P T; Baldaccini, F; Ballardin, G; Ballmer, S W; Barayoga, J C; Barclay, S E; Barish, B C; Barker, D; Barone, F; Barr, B; Barsotti, L; Barsuglia, M; Barta, D; Bartlett, J; Barton, M A; Bartos, I; Bassiri, R; Basti, A; Batch, J C; Baune, C; Bavigadda, V; Bazzan, M; Bécsy, B; Beer, C; Bejger, M; Belahcene, I; Belgin, M; Bell, A S; Berger, B K; Bergmann, G; Berry, C P L; Bersanetti, D; Bertolini, A; Betzwieser, J; Bhagwat, S; Bhandare, R; Bilenko, I A; Billingsley, G; Billman, C R; Birch, J; Birney, R; Birnholtz, O; Biscans, S; Bisht, A; Bitossi, M; Biwer, C; Bizouard, M A; Blackburn, J K; Blackman, J; Blair, C D; Blair, D G; Blair, R M; Bloemen, S; Bock, O; Boer, M; Bogaert, G; Bohe, A; Bondu, F; Bonnand, R; Boom, B A; Bork, R; Boschi, V; Bose, S; Bouffanais, Y; Bozzi, A; Bradaschia, C; Brady, P R; Braginsky, V B; Branchesi, M; Brau, J E; Briant, T; Brillet, A; Brinkmann, M; Brisson, V; Brockill, P; Broida, J E; Brooks, A F; Brown, D A; Brown, D D; Brown, N M; Brunett, S; Buchanan, C C; Buikema, A; Bulik, T; Bulten, H J; Buonanno, A; Buskulic, D; Buy, C; Byer, R L; Cabero, M; Cadonati, L; Cagnoli, G; Cahillane, C; Calderón Bustillo, J; Callister, T A; Calloni, E; Camp, J B; Cannon, K C; Cao, H; Cao, J; Capano, C D; Capocasa, E; Carbognani, F; Caride, S; Casanueva Diaz, J; Casentini, C; Caudill, S; Cavaglià, M; Cavalier, F; Cavalieri, R; Cella, G; Cepeda, C B; Cerboni Baiardi, L; Cerretani, G; Cesarini, E; Chamberlin, S J; Chan, M; Chao, S; Charlton, P; Chassande-Mottin, E; Cheeseboro, B D; Chen, H Y; Chen, Y; Cheng, H-P; Chincarini, A; Chiummo, A; Chmiel, T; Cho, H S; Cho, M; Chow, J H; Christensen, N; Chu, Q; Chua, A J K; Chua, S; Chung, S; Ciani, G; Clara, F; Clark, J A; Cleva, F; Cocchieri, C; Coccia, E; Cohadon, P-F; Colla, A; Collette, C G; Cominsky, L; Constancio, M; Conti, L; Cooper, S J; Corbitt, T R; Cornish, N; Corsi, A; Cortese, S; Costa, C A; Coughlin, M W; Coughlin, S B; Coulon, J-P; Countryman, S T; Couvares, P; Covas, P B; Cowan, E E; Coward, D M; Cowart, M J; Coyne, D C; Coyne, R; Creighton, J D E; Creighton, T D; Cripe, J; Crowder, S G; Cullen, T J; Cumming, A; Cunningham, L; Cuoco, E; Canton, T Dal; Danilishin, S L; D'Antonio, S; Danzmann, K; Dasgupta, A; Da Silva Costa, C F; Dattilo, V; Dave, I; Davier, M; Davies, G S; Davis, D; Daw, E J; Day, B; Day, R; De, S; DeBra, D; Debreczeni, G; Degallaix, J; De Laurentis, M; Deléglise, S; Del Pozzo, W; Denker, T; Dent, T; Dergachev, V; De Rosa, R; DeRosa, R T; DeSalvo, R; Devine, R C; Dhurandhar, S; Díaz, M C; Fiore, L Di; Giovanni, M Di; Girolamo, T Di; Lieto, A Di; Pace, S Di; Palma, I Di; Virgilio, A Di; Doctor, Z; Doi, K; Dolique, V; Donovan, F; Dooley, K L; Doravari, S; Dorrington, I; Douglas, R; Dovale Álvarez, M; Downes, T P; Drago, M; Drever, R W P; Driggers, J C; Du, Z; Ducrot, M; Dwyer, S E; Eda, K; Edo, T B; Edwards, M C; Effler, A; Eggenstein, H-B; Ehrens, P; Eichholz, J; Eikenberry, S S; Eisenstein, R A; Essick, R C; Etienne, Z; Etzel, T; Evans, M; Evans, T M; Everett, R; Factourovich, M; Fafone, V; Fair, H; Fairhurst, S; Fan, X; Farinon, S; Farr, B; Farr, W M; Fauchon-Jones, E J; Favata, M; Fays, M; Fehrmann, H; Fejer, M M; Fernández Galiana, A; Ferrante, I; Ferreira, E C; Ferrini, F; Fidecaro, F; Fiori, I; Fiorucci, D; Fisher, R P; Flaminio, R; Fletcher, M; Fong, H; Forsyth, S S; Fournier, J-D; Frasca, S; Frasconi, F; Frei, Z; Freise, A; Frey, R; Frey, V; Fries, E M; Fritschel, P; Frolov, V V; Fujii, Y; 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Kirchhoff, R; Kissel, J S; Klein, B; Kleybolte, L; Klimenko, S; Koch, P; Koehlenbeck, S M; Kojima, Y; Kokeyama, K; Koley, S; Komori, K; Kondrashov, V; Kontos, A; Korobko, M; Korth, W Z; Kotake, K; Kowalska, I; Kozak, D B; Krämer, C; Kringel, V; Krishnan, B; Królak, A; Kuehn, G; Kumar, P; Kumar, Rahul; Kumar, Rakesh; Kuo, L; Kuroda, K; Kutynia, A; Kuwahara, Y; Lackey, B D; Landry, M; Lang, R N; Lange, J; Lantz, B; Lanza, R K; Lartaux-Vollard, A; Lasky, P D; Laxen, M; Lazzarini, A; Lazzaro, C; Leaci, P; Leavey, S; Lebigot, E O; Lee, C H; Lee, H K; Lee, H M; Lee, H W; Lee, K; Lehmann, J; Lenon, A; Leonardi, M; Leong, J R; Leroy, N; Letendre, N; Levin, Y; Li, T G F; Libson, A; Littenberg, T B; Liu, J; Lockerbie, N A; Lombardi, A L; London, L T; Lord, J E; Lorenzini, M; Loriette, V; Lormand, M; Losurdo, G; Lough, J D; Lousto, C O; Lovelace, G; Lück, H; Lundgren, A P; Lynch, R; Ma, Y; Macfoy, S; Machenschalk, B; MacInnis, M; Macleod, D M; Magaña-Sandoval, F; Majorana, E; Maksimovic, I; Malvezzi, V; Man, N; Mandic, V; Mangano, V; Mano, S; Mansell, G L; Manske, M; Mantovani, M; Marchesoni, F; Marchio, M; Marion, F; Márka, S; Márka, Z; Markosyan, A S; Maros, E; Martelli, F; Martellini, L; Martin, I W; Martynov, D V; Mason, K; Masserot, A; Massinger, T J; Masso-Reid, M; Mastrogiovanni, S; Matichard, F; Matone, L; Matsumoto, N; Matsushima, F; Mavalvala, N; Mazumder, N; McCarthy, R; McClelland, D E; McCormick, S; McGrath, C; McGuire, S C; McIntyre, G; McIver, J; McManus, D J; McRae, T; McWilliams, S T; Meacher, D; Meadors, G D; Meidam, J; Melatos, A; Mendell, G; Mendoza-Gandara, D; Mercer, R A; Merilh, E L; Merzougui, M; Meshkov, S; Messenger, C; Messick, C; Metzdorff, R; Meyers, P M; Mezzani, F; Miao, H; Michel, C; Michimura, Y; Middleton, H; Mikhailov, E E; Milano, L; Miller, A L; Miller, A; Miller, B B; Miller, J; Millhouse, M; Minenkov, Y; Ming, J; Mirshekari, S; Mishra, C; Mitrofanov, V P; Mitselmakher, G; Mittleman, R; Miyakawa, O; Miyamoto, A; Miyamoto, T; Miyoki, S; Moggi, A; Mohan, M; Mohapatra, S R P; Montani, M; Moore, B C; Moore, C J; Moraru, D; Moreno, G; Morii, W; Morisaki, S; Moriwaki, Y; Morriss, S R; Mours, B; Mow-Lowry, C M; Mueller, G; Muir, A W; Mukherjee, Arunava; Mukherjee, D; Mukherjee, S; Mukund, N; Mullavey, A; Munch, J; Muniz, E A M; Murray, P G; Mytidis, A; Nagano, S; Nakamura, K; Nakamura, T; Nakano, H; Nakano, Masaya; Nakano, Masayuki; Nakao, K; Napier, K; Nardecchia, I; Narikawa, T; Naticchioni, L; Nelemans, G; Nelson, T J N; Neri, M; Nery, M; Neunzert, A; Newport, J M; Newton, G; Nguyen, T T; Ni, W-T; Nielsen, A B; Nissanke, S; Nitz, A; Noack, A; Nocera, F; Nolting, D; Normandin, M E N; Nuttall, L K; Oberling, J; Ochsner, E; Oelker, E; Ogin, G H; Oh, J J; Oh, S H; Ohashi, M; Ohishi, N; Ohkawa, M; Ohme, F; Okutomi, K; Oliver, M; Ono, K; Ono, Y; Oohara, K; Oppermann, P; Oram, Richard J; O'Reilly, B; O'Shaughnessy, R; Ottaway, D J; Overmier, H; Owen, B J; Pace, A E; Page, J; Pai, A; Pai, S A; Palamos, J R; Palashov, O; Palomba, C; Pal-Singh, A; Pan, H; 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2018-01-01

We present possible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves. We estimate the sensitivity of the network to transient gravitational-wave signals, and study the capability of the network to determine the sky location of the source. We report our findings for gravitational-wave transients, with particular focus on gravitational-wave signals from the inspiral of binary neutron star systems, which are the most promising targets for multi-messenger astronomy. The ability to localize the sources of the detected signals depends on the geographical distribution of the detectors and their relative sensitivity, and [Formula: see text] credible regions can be as large as thousands of square degrees when only two sensitive detectors are operational. Determining the sky position of a significant fraction of detected signals to areas of 5-[Formula: see text] requires at least three detectors of sensitivity within a factor of [Formula: see text] of each other and with a broad frequency bandwidth. When all detectors, including KAGRA and the third LIGO detector in India, reach design sensitivity, a significant fraction of gravitational-wave signals will be localized to a few square degrees by gravitational-wave observations alone.

Pediatric palliative care and eHealth opportunities for patient-centered care.

PubMed

Madhavan, Subha; Sanders, Amy E; Chou, Wen-Ying Sylvia; Shuster, Alex; Boone, Keith W; Dente, Mark A; Shad, Aziza T; Hesse, Bradford W

2011-05-01

Pediatric palliative care currently faces many challenges including unnecessary pain from insufficiently personalized treatment, doctor-patient communication breakdowns, and a paucity of usable patient-centric information. Recent advances in informatics for consumer health through eHealth initiatives have the potential to bridge known communication gaps, but overall these technologies remain under-utilized in practice. This paper seeks to identify effective uses of existing and developing health information technology (HIT) to improve communications and care within the clinical setting. A needs analysis was conducted by surveying seven pediatric oncology patients and their extended support network at the Lombardi Pediatric Clinic at Georgetown University Medical Center in May and June of 2010. Needs were mapped onto an existing inventory of emerging HIT technologies to assess what existing informatics solutions could effectively bridge these gaps. Through the patient interviews, a number of communication challenges and needs in pediatric palliative cancer care were identified from the interconnected group perspective surrounding each patient. These gaps mapped well, in most cases, to existing or emerging cyberinfrastructure. However, adoption and adaptation of appropriate technologies could improve, including for patient-provider communication, behavioral support, pain assessment, and education, all through integration within existing work flows. This study provides a blueprint for more optimal use of HIT technologies, effectively utilizing HIT standards-based technology solutions to improve communication. This research aims to further stimulate the development and adoption of interoperable, standardized technologies and delivery of context-sensitive information to substantially improve the quality of care patients receive within pediatric palliative care clinics and other settings. Copyright © 2011 American Journal of Preventive Medicine. All rights reserved.

Spatial Risk Analysis of Hydraulic Fracturing near Abandoned and Converted Oil and Gas Wells.

PubMed

Brownlow, Joshua W; Yelderman, Joe C; James, Scott C

2017-03-01

Interaction between hydraulically generated fractures and existing wells (frac hits) could represent a potential risk to groundwater. In particular, frac hits on abandoned oil and gas wells could lead to upward leakage into overlying aquifers, provided migration pathways are present along the abandoned well. However, potential risk to groundwater is relatively unknown because few studies have investigated the probability of frac hits on abandoned wells. In this study, actual numbers of frac hits were not determined. Rather, the probability for abandoned wells to intersect hypothetical stimulated reservoir sizes of horizontal wells was investigated. Well data were compiled and analyzed for location and reservoir information, and sensitivity analyses were conducted by varying assumed sizes of stimulated reservoirs. This study used public and industry data for the Eagle Ford Shale play in south Texas, with specific attention paid to abandoned oil and gas wells converted into water wells (converted wells). In counties with Eagle Ford Shale activity, well-data analysis identified 55,720 abandoned wells with a median age of 1983, and 2400 converted wells with a median age of 1954. The most aggressive scenario resulted in 823 abandoned wells and 184 converted wells intersecting the largest assumed stimulated reservoir size. Analysis showed abandoned wells have the potential to be intersected by multiple stimulated reservoirs, and risks for intersection would increase if currently permitted horizontal wells in the Eagle Ford Shale are actually completed. Results underscore the need to evaluate historical oil and gas activities in areas with modern unconventional oil and gas activities. © 2016, National Ground Water Association.

Sensitivity Analysis Based Approaches for Mitigating the Effects of Reducible Interval Input Uncertainty on Single- and Multi-Disciplinary Systems Using Multi-Objective Optimization

DTIC Science & Technology

2010-01-01

Multi-Disciplinary, Multi-Output Sensitivity Analysis ( MIMOSA ) .........29 3.1 Introduction to Research Thrust 1...39 3.3 MIMOSA Approach ..........................................................................................41 3.3.1...Collaborative Consistency of MIMOSA .......................................................41 3.3.2 Formulation of MIMOSA

Basic design of a multi wire proportional counter using Garfield++ for ILSF

NASA Astrophysics Data System (ADS)

Ghahremani Gol, M.; Ashrafi, S.; Rahighi, J.

2016-12-01

The Iranian Light Source Facility (ILSF) is a new 3 GeV third generation synchrotron radiation facility in Middle East, which at the time being is in its design stage. An important aspect for the scientific success of this new source will be the availability of well adapted detectors. Position-sensitive X-ray detectors have played an important role in synchrotron radiation X-ray experiments for many years and are still in use. An operational one-dimensional multiwire position sensitive detector with delay line readout produced by ILSF showed a position resolution of 230 μm. In this paper, we introduce a 2-D position sensitive gas detector based on a multiwire proportional chamber which will be used in small/wide angle scattering and diffraction experiments with synchrotron radiation at the ILSF. The parameters of its components, including the gas filling, gas pressure, temperature, the geometry of anode and cathodes planes as well as the expected performance of the designed system will be described in the following. For the design and the simulation of MWPC the Elmer and Garfield++ codes have been employed. We have built and tested a MWPC as a prototype at ILSF. The results obtained so far show a good position sensing. After primary test the detector has been optimized and is now ready for test at Elettra.

42 CFR 495.344 - Approval of the State Medicaid HIT plan, the HIT PAPD and update, the HIT IAPD and update, and...

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Approval of the State Medicaid HIT plan, the HIT... Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Requirements Specific to the Medicaid Program § 495.344 Approval of the State Medicaid HIT plan, the HIT PAPD...

A parallel genome-wide RNAi screening strategy to identify host proteins important for entry of Marburg virus and H5N1 influenza virus.

PubMed

Cheng, Han; Koning, Katie; O'Hearn, Aileen; Wang, Minxiu; Rumschlag-Booms, Emily; Varhegyi, Elizabeth; Rong, Lijun

2015-11-24

Genome-wide RNAi screening has been widely used to identify host proteins involved in replication and infection of different viruses, and numerous host factors are implicated in the replication cycles of these viruses, demonstrating the power of this approach. However, discrepancies on target identification of the same viruses by different groups suggest that high throughput RNAi screening strategies need to be carefully designed, developed and optimized prior to the large scale screening. Two genome-wide RNAi screens were performed in parallel against the entry of pseudotyped Marburg viruses and avian influenza virus H5N1 utilizing an HIV-1 based surrogate system, to identify host factors which are important for virus entry. A comparative analysis approach was employed in data analysis, which alleviated systematic positional effects and reduced the false positive number of virus-specific hits. The parallel nature of the strategy allows us to easily identify the host factors for a specific virus with a greatly reduced number of false positives in the initial screen, which is one of the major problems with high throughput screening. The power of this strategy is illustrated by a genome-wide RNAi screen for identifying the host factors important for Marburg virus and/or avian influenza virus H5N1 as described in this study. This strategy is particularly useful for highly pathogenic viruses since pseudotyping allows us to perform high throughput screens in the biosafety level 2 (BSL-2) containment instead of the BSL-3 or BSL-4 for the infectious viruses, with alleviated safety concerns. The screening strategy together with the unique comparative analysis approach makes the data more suitable for hit selection and enables us to identify virus-specific hits with a much lower false positive rate.

Shielded capacitive electrode

DOEpatents

Kireeff Covo, Michel

2013-07-09

A device is described, which is sensitive to electric fields, but is insensitive to stray electrons/ions and unlike a bare, exposed conductor, it measures capacitively coupled current while rejecting currents due to charged particle collected or emitted. A charged particle beam establishes an electric field inside the beam pipe. A grounded metallic box with an aperture is placed in a drift region near the beam tube radius. The produced electric field that crosses the aperture generates a fringe field that terminates in the back surface of the front of the box and induces an image charge. An electrode is placed inside the grounded box and near the aperture, where the fringe fields terminate, in order to couple with the beam. The electrode is negatively biased to suppress collection of electrons and is protected behind the front of the box, so the beam halo cannot directly hit the electrode and produce electrons. The measured signal shows the net potential (positive ion beam plus negative electrons) variation with time, as it shall be observed from the beam pipe wall.

Front-end circuit for position sensitive silicon and vacuum tube photomultipliers with gain control and depth of interaction measurement

NASA Astrophysics Data System (ADS)

Herrero, Vicente; Colom, Ricardo; Gadea, Rafael; Lerche, Christoph W.; Cerdá, Joaquín; Sebastiá, Ángel; Benlloch, José M.

2007-06-01

Silicon Photomultipliers, though still under development for mass production, may be an alternative to traditional Vacuum Photomultipliers Tubes (VPMT). As a consequence, electronic front-ends initially designed for VPMT will need to be modified. In this simulation, an improved architecture is presented which is able to obtain impact position and depth of interaction of a gamma ray within a continuous scintillation crystal, using either kind of PM. A current sensitive preamplifier stage with individual gain adjustment interfaces the multi-anode PM outputs with a current division resistor network. The preamplifier stage allows to improve front-end processing delay and temporal resolution behavior as well as to increase impact position calculation resolution. Depth of interaction (DOI) is calculated from the width of the scintillation light distribution, which is related to the sum of voltages in resistor network input nodes. This operation is done by means of a high-speed current mode scheme.

Plasma response to sustainment with imposed-dynamo current drive in HIT-SI and HIT-SI3

NASA Astrophysics Data System (ADS)

Hossack, A. C.; Jarboe, T. R.; Chandra, R. N.; Morgan, K. D.; Sutherland, D. A.; Penna, J. M.; Everson, C. J.; Nelson, B. A.

2017-07-01

The helicity injected torus—steady inductive (HIT-SI) program studies efficient, steady-state current drive for magnetic confinement plasmas using a novel experimental method. Stable, high-beta spheromaks have been sustained using steady, inductive current drive. Externally induced loop voltage and magnetic flux are oscillated together so that helicity and power injection are always positive, sustaining the edge plasma current indefinitely. Imposed-dynamo current drive (IDCD) theory further shows that the entire plasma current is sustained. The method is ideal for low aspect ratio, toroidal geometries with closed flux surfaces. Experimental studies of spheromak plasmas sustained with IDCD have shown stable magnetic profiles with evidence of pressure confinement. New measurements show coherent motion of a stable spheromak in response to the imposed perturbations. On the original device two helicity injectors were mounted on either side of the spheromak and the injected mode spectrum was predominantly n  =  1. Coherent, rigid motion indicates that the spheromak is stable and a lack of plasma-generated n  =  1 energy indicates that the maximum q is maintained below 1 during sustainment. Results from the HIT-SI3 device are also presented. Three inductive helicity injectors are mounted on one side of the spheromak flux conserver. Varying the relative injector phasing changes the injected mode spectrum which includes n  =  2, 3, and higher modes.

Saccadic entropy of head impulses in acute unilateral vestibular loss.

PubMed

Hsieh, Li-Chun; Lin, Hung-Ching; Lee, Guo-She

2017-10-01

To evaluate the complexity of vestibular-ocular reflex (VOR) in patients with acute unilateral vestibular loss (AUVL) via entropy analysis of head impulses. Horizontal head impulse test (HIT) with high-velocity alternating directions was used to evaluate 12 participants with AUVL and 16 healthy volunteers. Wireless electro-oculography and electronic gyrometry were used to acquire eye positional signals and head velocity signals. The eye velocity signals were then obtained through differentiation, band-pass filtering. The approximate entropy of eye velocity to head velocity (R ApEn ) was used to evaluate chaos property. VOR gain, gain asymmetry ratio, and R ApEn asymmetry ratio were also used to compare the groups. For the lesion-side HIT of the patient group, the mean VOR gain was significantly lower and the mean R ApEn was significantly greater compared with both nonlesion-side HIT and healthy controls (p < 0.01, one-way analysis of variance). Both the R ApEn asymmetry ratio and gain asymmetry ratio of the AUVL group were significantly greater compared with those of the control group (p < 0.05, independent sample t test). Entropy and gain analysis of HIT using wireless electro-oculography system could be used to detect the VOR dysfunctions of AUVL and may become effective methods for evaluating vestibular disorders. Copyright © 2017. Published by Elsevier B.V.

Screening of HIV-1 Protease Using a Combination of an Ultra-High-Throughput Fluorescent-Based Assay and RapidFire Mass Spectrometry.

PubMed

Meng, Juncai; Lai, Ming-Tain; Munshi, Vandna; Grobler, Jay; McCauley, John; Zuck, Paul; Johnson, Eric N; Uebele, Victor N; Hermes, Jeffrey D; Adam, Gregory C

2015-06-01

HIV-1 protease (PR) represents one of the primary targets for developing antiviral agents for the treatment of HIV-infected patients. To identify novel PR inhibitors, a label-free, high-throughput mass spectrometry (HTMS) assay was developed using the RapidFire platform and applied as an orthogonal assay to confirm hits identified in a fluorescence resonance energy transfer (FRET)-based primary screen of > 1 million compounds. For substrate selection, a panel of peptide substrates derived from natural processing sites for PR was evaluated on the RapidFire platform. As a result, KVSLNFPIL, a new substrate measured to have a ~ 20- and 60-fold improvement in k cat/K m over the frequently used sequences SQNYPIVQ and SQNYPIV, respectively, was identified for the HTMS screen. About 17% of hits from the FRET-based primary screen were confirmed in the HTMS confirmatory assay including all 304 known PR inhibitors in the set, demonstrating that the HTMS assay is effective at triaging false-positives while capturing true hits. Hence, with a sampling rate of ~7 s per well, the RapidFire HTMS assay enables the high-throughput evaluation of peptide substrates and functions as an efficient tool for hits triage in the discovery of novel PR inhibitors. © 2015 Society for Laboratory Automation and Screening.

Intrinsic motivation in two exercise interventions: Associations with fitness and body composition.

PubMed

Thøgersen-Ntoumani, Cecilie; Shepherd, Sam O; Ntoumanis, Nikos; Wagenmakers, Anton J M; Shaw, Christopher S

2016-02-01

To examine the motivational process through which increases in aerobic capacity and decreases in total body fat are achieved during high-intensity intermittent training (HIT) and moderate-intensity continuous training (MICT) interventions. Eighty-seven physically inactive adults (65% women, age = 42 ± 12, BMI = 27.67 ± 4.99 kg/m²) took part in a 10-week randomized intervention testing group-based HIT, operationalized as repeated sprints of 15-60 s interspersed with periods of recovery cycling ≤ 25 min/session, 3 sessions/wk⁻¹, or MICT, operationalized as cycling at constant workload of ∼65% maximum aerobic capacity (VO2max, 30-45 min/session⁻¹, 5 sessions/wk⁻¹. Assessments of VO2max and total body fat were made pre- and postintervention. Motivation variables were assessed midintervention and class attendance was monitored throughout. Path analysis was employed, controlling for treatment arm and baseline values of VO2max and total body fat. The 2 groups differed in adherence only, favoring HIT. Baseline VO2max predicted intrinsic motivation midintervention. Intrinsic motivation predicted program adherence, which in turn predicted increases in VO2max and decreases in total body fat by the end of the study. Intrinsic motivation in HIT and MICT is positively linked to adherence to these programs, which can facilitate improvements in fitness and body composition. (c) 2016 APA, all rights reserved).

Correct acceptance weighs more than correct rejection: a decision bias induced by question framing.

PubMed

Kareev, Yaakov; Trope, Yaacov

2011-02-01

We propose that in attempting to detect whether an effect exists or not, people set their decision criterion so as to increase the number of hits and decrease the number of misses, at the cost of increasing false alarms and decreasing correct rejections. As a result, we argue, if one of two complementary events is framed as the positive response to a question and the other as the negative response, people will tend to predict the former more often than the latter. Performance in a prediction task with symmetric payoffs and equal base rates supported our proposal. Positive responses were indeed more prevalent than negative responses, irrespective of the phrasing of the question. The bias, slight but consistent and significant, was evident from early in a session and then remained unchanged to the end. A regression analysis revealed that, in addition, individuals' decision criteria reflected their learning experiences, with the weight of hits being greater than that of correct rejections.

KSC-06pd0259

NASA Image and Video Library

2005-12-27

VANDENBERG AIR FORCE BASE, CALIF. - Inside Orbital Sciences Building 1555 at Vandenberg Air Force Base in California, workers attach segments of the Pegasus XL rocket that will launch the Space Technology 5 spacecraft later this month. ST5 contains three micro-satellites that will be positioned in a "string of pearls" constellation to perform simultaneous multi-point measurements of the Earth's magnetic field using highly sensitive magnetometers. The scheduled launch date is Feb. 28.

Towards point of care testing for C. difficile infection by volatile profiling, using the combination of a short multi-capillary gas chromatography column with metal oxide sensor detection

NASA Astrophysics Data System (ADS)

McGuire, N. D.; Ewen, R. J.; de Lacy Costello, B.; Garner, C. E.; Probert, C. S. J.; Vaughan, K.; Ratcliffe, N. M.

2014-06-01

Rapid volatile profiling of stool sample headspace was achieved using a combination of short multi-capillary chromatography column (SMCC), highly sensitive heated metal oxide semiconductor sensor and artificial neural network software. For direct analysis of biological samples this prototype offers alternatives to conventional gas chromatography (GC) detectors and electronic nose technology. The performance was compared to an identical instrument incorporating a long single capillary column (LSCC). The ability of the prototypes to separate complex mixtures was assessed using gas standards and homogenized in house ‘standard’ stool samples, with both capable of detecting more than 24 peaks per sample. The elution time was considerably faster with the SMCC resulting in a run time of 10 min compared to 30 min for the LSCC. The diagnostic potential of the prototypes was assessed using 50 C. difficile positive and 50 negative samples. The prototypes demonstrated similar capability of discriminating between positive and negative samples with sensitivity and specificity of 85% and 80% respectively. C. difficile is an important cause of hospital acquired diarrhoea, with significant morbidity and mortality around the world. A device capable of rapidly diagnosing the disease at the point of care would reduce cases, deaths and financial burden.

Towards point of care testing for C. difficile infection by volatile profiling, using the combination of a short multi-capillary gas chromatography column with metal oxide sensor detection

PubMed Central

McGuire, N D; Ewen, R J; de Lacy Costello, B; Garner, C E; Probert, C S J; Vaughan, K.; Ratcliffe, N M

2016-01-01

Rapid volatile profiling of stool sample headspace was achieved using a combination of short multi-capillary chromatography column (SMCC), highly sensitive heated metal oxide semiconductor (MOS) sensor and artificial neural network (ANN) software. For direct analysis of biological samples this prototype offers alternatives to conventional GC detectors and electronic nose technology. The performance was compared to an identical instrument incorporating a long single capillary column (LSCC). The ability of the prototypes to separate complex mixtures was assessed using gas standards and homogenised in house ‘standard’ stool samples, with both capable of detecting more than 24 peaks per sample. The elution time was considerably faster with the SMCC resulting in a run time of 10 minutes compared to 30 minutes for the LSCC. The diagnostic potential of the prototypes was assessed using 50 C. difficile positive and 50 negative samples. The prototypes demonstrated similar capability of discriminating between positive and negative samples with sensitivity and specificity of 85% and 80% respectively. C. difficile is an important cause of hospital acquired diarrhoea, with significant morbidity and mortality around the world. A device capable of rapidly diagnosing the disease at the point of care would reduce cases, deaths and financial burden. PMID:27212803

Novel method for hit-position reconstruction using voltage signals in plastic scintillators and its application to Positron Emission Tomography

NASA Astrophysics Data System (ADS)

Raczyński, L.; Moskal, P.; Kowalski, P.; Wiślicki, W.; Bednarski, T.; Białas, P.; Czerwiński, E.; Kapłon, Ł.; Kochanowski, A.; Korcyl, G.; Kowal, J.; Kozik, T.; Krzemień, W.; Kubicz, E.; Molenda, M.; Moskal, I.; Niedźwiecki, Sz.; Pałka, M.; Pawlik-Niedźwiecka, M.; Rudy, Z.; Salabura, P.; Sharma, N. G.; Silarski, M.; Słomski, A.; Smyrski, J.; Strzelecki, A.; Wieczorek, A.; Zieliński, M.; Zoń, N.

2014-11-01

Currently inorganic scintillator detectors are used in all commercial Time of Flight Positron Emission Tomograph (TOF-PET) devices. The J-PET collaboration investigates a possibility of construction of a PET scanner from plastic scintillators which would allow for single bed imaging of the whole human body. This paper describes a novel method of hit-position reconstruction based on sampled signals and an example of an application of the method for a single module with a 30 cm long plastic strip, read out on both ends by Hamamatsu R4998 photomultipliers. The sampling scheme to generate a vector with samples of a PET event waveform with respect to four user-defined amplitudes is introduced. The experimental setup provides irradiation of a chosen position in the plastic scintillator strip with an annihilation gamma quanta of energy 511 keV. The statistical test for a multivariate normal (MVN) distribution of measured vectors at a given position is developed, and it is shown that signals sampled at four thresholds in a voltage domain are approximately normally distributed variables. With the presented method of a vector analysis made out of waveform samples acquired with four thresholds, we obtain a spatial resolution of about 1 cm and a timing resolution of about 80 ps (σ).

Psychological and Social Factors Affecting Internet Searches on Suicide in Korea: A Big Data Analysis of Google Search Trends

PubMed Central

Song, Tae Min; Song, Juyoung; Hayman, Laura L.; Woo, Jong-Min

2014-01-01

Purpose The average mortality rate for death by suicide among OECD countries is 12.8 per 100000, and 33.5 for Korea. The present study analyzed big data extracted from Google to identify factors related to searches on suicide in Korea. Materials and Methods Google search trends for the search words of suicide, stress, exercise, and drinking were obtained for 2004-2010. Analyzing data by month, the relationship between the actual number of suicides and search words per year was examined using multi-level models. Results Both suicide rates and Google searches on suicide in Korea increased since 2007. An unconditional slope model indicated stress and suicide-related searches were positively related. A conditional model showed that factors associated with suicide by year directly affected suicide-related searches. The interaction between stress-related searches and the actual number of suicides was significant. Conclusion A positive relationship between stress- and suicide-related searches further confirmed that stress affects suicide. Taken together and viewed in context of the big data analysis, our results point to the need for a tailored prevention program. Real-time big data can be of use in indicating increases in suicidality when search words such as stress and suicide generate greater numbers of hits on portals and social network sites. PMID:24339315

Spontaneous heparin-induced thrombocytopenia (HIT) syndrome: HIT without any heparin exposure.

PubMed

Miyata, Shigeki

2016-01-01

Heparin-induced thrombocytopenia (HIT) is a pro-thrombotic side effect of heparin therapy caused by HIT antibodies with platelet-activating properties. Recent advances in understanding of spontaneous HIT syndrome, which can occur even without any heparin exposure despite its clinical and serological characteristics being similar to those of HIT, reveal the following HIT clinical features atypical for an immune-mediated disease. Heparin-naïve patients can develop IgG antibodies as early as day 4, as in a secondary immune response. Evidence for an anamnestic response upon heparin re-exposure is lacking. In addition, HIT antibodies are relatively short-lived, unlike those in a secondary immune response. Antigen immunoassays are commonly used worldwide for serological diagnosis of HIT. However, such assays do not indicate whether HIT antibodies have platelet-activating properties, leading to low diagnostic specificity for HIT. The detection of platelet-activating antibodies using a washed platelet activation assay is crucial for making a HIT diagnosis. These atypical clinical and serological features should be carefully considered while appropriately diagnosing HIT, which leads to appropriate therapy such as immediate administration of an alternative anticoagulant for preventing thromboembolic events and re-administration of heparin during surgery involving cardiopulmonary bypass when HIT antibodies are no longer detectable.

Detecting Migraine in Patients with Mild Traumatic Brain Injury Using Three Different Headache Measures

PubMed Central

Anderson, Kirsten; Tinawi, Simon; de Guise, Elaine

2015-01-01

Posttraumatic migraine may represent an important subtype of headache among the traumatic brain injury (TBI) population and is associated with increased recovery times. However, it is underdiagnosed in patients with mild traumatic brain injury (mTBI). This study examined the effectiveness of the self-administered Nine-Item Screener (Nine-Item Screener-SA), the Headache Impact Test- 6 (HIT-6), the 3-Item Migraine Screener, and the Rivermead Post-Concussion Questionnaire (RPQ) at discriminating between mTBI patients with (n = 23) and without (n = 20) migraines. The Nine-Item Screener demonstrated significant differences between migraine patients with and without migraine on nearly every question, especially on Question 9 (disability), sensitivity: 0.95 and specificity: 0.65 (95% CI, 0.64–0.90). The HIT-6 demonstrated significant differences between migraine and no-migraine patients on disability and pain severity, with disability having a sensitivity of 0.70 and specificity of 0.75 (95% CI, 0.54–0.83). Only Question 3 of the 3-Item ID Migraine Screener (photosensitivity) showed significant differences between migraine and no-migraine patients, sensitivity: 0.84 and specificity: 0.55 (CI, 0.52–0.82). The RPQ did not reveal greater symptoms in migraine patients compared with those without. Among headache measures, the Nine-Item Screener-SA best differentiated between mTBI patients with and without migraine. Disability may best identify migraine sufferers among the TBI population. PMID:26106255

Data processing and analysis for 2D imaging GEM detector system

NASA Astrophysics Data System (ADS)

Czarski, T.; Chernyshova, M.; Pozniak, K. T.; Kasprowicz, G.; Byszuk, A.; Juszczyk, B.; Kolasinski, P.; Linczuk, M.; Wojenski, A.; Zabolotny, W.; Zienkiewicz, P.

2014-11-01

The Triple Gas Electron Multiplier (T-GEM) is presented as soft X-ray (SXR) energy and position sensitive detector for high-resolution X-ray diagnostics of magnetic confinement fusion plasmas [1]. Multi-channel measurement system and essential data processing for X-ray energy and position recognition is consider. Several modes of data acquisition are introduced depending on processing division for hardware and software components. Typical measuring issues aredeliberated for enhancement of data quality. Fundamental output characteristics are presented for one and two dimensional detector structure. Representative results for reference X-ray source and tokamak plasma are demonstrated.

Detecting non-orthology in the COGs database and other approaches grouping orthologs using genome-specific best hits.

PubMed

Dessimoz, Christophe; Boeckmann, Brigitte; Roth, Alexander C J; Gonnet, Gaston H

2006-01-01

Correct orthology assignment is a critical prerequisite of numerous comparative genomics procedures, such as function prediction, construction of phylogenetic species trees and genome rearrangement analysis. We present an algorithm for the detection of non-orthologs that arise by mistake in current orthology classification methods based on genome-specific best hits, such as the COGs database. The algorithm works with pairwise distance estimates, rather than computationally expensive and error-prone tree-building methods. The accuracy of the algorithm is evaluated through verification of the distribution of predicted cases, case-by-case phylogenetic analysis and comparisons with predictions from other projects using independent methods. Our results show that a very significant fraction of the COG groups include non-orthologs: using conservative parameters, the algorithm detects non-orthology in a third of all COG groups. Consequently, sequence analysis sensitive to correct orthology assignments will greatly benefit from these findings.

Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles

PubMed Central

2016-01-01

The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work. PMID:27800551

Inflammatory Mediators of Hepatic Steatosis

PubMed Central

Hijona, Elizabeth; Hijona, Lander; Arenas, Juan I.; Bujanda, Luis

2010-01-01

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming a world-wide public health problem. NAFLD represents a spectrum of disease ranging from “simple steatosis”, which is considered relatively benign, to nonalcoholic steatohepatitis and to NAFLD-associated cirrhosis and end-stage liver disease. The etiology of NAFLD and its progression is complex and remains incompletely understood. The progression of the disease involves many factors. Apart from the two hits, the accumulation of TG and the development of fibrosis and necroinflammatory processes, exit numerous molecules associated with these two hits. Among them we can highlight the pro-inflammatory molecules and adiponectins. This review focuses on the growing evidence from both experimental and human studies suggesting a central role of cytokines in the pathogenesis of NAFLD. We review the role of cytokines as key regulators of insulin sensitivity and hepatic lipid overloading, liver injury and inflammation, and fibrosis with an emphasis on potential therapeutic implications. PMID:20300479

Recent development of the Multi-Grid detector for large area neutron scattering instruments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guerard, Bruno

2015-07-01

Most of the Neutron Scattering facilities are committed in a continuous program of modernization of their instruments, requiring large area and high performance thermal neutron detectors. Beside scintillators detectors, {sup 3}He detectors, like linear PSDs (Position Sensitive Detectors) and MWPCs (Multi-Wires Proportional Chambers), are the most current techniques nowadays. Time Of Flight instruments are using {sup 3}He PSDs mounted side by side to cover tens of m{sup 2}. As a result of the so-called '{sup 3}He shortage crisis{sup ,} the volume of 3He which is needed to build one of these instruments is not accessible anymore. The development of alternativemore » techniques requiring no 3He, has been given high priority to secure the future of neutron scattering instrumentation. This is particularly important in the context where the future ESS (European Spallation Source) will start its operation in 2019-2020. Improved scintillators represent one of the alternative techniques. Another one is the Multi-Grid introduced at the ILL in 2009. A Multi-Grid detector is composed of several independent modules of typically 0.8 m x 3 m sensitive area, mounted side by side in air or in a vacuum TOF chamber. One module is composed of segmented boron-lined proportional counters mounted in a gas vessel; the counters, of square section, are assembled with Aluminium grids electrically insulated and stacked together. This design provides two advantages: First, magnetron sputtering techniques can be used to coat B{sub 4}C films on planar substrates, and second, the neutron position along the anode wires can be measured by reading out individually the grid signals with fast shaping amplifiers followed by comparators. Unlike charge division localisation in linear PSDs, the individual readout of the grids allows operating the Multi-Grid at a low amplification gain, hence this detector is tolerant to mechanical defects and its production accessible to laboratories equipped with standard equipment. Prototypes of different configurations and sizes have been developed and tested. A demonstrator, with a sensitive area of 0.8 m x 3 m, has been studied during the CRISP European project; it contains 1024 grids, and a surface of isotopically enriched B{sub 4}C film close to 80 m{sup 2}. Its size represented a challenge in terms of fabrication and mounting of the detection elements. Another challenge was to make the gas chamber mechanically compatible with operation in a vacuum TOF chamber. Optimal working condition of this detector was achieved by flushing Ar-CO{sub 2} at a pressure of 50 mbar, and by applying 400 Volts on the anodes. This unusual gas pressure allows to greatly simplifying the mechanics of the gas vessel in vacuum. The detection efficiency has been measured with high precision for different film thicknesses. 52% has been measured at 2.5 Angstrom, in good agreement with the MC simulation. A high position resolution has been achieved by centre of gravity measurement of the TOT (Time-Over-Threshold) signals between neighbouring grids. These results, as well as other detection parameters, including gamma sensitivity and spatial uniformity, will be presented. (author)« less

Learning to perceive differences in solid shape through vision and touch.

PubMed

Norman, J Farley; Clayton, Anna Marie; Norman, Hideko F; Crabtree, Charles E

2008-01-01

A single experiment was designed to investigate perceptual learning and the discrimination of 3-D object shape. Ninety-six observers were presented with naturally shaped solid objects either visually, haptically, or across the modalities of vision and touch. The observers' task was to judge whether the two sequentially presented objects on any given trial possessed the same or different 3-D shapes. The results of the experiment revealed that significant perceptual learning occurred in all modality conditions, both unimodal and cross-modal. The amount of the observers' perceptual learning, as indexed by increases in hit rate and d', was similar for all of the modality conditions. The observers' hit rates were highest for the unimodal conditions and lowest in the cross-modal conditions. Lengthening the inter-stimulus interval from 3 to 15 s led to increases in hit rates and decreases in response bias. The results also revealed the existence of an asymmetry between two otherwise equivalent cross-modal conditions: in particular, the observers' perceptual sensitivity was higher for the vision-haptic condition and lower for the haptic-vision condition. In general, the results indicate that effective cross-modal shape comparisons can be made between the modalities of vision and active touch, but that complete information transfer does not occur.

Signal Propagation in Proteins and Relation to Equilibrium Fluctuations

PubMed Central

Chennubhotla, Chakra; Bahar, Ivet

2007-01-01

Elastic network (EN) models have been widely used in recent years for describing protein dynamics, based on the premise that the motions naturally accessible to native structures are relevant to biological function. We posit that equilibrium motions also determine communication mechanisms inherent to the network architecture. To this end, we explore the stochastics of a discrete-time, discrete-state Markov process of information transfer across the network of residues. We measure the communication abilities of residue pairs in terms of hit and commute times, i.e., the number of steps it takes on an average to send and receive signals. Functionally active residues are found to possess enhanced communication propensities, evidenced by their short hit times. Furthermore, secondary structural elements emerge as efficient mediators of communication. The present findings provide us with insights on the topological basis of communication in proteins and design principles for efficient signal transduction. While hit/commute times are information-theoretic concepts, a central contribution of this work is to rigorously show that they have physical origins directly relevant to the equilibrium fluctuations of residues predicted by EN models. PMID:17892319

A Prospective Virtual Screening Study: Enriching Hit Rates and Designing Focus Libraries To Find Inhibitors of PI3Kδ and PI3Kγ.

PubMed

Damm-Ganamet, Kelly L; Bembenek, Scott D; Venable, Jennifer W; Castro, Glenda G; Mangelschots, Lieve; Peeters, Daniëlle C G; Mcallister, Heather M; Edwards, James P; Disepio, Daniel; Mirzadegan, Taraneh

2016-05-12

Here, we report a high-throughput virtual screening (HTVS) study using phosphoinositide 3-kinase (both PI3Kγ and PI3Kδ). Our initial HTVS results of the Janssen corporate database identified small focused libraries with hit rates at 50% inhibition showing a 50-fold increase over those from a HTS (high-throughput screen). Further, applying constraints based on "chemically intuitive" hydrogen bonds and/or positional requirements resulted in a substantial improvement in the hit rates (versus no constraints) and reduced docking time. While we find that docking scoring functions are not capable of providing a reliable relative ranking of a set of compounds, a prioritization of groups of compounds (e.g., low, medium, and high) does emerge, which allows for the chemistry efforts to be quickly focused on the most viable candidates. Thus, this illustrates that it is not always necessary to have a high correlation between a computational score and the experimental data to impact the drug discovery process.

Development and experimental test of support vector machines virtual screening method for searching Src inhibitors from large compound libraries

PubMed Central

2012-01-01

Background Src plays various roles in tumour progression, invasion, metastasis, angiogenesis and survival. It is one of the multiple targets of multi-target kinase inhibitors in clinical uses and trials for the treatment of leukemia and other cancers. These successes and appearances of drug resistance in some patients have raised significant interest and efforts in discovering new Src inhibitors. Various in-silico methods have been used in some of these efforts. It is desirable to explore additional in-silico methods, particularly those capable of searching large compound libraries at high yields and reduced false-hit rates. Results We evaluated support vector machines (SVM) as virtual screening tools for searching Src inhibitors from large compound libraries. SVM trained and tested by 1,703 inhibitors and 63,318 putative non-inhibitors correctly identified 93.53%~ 95.01% inhibitors and 99.81%~ 99.90% non-inhibitors in 5-fold cross validation studies. SVM trained by 1,703 inhibitors reported before 2011 and 63,318 putative non-inhibitors correctly identified 70.45% of the 44 inhibitors reported since 2011, and predicted as inhibitors 44,843 (0.33%) of 13.56M PubChem, 1,496 (0.89%) of 168 K MDDR, and 719 (7.73%) of 9,305 MDDR compounds similar to the known inhibitors. Conclusions SVM showed comparable yield and reduced false hit rates in searching large compound libraries compared to the similarity-based and other machine-learning VS methods developed from the same set of training compounds and molecular descriptors. We tested three virtual hits of the same novel scaffold from in-house chemical libraries not reported as Src inhibitor, one of which showed moderate activity. SVM may be potentially explored for searching Src inhibitors from large compound libraries at low false-hit rates. PMID:23173901

The Helicity Injected Torus (HIT) Program

NASA Astrophysics Data System (ADS)

Jarboe, T. R.; Gu, P.; Hamp, W.; Izzo, V.; Jewell, P.; Liptac, J.; McCollam, K. J.; Nelson, B. A.; Raman, R.; Redd, A. J.; Shumlak, U.; Sieck, P. E.; Smith, R. J.; Jain, K. K.; Nagata, M.; Uyama, T.

2000-10-01

The purpose of the Helicity Injected Torus (HIT) program is to develop current drive techniques for low-aspect-ratio toroidal plasmas. The present HIT-II spherical tokamak experiment is capable of both Coaxial Helicity Injection (CHI) and transformer action current drive. The HIT-II device itself is modestly sized (major radius R = 0.3 m, minor radius a = 0.2 m, with an on-axis magnetic field of up to Bo = 0.5 T), but has demonstrated toroidal plasma currents of up to 200 kA, using either CHI or transformer drive. An overview of ongoing research on HIT-II plasmas, including recent results, will be presented. An electron-locking model has been developed for helicity injection current drive; a description of this model will be presented, as well as comparisons to experimental results from the HIT and HIT-II devices. Empirical results from both the HIT program and past spheromak research, buttressed by theoretical developments, have led to the design of the upcoming HIT-SI (Helicity Injected Torus with Steady Inductive helicity injection) device (T.R. Jarboe, Fusion Technology 36, p. 85, 1999). HIT-SI will be able to form a high-beta spheromak, a low aspect ratio RFP or a spherical tokamak using constant inductive helicity injection. The HIT-SI design and construction progress will be presented.

Novel 3-D laparoscopic magnetic ultrasound image guidance for lesion targeting

PubMed Central

Sindram, David; McKillop, Iain H; Martinie, John B; Iannitti, David A

2010-01-01

Objectives: Accurate laparoscopic liver lesion targeting for biopsy or ablation depends on the ability to merge laparoscopic and ultrasound images with proprioceptive instrument positioning, a skill that can be acquired only through extensive experience. The aim of this study was to determine whether using magnetic positional tracking to provide three-dimensional, real-time guidance improves accuracy during laparoscopic needle placement. Methods: Magnetic sensors were embedded into a needle and laparoscopic ultrasound transducer. These sensors interrupted the magnetic fields produced by an electromagnetic field generator, allowing for real-time, 3-D guidance on a stereoscopic monitor. Targets measuring 5 mm were embedded 3–5 cm deep in agar and placed inside a laparoscopic trainer box. Two novices (a college student and an intern) and two experts (hepatopancreatobiliary surgeons) targeted the lesions out of the ultrasound plane using either traditional or 3-D guidance. Results: Each subject targeted 22 lesions, 11 with traditional and 11 with the novel guidance (n = 88). Hit rates of 32% (14/44) and 100% (44/44) were observed with the traditional approach and the 3-D magnetic guidance approach, respectively. The novices were essentially unable to hit the targets using the traditional approach, but did not miss using the novel system. The hit rate of experts improved from 59% (13/22) to 100% (22/22) (P < 0.0001). Conclusions: The novel magnetic 3-D laparoscopic ultrasound guidance results in perfect targeting of 5-mm lesions, even by surgical novices. PMID:21083797

The Pandora multi-algorithm approach to automated pattern recognition in LAr TPC detectors

NASA Astrophysics Data System (ADS)

Marshall, J. S.; Blake, A. S. T.; Thomson, M. A.; Escudero, L.; de Vries, J.; Weston, J.; MicroBooNE Collaboration

2017-09-01

The development and operation of Liquid Argon Time Projection Chambers (LAr TPCs) for neutrino physics has created a need for new approaches to pattern recognition, in order to fully exploit the superb imaging capabilities offered by this technology. The Pandora Software Development Kit provides functionality to aid the process of designing, implementing and running pattern recognition algorithms. It promotes the use of a multi-algorithm approach to pattern recognition: individual algorithms each address a specific task in a particular topology; a series of many tens of algorithms then carefully builds-up a picture of the event. The input to the Pandora pattern recognition is a list of 2D Hits. The output from the chain of over 70 algorithms is a hierarchy of reconstructed 3D Particles, each with an identified particle type, vertex and direction.

Multi-Country Evaluation of the Sensitivity and Specificity of Two Commercially-Available NS1 ELISA Assays for Dengue Diagnosis

PubMed Central

Guzman, Maria G.; Jaenisch, Thomas; Gaczkowski, Roger; Ty Hang, Vo Thi; Sekaran, Shamala Devi; Kroeger, Axel; Vazquez, Susana; Ruiz, Didye; Martinez, Eric; Mercado, Juan C.; Balmaseda, Angel; Harris, Eva; Dimano, Efren; Leano, Prisca Susan A.; Yoksan, Sutee; Villegas, Elci; Benduzu, Herminia; Villalobos, Iris; Farrar, Jeremy; Simmons, Cameron P.

2010-01-01

Background Early diagnosis of dengue can assist patient triage and management and prevent unnecessary treatments and interventions. Commercially available assays that detect the dengue virus protein NS1 in the plasma/serum of patients offers the possibility of early and rapid diagnosis. Methodology/Principal Findings The sensitivity and specificity of the Pan-E Dengue Early ELISA and the Platelia™ Dengue NS1 Ag assays were compared against a reference diagnosis in 1385 patients in 6 countries in Asia and the Americas. Platelia was more sensitive (66%) than Pan-E (52%) in confirmed dengue cases. Sensitivity varied by geographic region, with both assays generally being more sensitive in patients from SE Asia than the Americas. Both kits were more sensitive for specimens collected within the first few days of illness onset relative to later time points. Pan-E and Platelia were both 100% specific in febrile patients without evidence of acute dengue. In patients with other confirmed diagnoses and healthy blood donors, Platelia was more specific (100%) than Pan-E (90%). For Platelia, when either the NS1 test or the IgM test on the acute sample was positive, the sensitivity versus the reference result was 82% in samples collected in the first four days of fever. NS1 sensitivity was not associated to disease severity (DF or DHF) in the Platelia test, whereas a trend for higher sensitivity in DHF cases was seen in the Pan-E test (however combined with lower overall sensitivity). Conclusions/Significance Collectively, this multi-country study suggests that the best performing NS1 assay (Platelia) had moderate sensitivity (median 64%, range 34–76%) and high specificity (100%) for the diagnosis of dengue. The poor sensitivity of the evaluated assays in some geographical regions suggests further assessments are needed. The combination of NS1 and IgM detection in samples collected in the first few days of fever increased the overall dengue diagnostic sensitivity. PMID:20824173

Raster-scanning serial protein crystallography using micro- and nano-focused synchrotron beams

PubMed Central

Coquelle, Nicolas; Brewster, Aaron S.; Kapp, Ulrike; Shilova, Anastasya; Weinhausen, Britta; Burghammer, Manfred; Colletier, Jacques-Philippe

2015-01-01

High-resolution structural information was obtained from lysozyme microcrystals (20 µm in the largest dimension) using raster-scanning serial protein crystallography on micro- and nano-focused beamlines at the ESRF. Data were collected at room temperature (RT) from crystals sandwiched between two silicon nitride wafers, thereby preventing their drying, while limiting background scattering and sample consumption. In order to identify crystal hits, new multi-processing and GUI-driven Python-based pre-analysis software was developed, named NanoPeakCell, that was able to read data from a variety of crystallographic image formats. Further data processing was carried out using CrystFEL, and the resultant structures were refined to 1.7 Å resolution. The data demonstrate the feasibility of RT raster-scanning serial micro- and nano-protein crystallography at synchrotrons and validate it as an alternative approach for the collection of high-resolution structural data from micro-sized crystals. Advantages of the proposed approach are its thriftiness, its handling-free nature, the reduced amount of sample required, the adjustable hit rate, the high indexing rate and the minimization of background scattering. PMID:25945583

Raster-scanning serial protein crystallography using micro- and nano-focused synchrotron beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coquelle, Nicolas; Brewster, Aaron S.; Kapp, Ulrike

High-resolution structural information was obtained from lysozyme microcrystals (20 µm in the largest dimension) using raster-scanning serial protein crystallography on micro- and nano-focused beamlines at the ESRF. Data were collected at room temperature (RT) from crystals sandwiched between two silicon nitride wafers, thereby preventing their drying, while limiting background scattering and sample consumption. In order to identify crystal hits, new multi-processing and GUI-driven Python-based pre-analysis software was developed, named NanoPeakCell, that was able to read data from a variety of crystallographic image formats. Further data processing was carried out using CrystFEL, and the resultant structures were refined to 1.7 Åmore » resolution. The data demonstrate the feasibility of RT raster-scanning serial micro- and nano-protein crystallography at synchrotrons and validate it as an alternative approach for the collection of high-resolution structural data from micro-sized crystals. Advantages of the proposed approach are its thriftiness, its handling-free nature, the reduced amount of sample required, the adjustable hit rate, the high indexing rate and the minimization of background scattering.« less

Raster-scanning serial protein crystallography using micro- and nano-focused synchrotron beams.

PubMed

Coquelle, Nicolas; Brewster, Aaron S; Kapp, Ulrike; Shilova, Anastasya; Weinhausen, Britta; Burghammer, Manfred; Colletier, Jacques Philippe

2015-05-01

High-resolution structural information was obtained from lysozyme microcrystals (20 µm in the largest dimension) using raster-scanning serial protein crystallography on micro- and nano-focused beamlines at the ESRF. Data were collected at room temperature (RT) from crystals sandwiched between two silicon nitride wafers, thereby preventing their drying, while limiting background scattering and sample consumption. In order to identify crystal hits, new multi-processing and GUI-driven Python-based pre-analysis software was developed, named NanoPeakCell, that was able to read data from a variety of crystallographic image formats. Further data processing was carried out using CrystFEL, and the resultant structures were refined to 1.7 Å resolution. The data demonstrate the feasibility of RT raster-scanning serial micro- and nano-protein crystallography at synchrotrons and validate it as an alternative approach for the collection of high-resolution structural data from micro-sized crystals. Advantages of the proposed approach are its thriftiness, its handling-free nature, the reduced amount of sample required, the adjustable hit rate, the high indexing rate and the minimization of background scattering.

Raster-scanning serial protein crystallography using micro- and nano-focused synchrotron beams

DOE PAGES

Coquelle, Nicolas; Brewster, Aaron S.; Kapp, Ulrike; ...

2015-04-25

High-resolution structural information was obtained from lysozyme microcrystals (20 µm in the largest dimension) using raster-scanning serial protein crystallography on micro- and nano-focused beamlines at the ESRF. Data were collected at room temperature (RT) from crystals sandwiched between two silicon nitride wafers, thereby preventing their drying, while limiting background scattering and sample consumption. In order to identify crystal hits, new multi-processing and GUI-driven Python-based pre-analysis software was developed, named NanoPeakCell, that was able to read data from a variety of crystallographic image formats. Further data processing was carried out using CrystFEL, and the resultant structures were refined to 1.7 Åmore » resolution. The data demonstrate the feasibility of RT raster-scanning serial micro- and nano-protein crystallography at synchrotrons and validate it as an alternative approach for the collection of high-resolution structural data from micro-sized crystals. Advantages of the proposed approach are its thriftiness, its handling-free nature, the reduced amount of sample required, the adjustable hit rate, the high indexing rate and the minimization of background scattering.« less

extendFromReads

DOE Office of Scientific and Technical Information (OSTI.GOV)

Williams, Kelly P.

2013-10-03

This package assists in genome assembly. extendFromReads takes as input a set of Illumina (eg, MiSeq) DNA sequencing reads, a query seed sequence and a direction to extend the seed. The algorithm collects all seed-- ]matching reads (flipping reverse-- ]orientation hits), trims off the seed and additional sequence in the other direction, sorts the remaining sequences alphabetically, and prints them aligned without gaps from the point of seed trimming. This produces a visual display distinguishing the flanks of multi- ]copy seeds. A companion script hitMates.pl collects the mates of seed-- ]hi]ng reads, whose alignment reveals longer extensions from the seed.more » The collect/trim/sort strategy was made iterative and scaled up in the script denovo.pl, for de novo contig assembly. An index is pre-- ]built using indexReads.pl that for each unique 21-- ]mer found in all the reads, records its gfate h of extension (whether extendable, blocked by low coverage, or blocked by branching after a duplicated sequence) and other characteristics. Importantly, denovo.pl records all branchings that follow a branching contig endpoint, providing contig- ]extension information« less

Development of resazurin-based assay in 384-well format for high throughput whole cell screening of Trypanosoma brucei rhodesiense strain STIB 900 for the identification of potential anti-trypanosomal agents.

PubMed

Lim, Kah Tee; Zahari, Zuriati; Amanah, Azimah; Zainuddin, Zafarina; Adenan, Mohd Ilham

2016-03-01

To accelerate the discovery of novel leads for the treatment of Human African Trypanosomiasis (HAT), it is necessary to have a simple, robust and cost-effective assay to identify positive hits by high throughput whole cell screening. Most of the fluorescence assay was made in black plate however in this study the HTS assay developed in 384-well format using clear plate and black plate, for comparison. The HTS assay developed is simple, sensitive, reliable and reproducible in both types of plates. Assay robustness and reproducibility were determined under the optimized conditions in 384-well plate was well tolerated in the HTS assay, including percentage of coefficient of variation (% CV) of 4.68% and 4.74% in clear and black 384-well plate, signal-to-background ratio (S/B) of 12.75 in clear 384-well plate and 12.07 in black 384-well plate, Z' factor of 0.79 and 0.82 in clear 384-well plate and black 384-well plate, respectively and final concentration of 0.30% dimethylsulfoxide (DMSO) in both types of plate. Drug sensitivity was found to be comparable to the reported anti-trypanosomal assay in 96-well format. The reproducibility and sensitivity of this assay make it compliant to automated liquid handler use in HTS applications. Copyright © 2016 Elsevier Inc. All rights reserved.

The effect of stereotype threat on performance of a rhythmic motor skill.

PubMed

Huber, Meghan E; Seitchik, Allison E; Brown, Adam J; Sternad, Dagmar; Harkins, Stephen G

2015-04-01

Many studies using cognitive tasks have found that stereotype threat, or concern about confirming a negative stereotype about one's group, debilitates performance. The few studies that documented similar effects on sensorimotor performance have used only relatively coarse measures to quantify performance. This study tested the effect of stereotype threat on a rhythmic ball bouncing task, where previous analyses of the task dynamics afforded more detailed quantification of the effect of threat on motor control. In this task, novices hit the ball with positive racket acceleration, indicative of unstable performance. With practice, they learn to stabilize error by changing their ball-racket impact from positive to negative acceleration. Results showed that for novices, stereotype threat potentiated hitting the ball with positive racket acceleration, leading to poorer performance of stigmatized females. However, when the threat manipulation was delivered after having acquired some skill, reflected by negative racket acceleration, the stigmatized females performed better. These findings are consistent with the mere effort account that argues that stereotype threat potentiates the most likely response on the given task. The study also demonstrates the value of identifying the control mechanisms through which stereotype threat has its effects on outcome measures. (c) 2015 APA, all rights reserved.

The Effect of Stereotype Threat on Performance of a Rhythmic Motor Skill

PubMed Central

Huber, Meghan E.; Seitchik, Allison E.; Brown, Adam J.; Sternad, Dagmar; Harkins, Stephen G.

2015-01-01

Many studies using cognitive tasks have found that stereotype threat, or concern about confirming a negative stereotype about one's group, debilitates performance. The few studies that documented similar effects on sensorimotor performance have used only relatively coarse measures to quantify performance. Three experiments tested the effect of stereotype threat on a rhythmic ball bouncing task, both at the novice and skilled level. Previous analysis of the task dynamics afforded more detailed quantification of the effect of threat on motor control. In this task, novices hit the ball with positive racket acceleration, indicative of unstable performance. With practice, they learn to stabilize error by changing their ball-racket impact from positive to negative acceleration. Results showed that for novices, stereotype threat potentiated hitting the ball with positive racket acceleration, leading to poorer performance of stigmatized females. However, when the threat manipulation was delivered after having acquired some skill, reflected by negative racket acceleration, the stigmatized females performed better. These findings are consistent with the mere effort account that argues that stereotype threat potentiates the most likely response on the given task. The study also demonstrates the value of identifying the control mechanisms through which stereotype threat has its effects on outcome measures. PMID:25706769

Heparin-induced thrombocytopenia: real-world issues.

PubMed

Linkins, Lori-Ann; Warkentin, Theodore E

2011-09-01

Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating antibodies. HIT sera often activate platelets without needing heparin-such heparin-"independent" platelet activation can be associated with HIT beginning or worsening despite stopping heparin ("delayed-onset HIT"). We address important issues in HIT diagnosis and therapy, using a recent cohort of HIT patients to illustrate influences of heparin type; triggers for HIT investigation; serological features of heparin-independent platelet activation; and treatment. In our cohort of recent HIT cases ( N = 13), low-molecular-weight heparin (dalteparin) was a common causative agent ( N = 8, 62%); most patients were diagnosed after HIT-thrombosis had occurred; and danaparoid was the most frequently selected treatment. Heparin-independent platelet activation was common (7/13 [54%]) and predicted slower platelet count recovery (>1 week) among evaluable patients (5/5 vs 1/6; P = 0.015). In our experience with argatroban-treated patients, HIT-associated consumptive coagulopathy confounds anticoagulant monitoring. Our observations provide guidance on practical aspects of HIT diagnosis and management. Thieme Medical Publishers.

Effects of Memory Load and Test Position on Short-Duration Sustained Attention Tasks.

PubMed

Laurie-Rose, Cynthia; Frey, Meredith C; Sibata, Erick; Zamary, Amanda

2015-01-01

The current study applies a dual-task working memory and vigilance task to examine sustained attention performance and perceived workload in a multi-instrument battery. In Experiment 1 we modified a task developed by Helton and Russell (2011) to examine declines in performance and to assess the effects of its position within a larger battery. Experiment 1 failed to reveal a sensitivity decrement, and test position revealed only spurious influence. Workload scores derived from the NASA-TLX fell at the high end of the scale, with mental and temporal demand receiving the highest ratings. In Experiment 2, we modified the dual task to place more emphasis on attention rather than working memory. Results revealed a significant decline in performance across the vigil for the perceptual sensitivity index A'. Test position (early vs. late) effects appeared with the reaction time variability measure, with performance becoming more variable when the task appeared in the latter half of the battery. Workload scores varied according to position in the battery: Workload scores were higher when the vigilance task appeared in the latter half of the battery. Practical and theoretical implications are discussed.

Multi-capillary based optical sensors for highly sensitive protein detection

NASA Astrophysics Data System (ADS)

Okuyama, Yasuhira; Katagiri, Takashi; Matsuura, Yuji

2017-04-01

A fluorescence measuring method based on glass multi-capillary for detecting trace amounts of proteins is proposed. It promises enhancement of sensitivity due to effects of the adsorption area expansion and the longitudinal excitation. The sensitivity behavior of this method was investigated by using biotin-streptavidin binding. According to experimental examinations, it was found that the sensitivity was improved by a factor of 70 from common glass wells. We also confirmed our measuring system could detect 1 pg/mL of streptavidin. These results suggest that multi-capillary has a potential as a high-sensitive biosensor.

Telomere formation on macronuclear chromosomes of Oxytricha trifallax and O. fallax: alternatively processed regions have multiple telomere addition sites

PubMed Central

Williams, Kevin R; Doak, Thomas G; Herrick, Glenn

2002-01-01

Background Ciliates employ massive chromatid breakage and de novo telomere formation during generation of the somatic macronucleus. Positions flanking the 81-MAC locus are reproducibly cut. But those flanking the Common Region are proposed to often escape cutting, generating three nested macronuclear chromosomes, two retaining "arms" still appended to the Common Region. Arm-distal positions must differ (in cis) from the Common Region flanks. Results The Common-Region-flanking positions also differ from the arm-distal positions in that they are "multi-TAS" regions: anchored PCR shows heterogeneous patterns of telomere addition sites, but arm-distal sites do not. The multi-TAS patterns are reproducible, but are sensitive to the sequence of the allele being processed. Thus, random degradation following chromatid cutting does not create this heterogeneity; these telomere addition sites also must be dictated by cis-acting sequences. Conclusions Most ciliates show such micro-heterogeneity in the precise positions of telomere addition sites. Telomerase is believed to be tightly associated with, and act in concert with, the chromatid-cutting nuclease: heterogeneity must be the result of intervening erosion activity. Our "weak-sites" hypothesis explains the correlation between alternative chromatid cutting at the Common Region boundaries and their multi-TAS character: when the chromatid-breakage machine encounters either a weak binding site or a weak cut site at these regions, then telomerase dissociates prematurely, leaving the new end subject to erosion by an exonuclease, which pauses at cis-acting sequences; telomerase eventually heals these resected termini. Finally, we observe TAS positioning influenced by trans-allelic interactions, reminiscent of transvection. PMID:12199911

Hit identification and optimization in virtual screening: practical recommendations based on a critical literature analysis.

PubMed

Zhu, Tian; Cao, Shuyi; Su, Pin-Chih; Patel, Ram; Shah, Darshan; Chokshi, Heta B; Szukala, Richard; Johnson, Michael E; Hevener, Kirk E

2013-09-12

A critical analysis of virtual screening results published between 2007 and 2011 was performed. The activity of reported hit compounds from over 400 studies was compared to their hit identification criteria. Hit rates and ligand efficiencies were calculated to assist in these analyses, and the results were compared with factors such as the size of the virtual library and the number of compounds tested. A series of promiscuity, druglike, and ADMET filters were applied to the reported hits to assess the quality of compounds reported, and a careful analysis of a subset of the studies that presented hit optimization was performed. These data allowed us to make several practical recommendations with respect to selection of compounds for experimental testing, definition of hit identification criteria, and general virtual screening hit criteria to allow for realistic hit optimization. A key recommendation is the use of size-targeted ligand efficiency values as hit identification criteria.

Methods to identify, study and understand end-user participation in HIT development.

PubMed

Høstgaard, Anna Marie; Bertelsen, Pernille; Nøhr, Christian

2011-09-28

Experience has shown that for new health-information-technology (HIT) to be suc-cessful clinicians must obtain positive clinical benefits as a result of its implementation and joint-ownership of the decisions made during the development process. A prerequisite for achieving both success criteria is real end-user-participation. Experience has also shown that further research into developing improved methods to collect more detailed information on social groups participating in HIT development is needed in order to support, facilitate and improve real end-user participation. A case study of an EHR planning-process in a Danish county from October 2003 until April 2006 was conducted using process-analysis. Three social groups (physicians, IT-professionals and administrators) were identified and studied in the local, present perspective. In order to understand the interactions between the three groups, the national, historic perspective was included through a literature-study. Data were collected through observations, interviews, insight gathered from documents and relevant literature. In the local, present perspective, the administrator's strategy for the EHR planning process meant that there was no clinical workload-reduction. This was seen as one of the main barriers to the physicians to achieving real influence. In the national, historic perspective, physicians and administrators have had/have different perceptions of the purpose of the patient record and they have both struggled to influence this definition. To date, the administrators have won the battle. This explains the conditions made available for the physicians' participation in this case, which led to their role being reduced to that of clinical consultants--rather than real participants. In HIT-development the interests of and the balance of power between the different social groups involved are decisive in determining whether or not the end-users become real participants in the development process. Real end-user-participation is essential for the successful outcome of the process. By combining and developing existing theories and methods, this paper presents an improved method to collect more detailed information on social groups participating in HIT-development and their interaction during the development. This allows HIT management to explore new avenues during the HIT development process in order to support, facilitate and improve real end-user participation.

Specific Intensity for Peaking: Is Race Pace the Best Option?

PubMed Central

Munoz, Iker; Seiler, Stephen; Alcocer, Alberto; Carr, Natasha; Esteve-Lanao, Jonathan

2015-01-01

Background: The peaking period for endurance competition is characterized for a relative increase of the intensity of training, after a longer period of training relatively dominated by lower intensity and higher volume Objectives: The present study was designed to compare physiological and 10 km performance effects of high intensity training (HIT) versus race pace interval training (RP) during peaking for competition in well-trained runners. Patients and Methods: 13 athletes took part in the study, they were divided into two groups: HIT and RP. HIT performed short intervals at ~105% of the maximal aerobic velocity (MAV), while RP trained longer intervals at a speed of ~90% of the MAV (a speed approximating 10 km race pace). After 12 weeks of baseline training, the athletes trained for 6 weeks under one of the two peaking regimes. Subjects performed 10 km prior to and after the intervention period. The total load of training was matched between groups during the treatment phase. Subjects completed a graded treadmill running test until volitional exhaustion prior to each 10 km race. MAV was determined as the minimal velocity eliciting maximal oxygen consumption (VO2max). Results: Both groups significantly improved their 10 km time (35 minutes 29 seconds ± 1 minutes 41 seconds vs 34 minutes 53 seconds ± 1 minutes 55 seconds, P < 0.01 for HIT; 35 minutes 27 seconds ± 1 minutes 40 seconds vs 34 minutes 53 seconds ± 1 minutes 18 seconds P < 0.01 for RP). VO2max increased after HIT (69 ± 3.6 vs 71.5 ± 4.2 ml.Kg-1.min-1, P < 0.05); while it didn’t for RP (68.4 ± 6 vs 69.8 ± 3 ml.Kg-1.min-1, p>0.05). In contrast, running economy decreased significantly after HIT (210 ± 6 ml.Kg-1.km-1 vs 218 ± 9, P < 0.05). Conclusions: A 6 week period of training at either 105% of MAV or 90% of MAV yielded similar performance gains in a 10km race performed at ~90% MAV. Therefore, the physiological impact of HIT training seems to be positive for VO2max but negative for running economy. PMID:26448854

Identification of potential anti-infectives against Staphylococcus aureus using a Caenorhabditis elegans infection model

NASA Astrophysics Data System (ADS)

Kong, Cin; Rahman, Noorsaadah Abd; Nathan, Sheila

2014-09-01

The alarming increase of antibiotic-resistant Staphylococcus aureus and a delay in antibiotics development point to the need for novel therapeutic approaches to combat infection. To discover novel anti-infective agents, we screened a number of synthetic compounds comprising mainly of chalcone derivatives to explore their potential in promoting the survival of the nematode Caenorhabditis elegans upon infection by S. aureus. Screening of seven chalcone derivatives using both agar- and liquid-based assays revealed three positive hits that significantly prolonged the survival of S. aureus-infected nematodes. All the hits did not interfere with bacterial growth in vitro, proposing that the three compounds identified most probably act through mechanisms distinct from conventional antibiotics that target bacterial replication.

Brightness and uniformity measurements of plastic scintillator tiles at the CERN H2 test beam

DOE PAGES

Chatrchyan, S.; Sirunyan, A. M.; Tumasyan, A.; ...

2018-01-05

Here, we study the light output, light collection efficiency and signal timing of a variety of organic scintillators that are being considered for the upgrade of the hadronic calorimeter of the CMS detector. The experimental data are collected at the H2 test-beam area at CERN, using a 150 GeV muon beam. In particular, we investigate the usage of over-doped and green-emitting plastic scintillators, two solutions that have not been extensively considered. We present a study of the energy distribution in plastic-scintillator tiles, the hit efficiency as a function of the hit position, and a study of the signal timing formore » blue and green scintillators.« less

Brightness and uniformity measurements of plastic scintillator tiles at the CERN H2 test beam

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chatrchyan, S.; Sirunyan, A. M.; Tumasyan, A.

Here, we study the light output, light collection efficiency and signal timing of a variety of organic scintillators that are being considered for the upgrade of the hadronic calorimeter of the CMS detector. The experimental data are collected at the H2 test-beam area at CERN, using a 150 GeV muon beam. In particular, we investigate the usage of over-doped and green-emitting plastic scintillators, two solutions that have not been extensively considered. We present a study of the energy distribution in plastic-scintillator tiles, the hit efficiency as a function of the hit position, and a study of the signal timing formore » blue and green scintillators.« less

Delayed-onset heparin-induced skin necrosis: a rare complication of perioperative heparin therapy.

PubMed

Gan, Weh Kiat

2017-11-03

An uncommon case of delayed-onset dalteparin-induced skin necrosis in an 83-year-old Caucasian female patient associated with heparin-induced thrombocytopaenia (HIT) presenting on day 30 following dalteparin therapy is reported. Investigations revealed mild thrombocytopaenia with normal protein C, protein S, coagulation screen and positive test for heparin-platelet factor-4 antibody. Clinical diagnosis of heparin-induced skin necrosis with HIT was made. Dalteparin injection was discontinued promptly and substituted with fondaparinux therapy. The patient achieved good recovery following cessation of dalteparin therapy and was subsequently discharged. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Discovery of novel bacterial RNA polymerase inhibitors: pharmacophore-based virtual screening and hit optimization.

PubMed

Hinsberger, Stefan; Hüsecken, Kristina; Groh, Matthias; Negri, Matthias; Haupenthal, Jörg; Hartmann, Rolf W

2013-11-14

The bacterial RNA polymerase (RNAP) is a validated target for broad spectrum antibiotics. However, the efficiency of drugs is reduced by resistance. To discover novel RNAP inhibitors, a pharmacophore based on the alignment of described inhibitors was used for virtual screening. In an optimization process of hit compounds, novel derivatives with improved in vitro potency were discovered. Investigations concerning the molecular mechanism of RNAP inhibition reveal that they prevent the protein-protein interaction (PPI) between σ(70) and the RNAP core enzyme. Besides of reducing RNA formation, the inhibitors were shown to interfere with bacterial lipid biosynthesis. The compounds were active against Gram-positive pathogens and revealed significantly lower resistance frequencies compared to clinically used rifampicin.

Ultra-Sensitive Detection of Plasmodium falciparum by Amplification of Multi-Copy Subtelomeric Targets

PubMed Central

Hofmann, Natalie; Mwingira, Felista; Shekalaghe, Seif; Robinson, Leanne J.; Mueller, Ivo; Felger, Ingrid

2015-01-01

Background Planning and evaluating malaria control strategies relies on accurate definition of parasite prevalence in the population. A large proportion of asymptomatic parasite infections can only be identified by surveillance with molecular methods, yet these infections also contribute to onward transmission to mosquitoes. The sensitivity of molecular detection by PCR is limited by the abundance of the target sequence in a DNA sample; thus, detection becomes imperfect at low densities. We aimed to increase PCR diagnostic sensitivity by targeting multi-copy genomic sequences for reliable detection of low-density infections, and investigated the impact of these PCR assays on community prevalence data. Methods and Findings Two quantitative PCR (qPCR) assays were developed for ultra-sensitive detection of Plasmodium falciparum, targeting the high-copy telomere-associated repetitive element 2 (TARE-2, ∼250 copies/genome) and the var gene acidic terminal sequence (varATS, 59 copies/genome). Our assays reached a limit of detection of 0.03 to 0.15 parasites/μl blood and were 10× more sensitive than standard 18S rRNA qPCR. In a population cross-sectional study in Tanzania, 295/498 samples tested positive using ultra-sensitive assays. Light microscopy missed 169 infections (57%). 18S rRNA qPCR failed to identify 48 infections (16%), of which 40% carried gametocytes detected by pfs25 quantitative reverse-transcription PCR. To judge the suitability of the TARE-2 and varATS assays for high-throughput screens, their performance was tested on sample pools. Both ultra-sensitive assays correctly detected all pools containing one low-density P. falciparum–positive sample, which went undetected by 18S rRNA qPCR, among nine negatives. TARE-2 and varATS qPCRs improve estimates of prevalence rates, yet other infections might still remain undetected when absent in the limited blood volume sampled. Conclusions Measured malaria prevalence in communities is largely determined by the sensitivity of the diagnostic tool used. Even when applying standard molecular diagnostics, prevalence in our study population was underestimated by 8% compared to the new assays. Our findings highlight the need for highly sensitive tools such as TARE-2 and varATS qPCR in community surveillance and for monitoring interventions to better describe malaria epidemiology and inform malaria elimination efforts. PMID:25734259

Radial magnetic resonance imaging (MRI) using a rotating radiofrequency (RF) coil at 9.4 T.

PubMed

Li, Mingyan; Weber, Ewald; Jin, Jin; Hugger, Thimo; Tesiram, Yasvir; Ullmann, Peter; Stark, Simon; Fuentes, Miguel; Junge, Sven; Liu, Feng; Crozier, Stuart

2018-02-01

The rotating radiofrequency coil (RRFC) has been developed recently as an alternative approach to multi-channel phased-array coils. The single-element RRFC avoids inter-channel coupling and allows a larger coil element with better B 1 field penetration when compared with an array counterpart. However, dedicated image reconstruction algorithms require accurate estimation of temporally varying coil sensitivities to remove artefacts caused by coil rotation. Various methods have been developed to estimate unknown sensitivity profiles from a few experimentally measured sensitivity maps, but these methods become problematic when the RRFC is used as a transceiver coil. In this work, a novel and practical radial encoding method is introduced for the RRFC to facilitate image reconstruction without the measurement or estimation of rotation-dependent sensitivity profiles. Theoretical analyses suggest that the rotation-dependent sensitivities of the RRFC can be used to create a uniform profile with careful choice of sampling positions and imaging parameters. To test this new imaging method, dedicated electronics were designed and built to control the RRFC speed and hence positions in synchrony with imaging parameters. High-quality phantom and animal images acquired on a 9.4 T pre-clinical scanner demonstrate the feasibility and potential of this new RRFC method. Copyright © 2017 John Wiley & Sons, Ltd.

The Role of Religion in 21st-Century Public Schools: Historic Perspectives on God and Goodness in the Classroom

ERIC Educational Resources Information Center

Jones, Steven P.; Sheffield, Eric C.

2010-01-01

No other educational issue hits a more sensitive nerve with the American public than the role of religion in the public schools. While the intentions and actions of the religious and non-religious parents and community members overlap a great deal as they conceive of the good people they want their children to become, there is no apparent…

Nanoscale molecularly imprinted polymers and method thereof

DOEpatents

Hart, Bradley R [Brentwood, CA; Talley, Chad E [Brentwood, CA

2008-06-10

Nanoscale molecularly imprinted polymers (MIP) having polymer features wherein the size, shape and position are predetermined can be fabricated using an xy piezo stage mounted on an inverted microscope and a laser. Using an AMF controller, a solution containing polymer precursors and a photo initiator are positioned on the xy piezo and hit with a laser beam. The thickness of the polymeric features can be varied from a few nanometers to over a micron.

Position-sensitive coincidence detection of nuclear reaction products at the Prague Van-de-Graaff accelerator

NASA Astrophysics Data System (ADS)

Granja, Carlos; Kraus, Vaclav; Pugatch, Valery; Kohout, Zdenek

2017-06-01

In low-energy nuclear reactions of astrophysical interest or fusion studies the spatial- and time-correlated detection of two and more reaction products can be a valuable tool in studies of reaction mechanisms, resolving reaction channels and measuring angular distributions of reaction products. For this purpose we constructed a configurable array of position-sensitive detectors based on the hybrid semiconductor pixel detector Timepix. Additional analog-signal electronics provide self-trigger together with extended multi-device control and synchronized readout electronics by a customized control and coincidence unit. The instrumentation, developed and used for detection of fission fragments in spontaneous and neutron induced fission as well as in charged particle detection in neutron induced reactions, is being implemented for low-energy light-ion induced nuclear reactions. Application and demonstration of the technique with two Timepix detectors on p+p elastic scattering at the Van-de-Graaff (VdG) accelerator in Prague is given.

Effects of D2 or combined D1/D2 receptor antagonism on the methamphetamine-induced one-trial and multi-trial behavioral sensitization of preweanling rats

PubMed Central

Mohd-Yusof, Alena; Veliz, Ana; Rudberg, Krista N.; Stone, Michelle J.; Gonzalez, Ashley E.; McDougall, Sanders A.

2015-01-01

Rationale There is suggestive evidence that the neural mechanisms mediating one-trial and multi-trial behavioral sensitization differ, especially when the effects of various classes of dopamine (DA) agonists are examined. Objective The purpose of the present study was to determine the role of the D2 receptor for the induction of one-trial and multi-trial methamphetamine sensitization in preweanling rats. Methods In a series of experiments, rats were injected with saline or raclopride (a selective D2 receptor antagonist), either alone or in combination with SCH23390 (a selective D1 receptor antagonist), 15 min prior to treatment with the indirect DA agonist methamphetamine. Acute control groups were given two injections of saline. This pretreatment regimen occurred on either postnatal days (PD) 13–16 (multi-trial) or PD 16 (one-trial). On PD 17, rats were challenged with methamphetamine and locomotor sensitization was determined. Results Blockade of D2 or D1/D2 receptors reduced or prevented, respectively, the induction of multi-trial methamphetamine sensitization in young rats, while the same manipulations had minimal effects on one-trial behavioral sensitization. Conclusions DA antagonist treatment differentially affected the methamphetamine-induced sensitized responding of preweanling rats depending on whether a one-trial or multi-trial procedure was used. The basis for this effect is uncertain, but there was some evidence that repeated DA antagonist treatment caused nonspecific changes that produced a weakened sensitized response. Importantly, DA antagonist treatment did not prevent the one-trial behavioral sensitization of preweanling rats. The latter result brings into question whether DA receptor stimulation is necessary for the induction of psychostimulant-induced behavioral sensitization during early ontogeny. PMID:26650612

Point-of-care Helicobacter pylori urine antibody detection in a multi-ethnic adult population in the United States.

PubMed

Opekun, Antone R; Luu, Phong; Gotschall, Ann B; Abdalla, Nageeb; Torres, Elizabeth; Rudd, Summer B; Graham, David Y; Nurgalieva, Zhannat Z; Tsuchiya, Kyoko

2006-07-01

A need exists for accurate point-of-care tests for diagnosis of Helicobacter pylori (H. pylori) infection to evaluate a rapid urine-H. pylori antibody test device for detection of H. pylori infection in a point-of-care setting in the United States. A multi-center study in a multi-ethnic population compared the RAPIRUN urine antibody test with the (13)C-urea breath test (C-UBT) and a traditional serologic test, the high-molecular-weight cell-associated protein enzyme immunoassay (HM-CAP EIA). The primary comparator was with "definite positive" and "definite negative" patients defined as a concordance of combined results of the UBT and the HM-CAP IgG EIA. Overall, 188 eligible patients were enrolled (61 men, age range: 18-73 years, including 84 Hispanics, 73 Asian-Pacific Americans, 22 Black African-Americans, 6 non-Hispanic Caucasians, and 3 of "other" ethnicity). Compared with "definite positive" and "definite negative" results, the sensitivity and specificity of the urine antibody test were 0.9 and 1.0, respectively. The urine antibody test proved suitable for point-of-care rapid diagnosis of anti-H. pylori antibodies indicative of active or past H. pylori infection.