1,190 results on '"S. Carey"'
Search Results
2. High-throughput drug screening identifies novel therapeutics for Low Grade Serous Ovarian Carcinoma
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Kathleen I. Pishas, Karla J. Cowley, Marta Llaurado-Fernandez, Hannah Kim, Jennii Luu, Robert Vary, Nikola A. Bowden, Ian G. Campbell, Mark S. Carey, Kaylene J. Simpson, and Dane Cheasley
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Science - Abstract
Abstract Low grade serous carcinoma (LGSOC) is a rare epithelial ovarian cancer with unique molecular characteristics compared to the more common tubo-ovarian high-grade serous ovarian carcinoma. Pivotal clinical trials guiding the management of epithelial ovarian cancer lack sufficient cases of LGSOC for meaningful subgroup analysis, hence overall findings cannot be extrapolated to rarer chemo-resistant subtypes such as LGSOC. Furthermore, there is a need for more effective therapies for the treatment of relapsed disease, as treatment options are limited. To address this, we conducted the largest quantitative high-throughput drug screening effort (n = 3436 compounds) in 12 patient-derived LGSOC cell lines and one normal ovary cell line to identify unexplored therapeutic avenues. Using a combination of high-throughput robotics, high-content imaging and novel data analysis pipelines, our data set identified 60 high and 19 moderate confidence hits which induced cancer cell specific cytotoxicity at the lowest compound dose assessed (0.1 µM). We also revealed a series of known (mTOR/PI3K/AKT) and novel (EGFR and MDM2-p53) drug classes in which LGSOC cell lines showed demonstrable susceptibility to.
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- 2024
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3. Ovarian carcinosarcomas: p53 status defines two distinct patterns of oncogenesis and outcomes
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Gurdial Dhillon, Marta Llaurado-Fernandez, Basile Tessier-Cloutier, Keiyan Sy, Dina Bassiouny, Guangming Han, Nelson K. Y. Wong, Kathryn McRae, Mary Kinloch, Jennifer Pors, Laura Hopkins, Allan Covens, Martin Köbel, Cheng-Han Lee, and Mark S. Carey
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ovarian cancer ,ovarian carcinosarcoma ,MMMT ,immunohistochemistry ,p53 IHC ,BRCA ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
ObjectivesOvarian carcinosarcoma (OCS) is a rare and lethal type of ovarian cancer. Despite its incredibly poor prognosis, it has received little research attention. In this study, we aim to evaluate the molecular features of OCS and elucidate their clinical significance.Study methodsWe examined 30 OCS by immunohistochemistry (IHC) and targeted panel sequencing collected from a single institution (2003–2013) as the initial molecularly characterized cohort (Cohort A). From November 2016 to April 2023, we collected an additional 67 OCS cases from three institutions across British Columbia and Alberta as the contemporary cohort (Cohort B) for clinical correlation. The Kaplan–Meier method was used to estimate overall and progression-free survival, and differences in survival rates were compared using the log-rank test. All tests were two-sided. A p-value of less than 0.05 was considered statistically significant.ResultsThe majority of OCS (82%) in the initial Cohort A were p53-mutated, and the carcinomatous component displayed the histological and molecular features of a high-grade tubo-ovarian serous carcinoma (HGSC-like). In a minority of OCS, the epithelial components were characteristics of endometrioid or clear cell carcinomas, and IHC staining was wild type for p53. In the contemporary Cohort B, we observed the same histological findings related to the p53 IHC staining pattern. The median overall survival of the p53-mutated HGSC-like OCS (47 patients) was significantly higher (43.5 months) compared with that of the p53 wild-type OCS (10 patients, 8.8 months; P < 0.01). Pathogenic BRCA1/2 germline/somatic mutations were observed in 7 patients (17.5%) of HGSC-like OCS, and all these patients were alive at 3 years from diagnosis compared to a 51% 3-year survival among the patients with BRCA1/2 wild-type HGSC-like OCS (33 patients) (p = 0.022). Majority of patients (6/7) with BRCA1/2-mutated OCS received poly (ADP-ribose) polymerase inhibitor as maintenance therapy in this cohort.ConclusionsMost OCSs have a morphologic and molecular profile resembling HGSC; however, some OCSs display a molecular profile that suggests origin through non-serous oncogenic pathways. This molecular distinction has both prognostic and treatment (predictive) implications. These findings underscore the importance of routine p53 IHC testing on all OCS and BRCA1/2 testing on p53-mutated OCS.
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- 2024
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4. A generic system dynamics model for simulating and evaluating the hydrological performance of reconstructed watersheds
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N. Keshta, A. Elshorbagy, and S. Carey
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Technology ,Environmental technology. Sanitary engineering ,TD1-1066 ,Geography. Anthropology. Recreation ,Environmental sciences ,GE1-350 - Abstract
A generic system dynamics watershed (GSDW) model is developed and applied to five reconstructed watersheds located in the Athabasca mining basin, Alberta, Canada, and one natural watershed (boreal forest) located in Saskatchewan, Canada, to simulate various hydrological processes in reconstructed and natural watersheds. This paper uses the root mean square error (RMSE), the mean absolute relative error (MARE), and the correlation coefficient (R) as the main performance indicators, in addition to the visual comparison. For the South Bison Hills (SBH), South West Sand Storage (SWSS) and Old Aspen (OA) simulated soil moisture, the RMSE values ranges between 2.5–4.8 mm, and the MARE ranges from 7% to 18%, except for the D2-cover it was 26% for the validation year. The R statistics ranges from 0.3 to 0.77 during the validation period. The error between the measured and simulated cumulative actual evapotranspiration (AET) flux for the SWSS, SBH, and the OA sites were 2%, 5%, and 8%, respectively. The developed GSDW model enables the investigation of the utility of different soil cover designs and evaluation of their performance. The model is capable of capturing the dynamics of water balance components, and may used to conduct short- and long- term predictions under different climate scenarios.
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- 2009
5. Enhancing the sensitivity of atom-interferometric inertial sensors using robust control
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Jack C. Saywell, Max S. Carey, Philip S. Light, Stuart S. Szigeti, Alistair R. Milne, Karandeep S. Gill, Matthew L. Goh, Viktor S. Perunicic, Nathanial M. Wilson, Calum D. Macrae, Alexander Rischka, Patrick J. Everitt, Nicholas P. Robins, Russell P. Anderson, Michael R. Hush, and Michael J. Biercuk
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Science - Abstract
Abstract Atom-interferometric quantum sensors could revolutionize navigation, civil engineering, and Earth observation. However, operation in real-world environments is challenging due to external interference, platform noise, and constraints on size, weight, and power. Here we experimentally demonstrate that tailored light pulses designed using robust control techniques mitigate significant error sources in an atom-interferometric accelerometer. To mimic the effect of unpredictable lateral platform motion, we apply laser-intensity noise that varies up to 20% from pulse-to-pulse. Our robust control solution maintains performant sensing, while the utility of conventional pulses collapses. By measuring local gravity, we show that our robust pulses preserve interferometer scale factor and improve measurement precision by 10× in the presence of this noise. We further validate these enhancements by measuring applied accelerations over a 200 μ g range up to 21× more precisely at the highest applied noise level. Our demonstration provides a pathway to improved atom-interferometric inertial sensing in real-world settings.
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- 2023
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6. Cervical PEComa: Challenges in diagnosis and prognosis of a rare neoplasm
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Sarah J. Mah, Lien Hoang, Shaina Lee, Sarah Finlayson, and Mark S. Carey
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Perivascular epithelioid cell neoplasms (PEComa) ,Cervical cancer ,Rare tumours ,Prognostication ,Pathologic classification ,Outcomes ,Gynecology and obstetrics ,RG1-991 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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7. Feasibility of a best–worst scaling exercise to set priorities for autism research
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Scott A. Davis, Kirsten Howard, Alan R. Ellis, Daniel E. Jonas, Timothy S. Carey, Joseph P. Morrissey, and Kathleen C. Thomas
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autism ,best–worst scaling ,direct prioritization ,discrete‐choice experiment ,stakeholder engagement ,stakeholder priorities ,Medicine (General) ,R5-920 ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background The preferences of autism stakeholders regarding the top priorities for future autism research are largely unknown. Objective This study had two objectives: First, to examine what autism stakeholders think new research investments should be and the attributes of investment that they consider important, and second, to explore the feasibility, acceptability and outcomes of two prioritization exercises among autism stakeholders regarding their priorities for future research in autism. Design This was a prospective stakeholder‐engaged iterative study consisting of best–worst scaling (BWS) and direct prioritization exercise. Setting and Participants A national snowball sample of 219 stakeholders was included: adults with autism, caregivers, service providers and researchers. Main Outcome Measures The main outcomes measures were attributes that participants value in future research investments, and priority research investments for future research. Results Two hundred and nineteen participants completed the exercises, of whom 11% were adults with autism, 58% were parents/family members, 37% were service providers and 21% were researchers. Among stakeholders, the BWS exercises were easier to understand than the direct prioritization, less frequently skipped and yielded more consistent results. The proportion of children with autism affected by the research was the most important attribute for all types of stakeholders. The top three priorities among future research investments were (1) evidence on which child, family and intervention characteristics lead to the best/worst outcomes; (2) evidence on how changes in one area of a child's life are related to changes in other areas; and (3) evidence on dietary interventions. Priorities were similar for all stakeholder types. Conclusions The values and priorities examined here provide a road map for investigators and funders to pursue autism research that matters to stakeholders. Patient or Public Contribution Stakeholders completed a BWS and direct prioritization exercise to inform us about their priorities for future autism research.
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- 2022
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8. 'Cookbook medicine': Exploring the impact of opioid prescribing limits legislation on clinical practice and patient experiences
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Elizabeth Joniak-Grant, Natalie A. Blackburn, Nabarun Dasgupta, Maryalice Nocera, Samantha Wooten Dorris, Paul R. Chelminski, Timothy S. Carey, and Shabbar I. Ranapurwala
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Drugs/medication ,Medical practice ,Pain ,Regulation ,Qualitative/in-depth interviews ,North America ,Public aspects of medicine ,RA1-1270 - Abstract
Opioid dependence and overdose are serious public health concerns. States have responded by enacting legislation regulating opioid-prescribing practices. Through in-depth interviews with clinicians, state officials, and organizational stakeholders, this paper examines opioid prescribing limits legislation (PLL) in North Carolina and how it impacts clinical practice. Since the advent of PLL, clinicians report being more mindful when prescribing opioids and as expected, writing for shorter durations for both acute and postoperative pain. But clinicians also report prescribing opioids less frequently for acute pain, refusing to write second opioid prescriptions, foisting responsibility for patient pain care onto other clinicians, and no longer writing opioid prescriptions for chronic pain patients. They directly credit PLL for these changes, including institutional policies enacted in response to PLL, and, to a lesser degree, notions of “do no harm.” However, we argue that misapplication of and ambiguities in PLL along with defensive medicine practices whereby clinicians and their institutions center their legal interests over patient care, amplify these restrictive changes in clinical practice. Clinicians’ narratives reveal downstream consequences for patients including undertreated pain, being viewed as drug-seeking when questioning opioid-prescribing decisions, and having to overuse the medical system to achieve pain relief.
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- 2023
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9. Molecular characterization of low-grade serous ovarian carcinoma identifies genomic aberrations according to hormone receptor expression
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Dane Cheasley, Marta Llaurado Fernandez, Martin Köbel, Hannah Kim, Amy Dawson, Joshua Hoenisch, Madison Bittner, Derek S. Chiu, Aline Talhouk, C. Blake Gilks, Madawa W. Jayawardana, Kathleen I. Pishas, Anne-Marie Mes-Masson, Diane Provencher, Abhimanyu Nigam, Neville F. Hacker, Kylie L. Gorringe, Ian G. Campbell, and Mark S. Carey
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Hormone receptor expression is a characteristic of low-grade serous ovarian carcinoma (LGSOC). Studies investigating estrogen receptor (ER) and progesterone receptor (PR) expression levels suggest its prognostic and predictive significance, although their associations with key molecular aberrations are not well understood. As such, we sought to describe the specific genomic profiles associated with different ER/PR expression patterns and survival outcomes in a cohort of patients with advanced disease. The study comprised fifty-five advanced-staged (III/IV) LGSOCs from the Canadian Ovarian Experimental Unified Resource (COEUR) for which targeted mutation sequencing, copy-number aberration, clinical and follow-up data were available. ER, PR, and p16 expression were assessed by immunohistochemistry. Tumors were divided into low and high ER/PR expression groups based on Allred scoring. Copy number analysis revealed that PR-low tumors (Allred score
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- 2022
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10. Supporting research, protecting data: one institution's approach to clinical data warehouse governance.
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Kellie M. Walters, Anna Jojic, Emily R. Pfaff, Marie Rape, Donald C. Spencer, Nicholas J. Shaheen, Brent Lamm, and Timothy S. Carey
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- 2022
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11. Multisite gynecologic endometrioid adenocarcinomas: Can mutation profiling be used to distinguish synchronous primary cancers from metastases?
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Dominique Barnes, Nissreen Mohammad, Lien Hoang, Michael Anglesio, Robert L. Hollis, Charlie Gourley, Heather C. Stuart, Mark S. Carey, and Gavin C.E. Stuart
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Endometrioid carcinoma ,Mutation analysis ,Clonality ,Gynecologic cancers ,Gynecology and obstetrics ,RG1-991 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
It is well recognized that some patients with endometrioid gynecological cancers have tumors arising in multiple sites (ovary, endometrium, and endometriosis) at the time of diagnosis. Molecular analysis has helped discern whether these multisite cancers represent synchronous primary tumors or alternatively metastatic disease. We present a complex case of a patient with endometrioid carcinomas arising in multiple sites. We discuss the use of mutation profiling to discern clonality and highlight how this information may inform the clinical management of such cases.
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- 2022
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12. Analyzing mobility trends of tracked vehicles on fine-grained soils in a progressive slip condition using full-scale test data presented in DROVE 3.0
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Arman Borazjani, Isaac L. Howard, Zach Griffing, Ashley S. Carey, Farshid Vahedifard, George L. Mason, and Jody D. Priddy
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Mechanical Engineering - Published
- 2023
13. Stress–strain behaviour and failure properties of ultra-high-performance concrete
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Isaac L. Howard, Robert D. Moser, Denver Seely, Dylan A. Scott, Ashley S. Carey, Megan N. McBride, Youssef Hammi, and Mark F. Horstemeyer
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Materials science ,Mechanics of Materials ,Stress–strain curve ,General Materials Science ,Ultra high performance ,Composite material ,Civil and Structural Engineering - Abstract
In this paper, ultra-high-performance concrete (UHPC) and its constituents were evaluated by way of instrumented and non-instrumented mechanical-property tests and imaging techniques. Through image analysis, the average size, per cent area, nearest-neighbour distance and relative number density of each inclusion type were determined. Instrumented mechanical-property testing was conducted to obtain estimates for the relative behaviour of UHPC's various constituents. Different combinations of constituents were produced to measure indirect tensile strength, compressive strength, elastic modulus, Poisson's ratio and overall stress–strain behaviour to failure at early and later ages. Stress–strain behaviour and Poisson's ratio of UHPC aligned well with the literature, while constituents of UHPC also showed linear stress–strain relationships and comparable Poisson's ratios. Tensile behaviour at early and late ages was characterised and was found to be driven by inclusion of fibres. Characterisation of UHPC and its constituents is envisioned to be used to further modelling efforts by basing mathematical relationships on physical measurements.
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- 2023
14. Promoting Computational Thinking, Computational Participation, and Spatial Reasoning with LEGO Robotics
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Jacqueline Leonard, Cara Djonko-Moore, Krista R. Francis, Aylin S. Carey, Monica B. Mitchell, and Imani D. Goffney
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Education - Published
- 2023
15. OGLE-2018-BLG-1185b: A Low-mass Microlensing Planet Orbiting a Low-mass Dwarf
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Iona Kondo, Jennifer C. Yee, David P. Bennett, Takahiro Sumi, Naoki Koshimoto, Ian A. Bond, Andrew Gould, Andrzej Udalski, Yossi Shvartzvald, Youn Kil Jung, Weicheng Zang, Valerio Bozza, Etienne Bachelet, Markus P. G. Hundertmark, Nicholas J. Rattenbury, F. Abe, R Barry, A. Bhattacharya, M. Donachie, A. Fukui, H. Fujii, Y. Hirao, S. Ishitani Silva, Y. Itow, R. Kirikawa, M. C. A. Li, Y. Matsubara, S. Miyazaki, Y. Muraki, G. Olmschenk, C. Ranc, Y. Satoh, H. Shoji, D. Suzuki, Y. Tanaka, K. Ulaczyk, P. J. Tristram, T. Yamawaki, A Yonehara, R. Poleski, J. Skowron, M. K. Szymański, K. A. Rybicki, I. Soszynski, S. Kozłowski, P. Pietrukowicz, P. Iwanek, M. Wrona, M. D. Albrow, J. Wambsganss, S. J. Chung, C. Han, K. H. Hwang, H. W. Kim, I. G. Shin, S. M. Cha, D. J. Kim, S. L. Kim, C. U. Lee, D. J. Lee, Y. Lee, B. G. Park, R. W. Pogge, Y.-H. Ryu, C. A. Beichman, G Bryden, S. Calchi Novati, S. Carey, B. S. Gaudi, C. B. Henderson, W. Zhu, D. Maoz, M. T. Penny, M. Dominik, U. G. Jorgensen, P. Longa-Pena, N. Peixinho, S. Sajadian, J. Skottfelt, C. Snodgrass, J. Tregloan-Reed, M. J. Burgdorf, J. Campbell-White, S. Dib, Y. I. Fujii, E. Khalouei, S. Rahvar, M. Rabus, J. Southworth, Y. Tsapras, R. A. Street, D. M. Bramich, A. Cassan, K. Horne, S. Mao, A. Saha, and P. Mroz
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Astronomy - Abstract
We report an analysis of the planetary microlensing event OGLE-2018-BLG-1185, which was observed by a large number of ground-based telescopes and by the Spitzer Space Telescope. The ground-based light curve indicates a low planet–host star mass ratio ofq=(6.9±0.2)×10−5, which is near the peak of the wide-orbit exoplanet mass-ratio distribution. We estimate the host star and planet masses with a Bayesian analysis using the measured angular Einstein radius under the assumption that stars of all masses have an equal probability of hosting the planet. The flux variation observed by Spitzer is marginal, but still places a constraint on the microlens parallax. Imposing a conservative constraint that this flux variation should beΔfSpz<4 instrumental flux units yields a host mass of=-+MM0.37 host 0.210.35 and a planet mass of =-+ÅmM8.4p4.77.9. A Bayesian analysis including the full parallax constraint from Spitzer suggests smaller host star and planet masses of =-+MM0.091 host 0.0180.064 and =-+ÅmM2.1p0.41.5, respectively. Future high-resolution imaging observations with the Hubble Space Telescope or Extremely Large Telescope could distinguish between these two scenarios and help reveal the planetary system properties in more detail.
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- 2021
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16. OGLE-2017-BLG-1186: first application of asteroseismology and Gaussian processes to microlensing
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S-S Li, W Zang, A Udalski, Y Shvartzvald, D Huber, C-U Lee, T Sumi, A Gould, S Mao, P Fouqué, T Wang, S Dong, U G Jørgensen, A Cole, P Mróz, M K Szymański, J Skowron, R Poleski, I Soszyński, P Pietrukowicz, S Kozłowski, K Ulaczyk, K A Rybicki, P Iwanek, J C Yee, S Calchi Novati, C A Beichman, G Bryden, S Carey, B S Gaudi, C B Henderson, W Zhu, M D Albrow, S-J Chung, C Han, K-H Hwang, Y K Jung, Y-H Ryu, I-G Shin, S-M Cha, D-J Kim, H-W Kim, S-L Kim, D-J Lee, Y Lee, B-G Park, R W Pogge, I A Bond, F Abe, R Barry, D P Bennett, A Bhattacharya, M Donachie, A Fukui, Y Hirao, Y Itow, I Kondo, N Koshimoto, M C A Li, Y Matsubara, Y Muraki, S Miyazaki, M Nagakane, C Ranc, N J Rattenbury, H Suematsu, D J Sullivan, D Suzuki, P J Tristram, A Yonehara, G Christie, J Drummond, J Green, S Hennerley, T Natusch, I Porritt, E Bachelet, D Maoz, R A Street, Y Tsapras, V Bozza, M Dominik, M Hundertmark, N Peixinho, S Sajadian, M J Burgdorf, D F Evans, R Figuera Jaimes, Y I Fujii, L K Haikala, C Helling, T Henning, T C Hinse, L Mancini, P Longa-Peña, S Rahvar, M Rabus, J Skottfelt, C Snodgrass, J Southworth, E Unda-Sanzana, C von Essen, J-P Beaulieu, J Blackman, and K Hill
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- 2019
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17. Innovations in suicide prevention research (INSPIRE): a protocol for a population-based case–control study
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Shabbar I Ranapurwala, Vanessa E Miller, Timothy S Carey, Bradley N Gaynes, Alexander P Keil, Kate Vinita Fitch, Monica E Swilley-Martinez, Andrew L Kavee, Toska Cooper, Samantha Dorris, David B Goldston, Lewis J Peiper, and Brian W Pence
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Public Health, Environmental and Occupational Health - Abstract
BackgroundSuicide deaths have been increasing for the past 20 years in the USA resulting in 45 979 deaths in 2020, a 29% increase since 1999. Lack of data linkage between entities with potential to implement large suicide prevention initiatives (health insurers, health institutions and corrections) is a barrier to developing an integrated framework for suicide prevention.ObjectivesData linkage between death records and several large administrative datasets to (1) estimate associations between risk factors and suicide outcomes, (2) develop predictive algorithms and (3) establish long-term data linkage workflow to ensure ongoing suicide surveillance.MethodsWe will combine six data sources from North Carolina, the 10th most populous state in the USA, from 2006 onward, including death certificate records, violent deaths reporting system, large private health insurance claims data, Medicaid claims data, University of North Carolina electronic health records and data on justice involved individuals released from incarceration. We will determine the incidence of death from suicide, suicide attempts and ideation in the four subpopulations to establish benchmarks. We will use a nested case–control design with incidence density-matched population-based controls to (1) identify short-term and long-term risk factors associated with suicide attempts and mortality and (2) develop machine learning-based predictive algorithms to identify individuals at risk of suicide deaths.DiscussionWe will address gaps from prior studies by establishing an in-depth linked suicide surveillance system integrating multiple large, comprehensive databases that permit establishment of benchmarks, identification of predictors, evaluation of prevention efforts and establishment of long-term surveillance workflow protocols.
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- 2022
18. Twenty-Five Years of Rubber Tire Wheel Tracking of Asphalt Pavements in a Laboratory
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Ben C. Cox, Ashley S. Carey, Jessica V. Lewis, and Isaac L. Howard
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Mechanical Engineering ,Civil and Structural Engineering - Abstract
This paper assesses the state-of-the-art for rubber tire wheel tracking of asphalt mixtures in a laboratory setting with emphasis on differentiating moisture damage from rutting. This assessment made use of a comprehensive literature review and roughly 300 experiments conducted over several years with the second generation of the Purdue Laboratory Wheel Tracker (PURWheel). The literature review revealed that direct separation of rutting from moisture damage with physical measurements taken with a rubber tire under otherwise identical conditions is not common practice. Collective analysis of these roughly 300 experiments revealed that second-generation PURWheel protocols offer two specific contributions to the asphalt mixture testing community: (1) a pneumatic rubber tire is used, which is most representative of vehicle traffic; and (2) the effects of moisture damage can be decoupled from rutting by testing under both wet and dry conditions where all other parameters are constant. The analysis was performed on data collected for other purposes, but the data did provide seven manners to evaluate moisture damage and three manners to evaluate variability in the context of standardizing protocols. These 10 evaluations clearly demonstrated the potential of rubber tire wheel tracking to improve characterization of asphalt mixtures beyond what has occurred to date. This paper works toward standardization of protocols for rubber tire wheel tracking in wet and dry conditions, and some discussion is provided on the status and needed advancements toward this eventual goal.
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- 2022
19. Supplementary Figure S4 from The Ubiquitin-specific Protease USP36 Associates with the Microprocessor Complex and Regulates miRNA Biogenesis by SUMOylating DGCR8
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Mu-Shui Dai, Xiao-Xin Sun, Hong-Ming Zhu, Catherine H. Feng, Timothy S. Carey, and Yanping Li
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Supplementary Fig. S4 shows the effects of USP36 on DGCR8 ubiquitination and that USP36 SUMOylation of DGCR8 does not depend on its DUB activity.
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- 2023
20. Data from The Ubiquitin-specific Protease USP36 Associates with the Microprocessor Complex and Regulates miRNA Biogenesis by SUMOylating DGCR8
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Mu-Shui Dai, Xiao-Xin Sun, Hong-Ming Zhu, Catherine H. Feng, Timothy S. Carey, and Yanping Li
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miRNA biogenesis is a cellular process that produces mature miRNAs from their primary transcripts, pri-miRNAs, via two RNAse III enzyme complexes: the Drosha-DGCR8 microprocessor complex in the nucleus and the Dicer-TRBP complex in the cytoplasm. Emerging evidence suggests that miRNA biogenesis is tightly regulated by posttranscriptional and posttranslational modifications and aberrant miRNA biogenesis is associated with various human diseases including cancer. DGCR8 has been shown to be modified by SUMOylation. Yet, the SUMO ligase mediating DGCR8 SUMOylation is currently unknown. Here, we report that USP36, a nucleolar ubiquitin-specific protease essential for ribosome biogenesis, is a novel regulator of DGCR8. USP36 interacts with the microprocessor complex and promotes DGCR8 SUMOylation, specifically modified by SUMO2. USP36-mediated SUMOylation does not affect the levels of DGCR8 and the formation of the Drosha-DGCR8 complex, but promotes the binding of DGCR8 to pri-miRNAs. Consistently, abolishing DGCR8 SUMOylation significantly attenuates its binding to pri-miRNAs and knockdown of USP36 attenuates pri-miRNA processing, resulting in marked reduction of tested mature miRNAs. Induced expression of a SUMOylation-defective mutant of DGCR8 inhibits cell proliferation. Together, these results suggest that USP36 plays an important role in regulating miRNA biogenesis by SUMOylating DGCR8.Significance:This study identifies that USP36 mediates DGCR8 SUMOylation by SUMO2 and is critical for miRNA biogenesis. As USP36 is frequently overexpressed in various human cancers, our study suggests that deregulated USP36-miRNA biogenesis pathway may contribute to tumorigenesis.
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- 2023
21. Supplementary Data from NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition
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Katrien Berns, René Bernards, Mark S. Carey, Steven de Jong, Roderick L. Beijersbergen, Cor Lieftink, Christianne A.R. Lok, Gabriel E. DiMattia, Hannah Kim, Madison Bittner, Cheng-Han Lee, Amy Dawson, Joshua Hoenisch, Aleksandra Hamilton, G. Bea A. Wisman, Shang Li, Nelson K.Y. Wong, Annemiek M.C. Gennissen, E. Marielle Hijmans, and Marta Llaurado Fernandez
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Supplementary Data from NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition
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- 2023
22. Supplementary Figure from NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition
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Katrien Berns, René Bernards, Mark S. Carey, Steven de Jong, Roderick L. Beijersbergen, Cor Lieftink, Christianne A.R. Lok, Gabriel E. DiMattia, Hannah Kim, Madison Bittner, Cheng-Han Lee, Amy Dawson, Joshua Hoenisch, Aleksandra Hamilton, G. Bea A. Wisman, Shang Li, Nelson K.Y. Wong, Annemiek M.C. Gennissen, E. Marielle Hijmans, and Marta Llaurado Fernandez
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Supplementary Figure from NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition
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- 2023
23. Related Article from A Systems Approach to Analysis of Molecular Complexity in Breast Cancer
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Gordon B. Mills, Mark S. Carey, Ana Maria Gonzalez-Angulo, and Bryan T. Hennessy
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Related Article from A Systems Approach to Analysis of Molecular Complexity in Breast Cancer
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- 2023
24. Data from A Systems Approach to Analysis of Molecular Complexity in Breast Cancer
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Gordon B. Mills, Mark S. Carey, Ana Maria Gonzalez-Angulo, and Bryan T. Hennessy
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In this issue of Clinical Cancer Research, Andre et al. apply high-resolution arrays to elucidate copy number anomalies in breast cancer. They identify distinct copy number anomaly patterns in different breast cancer subtypes that implicate a number of genes as potential therapeutic targets and as potential markers of therapy responsiveness.
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- 2023
25. Supplementary Data from Pharmacodynamic Markers of Perifosine Efficacy
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Gordon B. Mills, Vikas Kundra, I. Craig Henderson, Robert Birch, Ana Maria Gonzalez-Angulo, Murali Ravoori, Mark S. Carey, Hassan Hall, Shuangxing Yu, Qianghua Yu, Enrique Poradosu, Yiling Lu, and Bryan T. Hennessy
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Supplementary Data from Pharmacodynamic Markers of Perifosine Efficacy
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- 2023
26. Data from Functional Proteomic Analysis of Advanced Serous Ovarian Cancer Using Reverse Phase Protein Array: TGF-β Pathway Signaling Indicates Response to Primary Chemotherapy
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Bryan T. Hennessy, Gordon B. Mills, David Huntsman, Dianne Miller, Kevin R. Coombes, Fan Zhang, Yiling Lu, Zhenlin Ju, Jennifer Santos, Steve Kalloger, Kenneth Swenerton, Blake Gilks, Roshan Agarwal, and Mark S. Carey
- Abstract
Purpose: Using reverse phase protein array, we measured protein expression associated with response to primary chemotherapy in patients with advanced-stage, high-grade serous ovarian cancer.Experimental Design: Tumor samples were obtained from 45 patients with advanced high-grade serous cancers from the Gynecology Tumor Bank at the British Columbia Cancer Agency. Treatment consisted of platinum-based chemotherapy following debulking surgery. Protein lysates were prepared from fresh frozen tumor samples, and 80 validated proteins from signaling pathways implicated in ovarian carcinogenesis were measured by reverse phase protein array. Normalization of Ca-125 by the 3rd cycle of chemotherapy was chosen as the primary outcome measure of chemotherapy response. Logistic regression was used for multivariate analysis to identify protein predictors of Ca-125 normalization and Cox regression to test for the association between protein expression and progression-free survival. A significance level of P ≤ 0.05 was used.Results: The mean age at diagnosis was 56.8 years. epidermal growth factor receptor, YKL-40, and several transforming growth factor β (TGF-β) pathway proteins [c-jun–NH2–kinase (JNK), JNK phosphorylated at residues 183 and 185, plasminogen activator inhibitor 1, Smad3, TAZ] showed significant associations with Ca-125 normalization on univariate testing. On multivariate analysis, epidermal growth factor receptor (P < 0.02), JNK (P < 0.01), and Smad3 (P < 0.04) were significantly associated with normalization of Ca-125. Contingency table analysis of pathway-classified proteins revealed that the selection of TGF-β pathway proteins was unlikely because of false discovery (P < 0.007; Bonferroni adjusted).Conclusion: TGF-β pathway signaling likely plays an important role as a marker or mediator of chemoresistance in advanced serous ovarian cancer. On this basis, future studies to develop and validate a useful predictor of treatment failure are warranted. Clin Cancer Res; 16(10); 2852–60. ©2010 AACR.
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- 2023
27. Data from Pharmacodynamic Markers of Perifosine Efficacy
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Gordon B. Mills, Vikas Kundra, I. Craig Henderson, Robert Birch, Ana Maria Gonzalez-Angulo, Murali Ravoori, Mark S. Carey, Hassan Hall, Shuangxing Yu, Qianghua Yu, Enrique Poradosu, Yiling Lu, and Bryan T. Hennessy
- Abstract
Purpose: It is critical to develop methods to quantify the early pharmacodynamic effects of targeted therapeutics in vivo to make drug development more efficient and ensure biologically relevant dosing. Furthermore, an ability to identify patients likely to respond to targeted therapeutics would decrease the size, duration, and cost of clinical trials, resulting in more efficient translation to improved patient outcomes. Recent studies suggest that perifosine inhibits the phosphatidylinositol-3′-kinase (PI3K) pathway by preventing cell membrane recruitment of the AKT pleckstrin homology domain.Experimental Design: A novel functional proteomics technology, reverse phase protein array, was used to establish and quantify pharmacodynamic markers of perifosine efficacy.Results: Perifosine selectively prevents AKT recruitment to the membrane and blocks activation of downstream effectors. Perifosine inhibited breast, ovarian, and prostate cancer models. Growth inhibition was associated with apoptosis. Activation of AKT as a consequence of genomic aberrations predicted perifosine efficacy. In cell lines and xenografts, there was a highly statistically significant correlation between the degree of antitumor efficacy of different perifosine doses and quantified down-regulation of phosphorylation of AKT and of its downstream targets, particularly S6.Conclusions: Because of a strong correlation between proportional modulation of PI3K pathway biomarkers and quantified perifosine efficacy, it is likely that early measurement of such pharmacodynamic biomarkers with reverse phase protein array will optimize selection of responding patients and guide perifosine dosing. Furthermore, PI3K pathway activation status may allow baseline selection of patients most likely to respond to perifosine alone or in combination with other therapies.
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- 2023
28. Supplementary Data from c-Jun-NH2-kinase-1 Inhibition Leads to Antitumor Activity in Ovarian Cancer
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Gabriel Lopez-Berestein, Anil K. Sood, Zhengong Peng, Angela Sanguino, Bryan T.J. Hennessy, William Bornmann, Francois-Xavier Claret, Hye Sun Kim, Rebecca L. Stone, Alpa M. Nick, Mark S. Carey, Yvonne G. Lin, Arturo Chavez-Reyes, Cristian Rodriguez-Aguayo, Lingegowda Mangala, Hee-Dong Han, Ariel Fernandez, Juliana Maria Benito, and Pablo Vivas-Mejia
- Abstract
Supplementary Data from c-Jun-NH2-kinase-1 Inhibition Leads to Antitumor Activity in Ovarian Cancer
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- 2023
29. Supplementary Table S1 from Functional Proteomic Analysis of Advanced Serous Ovarian Cancer Using Reverse Phase Protein Array: TGF-β Pathway Signaling Indicates Response to Primary Chemotherapy
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Bryan T. Hennessy, Gordon B. Mills, David Huntsman, Dianne Miller, Kevin R. Coombes, Fan Zhang, Yiling Lu, Zhenlin Ju, Jennifer Santos, Steve Kalloger, Kenneth Swenerton, Blake Gilks, Roshan Agarwal, and Mark S. Carey
- Abstract
Supplementary Table S1 from Functional Proteomic Analysis of Advanced Serous Ovarian Cancer Using Reverse Phase Protein Array: TGF-β Pathway Signaling Indicates Response to Primary Chemotherapy
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- 2023
30. Data from c-Jun-NH2-kinase-1 Inhibition Leads to Antitumor Activity in Ovarian Cancer
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Gabriel Lopez-Berestein, Anil K. Sood, Zhengong Peng, Angela Sanguino, Bryan T.J. Hennessy, William Bornmann, Francois-Xavier Claret, Hye Sun Kim, Rebecca L. Stone, Alpa M. Nick, Mark S. Carey, Yvonne G. Lin, Arturo Chavez-Reyes, Cristian Rodriguez-Aguayo, Lingegowda Mangala, Hee-Dong Han, Ariel Fernandez, Juliana Maria Benito, and Pablo Vivas-Mejia
- Abstract
Purpose: To show the functional, clinical, and biological significance of c-Jun-NH2-kinase (JNK)-1 in ovarian carcinoma.Experimental Design: Analysis of the impact of JNK on 116 epithelial ovarian cancers was conducted. The role of JNK in vitro and in experimental models of ovarian cancer was assessed. We studied the role of N-5-[4-(4-methyl piperazine methyl)-benzoylamido]-2-methylphenyl-4-[3-(4-methyl)-pyridyl]-2-pyrimidine amine (WBZ_4), a novel JNK inhibitor redesigned from imatinib based on targeting wrapping defects, in cell lines and in experimental models of ovarian cancer.Results: We found a significant association of pJNK with progression-free survival in the 116 epithelial ovarian cancers obtained at primary debulking therapy. WBZ_4 led to cell growth inhibition and increased apoptosis in a dose-dependent fashion in four ovarian cancer cell lines. In vivo, whereas imatinib had no effect on tumor growth, WBZ_4 inhibited tumor growth in orthotopic murine models of ovarian cancer. The antitumor effect was further increased in combination with docetaxel. Silencing of JNK-1 with systemically administered siRNA led to significantly reduced tumor weights compared with nonsilencing siRNA controls, indicating that indeed the antitumor effects observed were due to JNK-1 inhibition.Conclusions: These studies identify JNK-1 as an attractive therapeutic target in ovarian carcinoma and that the redesigned WBZ_4 compound should be considered for further clinical development. Clin Cancer Res; 16(1); 184–94
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- 2023
31. Data from Multiomics Characterization of Low-Grade Serous Ovarian Carcinoma Identifies Potential Biomarkers of MEK Inhibitor Sensitivity and Therapeutic Vulnerability
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Mark S. Carey, Colin C. Collins, Gregg B. Morin, Stephane Le Bihan, Gabriel E. DiMattia, Cheng-Han Lee, Sonal Brahmbhatt, Robert H. Bell, Brian McConeghy, Nelson K.Y. Wong, Shane Colborne, Anne M. Haegert, Hannah Kim, Shawn Anderson, Yen-Yi Lin, Stanislav Volik, Joshua Hoenisch, Amy Dawson, Marta Llaurado Fernandez, and Raunak Shrestha
- Abstract
Low-grade serous ovarian carcinoma (LGSOC) is a rare tumor subtype with high case fatality rates in patients with metastatic disease. There is a pressing need to develop effective treatments using newly available preclinical models for therapeutic discovery and drug evaluation. Here, we use multiomics integration of whole-exome sequencing, RNA sequencing, and mass spectrometry–based proteomics on 14 LGSOC cell lines to elucidate novel biomarkers and therapeutic vulnerabilities. Comparison of LGSOC cell line data with LGSOC tumor data enabled predictive biomarker identification of MEK inhibitor (MEKi) efficacy, with KRAS mutations found exclusively in MEKi-sensitive cell lines and NRAS mutations found mostly in MEKi-resistant cell lines. Distinct patterns of Catalogue of Somatic Mutations in Cancer mutational signatures were identified in MEKi-sensitive and MEKi-resistant cell lines. Deletions of CDKN2A/B and MTAP genes were more frequent in cell lines than tumor samples and possibly represent key driver events in the absence of KRAS/NRAS/BRAF mutations. These LGSOC cell lines were representative models of the molecular aberrations found in LGSOC tumors. For prediction of in vitro MEKi efficacy, proteomic data provided better discrimination than gene expression data. Condensin, minichromosome maintenance, and replication factor C protein complexes were identified as potential treatment targets in MEKi-resistant cell lines. This study suggests that CDKN2A/B or MTAP deficiency may be exploited using synthetically lethal treatment strategies, highlighting the importance of using proteomic data as a tool for molecular drug prediction. Multiomics approaches are crucial to improving our understanding of the molecular underpinnings of LGSOC and applying this information to develop new therapies.Significance:These findings highlight the utility of global multiomics to characterize LGSOC cell lines as research models, to determine biomarkers of MEKi resistance, and to identify potential novel therapeutic targets.
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- 2023
32. Supplementary Data from Multiomics Characterization of Low-Grade Serous Ovarian Carcinoma Identifies Potential Biomarkers of MEK Inhibitor Sensitivity and Therapeutic Vulnerability
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Mark S. Carey, Colin C. Collins, Gregg B. Morin, Stephane Le Bihan, Gabriel E. DiMattia, Cheng-Han Lee, Sonal Brahmbhatt, Robert H. Bell, Brian McConeghy, Nelson K.Y. Wong, Shane Colborne, Anne M. Haegert, Hannah Kim, Shawn Anderson, Yen-Yi Lin, Stanislav Volik, Joshua Hoenisch, Amy Dawson, Marta Llaurado Fernandez, and Raunak Shrestha
- Abstract
Supplementary Data from Multiomics Characterization of Low-Grade Serous Ovarian Carcinoma Identifies Potential Biomarkers of MEK Inhibitor Sensitivity and Therapeutic Vulnerability
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- 2023
33. An efficient approach for surveillance of childhood diabetes by type derived from electronic health record data: the SEARCH for Diabetes in Youth Study.
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Victor W. Zhong, Jihad S. Obeid, Jean B. Craig, Emily R. Pfaff, Joan Thomas, Lindsay M. Jaacks, Daniel P. Beavers, Timothy S. Carey, Jean M. Lawrence, Dana Dabelea, Richard F. Hamman, Deborah A. Bowlby, Catherine Pihoker, Sharon H. Saydah, and Elizabeth J. Mayer-Davis
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- 2016
- Full Text
- View/download PDF
34. BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors
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Mattia Cremona, Cassandra J. Vandenberg, Angela M. Farrelly, Stephen F. Madden, Clare Morgan, Roshni Kalachand, Jessica N. McAlpine, Sinead Toomey, David G. Huntsman, Liam Grogan, Oscar Breathnach, Patrick Morris, Mark S. Carey, Clare L. Scott, and Bryan T. Hennessy
- Subjects
Cancer Research ,Oncology - Abstract
Background We tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered in BRCA1-mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors. Methods The levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors. The in vivo effects of treatments were evaluated in PDX mouse models. Results Expression of X-linked inhibitor of apoptosis (XIAP) is increased in BRCA1-mutated cancers and high levels are associated with improved patient outcomes after platinum chemotherapy. XIAP overexpression is mediated by NF-kB activation and is associated with an optimisation of PARP. BRCA1-mutated cell lines are particularly sensitive to IAP inhibitors due to an inhibitory effect on PARP. Both a BRCA1-mutated cell line with acquired resistance to PARP inhibitors and one with restored BRCA1 remain sensitive to IAP inhibitors. Treatment with IAP inhibitors restores the efficacy of PARP inhibition in these cell lines. The IAP inhibitor LCL161 alone and in combination with a PARP inhibitor, exhibited antitumour effects in PDX mouse models of resistant BRCA2 and 1-mutated ovarian cancer, respectively. Conclusion A clinical trial may be justified to further investigate the utility of IAP inhibitors.
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- 2022
35. Scalable and sustainable production of Ti3C2Tz MXene and fluorine recovery from wastewater through cryolite precipitation
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Michael S. Carey and Michel W. Barsoum
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General Chemical Engineering ,General Chemistry - Abstract
Treatment of HF or HCl/LiF etched Ti3C2Tz with 0.05 M NaHCO3 before water washing reduces the wastewater generated by 75%. Cryolite is precipated from the spent etching media.
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- 2022
36. The Back Pain Consortium (BACPAC) Research Program: Structure, Research Priorities, and Methods
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Matthew C, Mauck, Jeffrey, Lotz, Matthew A, Psioda, Timothy S, Carey, Daniel J, Clauw, Sharmila, Majumdar, William S, Marras, Nam, Vo, Ayleen, Aylward, Anna, Hoffmeyer, Patricia, Zheng, Anastasia, Ivanova, Micah, McCumber, Christiane, Carson, Kevin J, Anstrom, Anton E, Bowden, Diane, Dalton, Leslie, Derr, Jonathan, Dufour, Aaron J, Fields, Julie, Fritz, Afton L, Hassett, Steven E, Harte, Trisha F, Hue, Roland, Krug, Marco L, Loggia, Prasath, Mageswaran, Samuel A, McLean, Ulrike H, Mitchell, Conor, O'Neill, Valentina, Pedoia, David Adam, Quirk, Daniel I, Rhon, Viola, Rieke, Lubdha, Shah, Gwendolyn, Sowa, Brennan, Spiegel, Ajay D, Wasan, Hsiao-Ying Monica, Wey, and Lisa, LaVange
- Subjects
Anesthesiology and Pain Medicine ,Neurology (clinical) ,General Medicine - Abstract
In 2019, the National Health Interview survey found that nearly 59% of adults reported pain some, most, or every day in the past 3 months, with 39% reporting back pain, making back pain the most prevalent source of pain, and a significant issue among adults. Often, identifying a direct, treatable cause for back pain is challenging, especially as it is often attributed to complex, multifaceted issues involving biological, psychological, and social components. Due to the difficulty in treating the true cause of chronic low back pain (cLBP), an over-reliance on opioid pain medications among cLBP patients has developed, which is associated with increased prevalence of opioid use disorder and increased risk of death. To combat the rise of opioid-related deaths, the NIH initiated the Helping to End Addiction Long-TermSM (HEAL) initiative, whose goal is to address the causes and treatment of opioid use disorder while also seeking to better understand, diagnose, and treat chronic pain. The NIH Back Pain Consortium (BACPAC) Research Program, a network of 14 funded entities, was launched as a part of the HEAL initiative to help address limitations surrounding the diagnosis and treatment of cLBP. This paper provides an overview of the BACPAC research program‘s goals and overall structure, and describes the harmonization efforts across the consortium, define its research agenda, and develop a collaborative project which utilizes the strengths of the network. The purpose of this paper is to serve as a blueprint for other consortia tasked with the advancement of pain related science.
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- 2023
37. Spitzer Microlensing Parallax for OGLE-2016-BLG-1067: A Sub-Jupiter Orbiting an M Dwarf in the Disk
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S. Calchi Novati, D Suzuki, A. Udalski, A. Gould, Y. Shvartzvald, V. Bozza, D P Bennett, C. Beichman, G Bryden, S. Carey, B. S. Gaudi, C. B. Henderson, J. C. Yee, W. Zhu, F. Abe, Y. Asakura, R Barry, A Bhattacharya, I. A. Bond, M. Donachie, P. Evans, A. Fukui, Y. Hirao, Y. Itow, K. Kawasaki, N. Koshimoto, M. C. A. Li, C. H. Ling, Y. Matsubara, S. Miyazaki, Y. Muraki, M. Nagakane, K. Ohnishi, C Ranc, N. J. Rattenbury, To. Saito, A. Sharan, D. J. Sullivan, T. Sumi, P. J. Tristram, T. Yamada, A. Yonehara, P. Mroz, R. Poleski, J. Skowron, M. K. Szymanski, I. Soszynski, S. Kozłowski, P. Pietrukowicz, K. Ulaczyk, M. Pawlak, M. D. Albrow, S.-J. Chung, C. Han, K.-H. Hwang, Y. K. Jung, Y.-H. Ryu, I.-G. Shin, W. Zang, S.-M. Cha, D.-J. Kim, H.-W. Kim, S.-L. Kim, C.-U. Lee, D.-J. Lee, Y. Lee, B.-G. Park, and R. W. Pogge
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Astronomy - Abstract
We report the discovery of a sub-Jupiter-mass planet orbiting beyond the snow line of an M dwarf most likely in the Galactic disk as part of the joint Spitzer and ground-based monitoring of planetary microlensing anomalies toward the Galactic bulge. Most of the microlensing parameters are strongly constrained by the light-curve modeling, and in particular there is a Spitzer-based measurement of the microlens parallax, π(E). However, there are no caustic crossings, so the angular Einstein radius has only an upper limit based on the light-curve modeling alone. Additionally, the analysis leads us to identify eight degenerate configurations: the fourfold microlensing parallax degeneracy being doubled by a degeneracy in the caustic structure present at the level of the ground-based solutions. To calculate the physical parameters, and at the same time to break the parallax degeneracy, we make use of a series of arguments: the χ(exp 2) hierarchy, the Rich argument (stating that the small-parallax solution is more likely), and a prior Galactic model. The preferred configuration, favored by a likelihood ratio of at least 4000, is for a host at D(L)={3.73}(-0.67+0.66)kpc with mass M(L)=0.30(-0.12+0.15) M(☉) , orbited by a Saturn-like planet with M(planet) =0.43(-0.17+0.21) M(Jup) at projected separation a(⊥) =1.70(-0.39+0.38) au, about 2.1 times beyond the system snow line. Therefore, it adds to the growing population of sub-Jupiter planets orbiting beyond the snow line of M dwarfs discovered by microlensing. Based on the rules of the real-time protocol for the selection of events to be followed up with Spitzer, this planet will not enter the sample for measuring the Galactic distribution of planets.
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- 2019
- Full Text
- View/download PDF
38. Development and validation of an electronic health records-based opioid use disorder algorithm by expert clinical adjudication among patients with prescribed opioids
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Shabbar I. Ranapurwala, Ishrat Z. Alam, Brian W. Pence, Timothy S. Carey, Sean Christensen, Marshall Clark, Paul R. Chelminski, Li‐Tzy Wu, Lawrence H. Greenblatt, Jeffrey E. Korte, Mark Wolfson, Heather E. Douglas, Lynn A. Bowlby, Michael Capata, and Stephen W. Marshall
- Subjects
Epidemiology ,Pharmacology (medical) - Abstract
In the US, over 200 lives are lost from opioid overdoses each day. Accurate and prompt diagnosis of opioid use disorders (OUD) may help prevent overdose deaths. However, International Classification of Disease (ICD) codes for OUD are known to underestimate prevalence, and their specificity and sensitivity are unknown. We developed and validated algorithms to identify OUD in electronic health records (EHR) and examined the validity of OUD ICD codes.Through four iterations, we developed EHR-based OUD identification algorithms among patients who were prescribed opioids from 2014-2017. The algorithms and OUD ICD codes were validated against 169 independent "gold standard" EHR chart reviews conducted by an expert adjudication panel across four healthcare systems. After using 2014-2020 EHR for validating iteration 1, the experts were advised to use 2014-2017 EHR thereafter.Of the 169 EHR charts, 81 (48%) were reviewed by more than one expert and exhibited 85% expert agreement. The experts identified 54 OUD cases. The experts endorsed all 11 OUD criteria from the Diagnostic and Statistical Manual of Mental Disorders-5, including craving (72%), tolerance (65%), withdrawal (56%), and recurrent use in physically hazardous conditions (50%). The OUD ICD codes had 10% sensitivity and 99% specificity, underscoring large underestimation. In comparison our algorithm identified OUD with 23% sensitivity and 98% specificity.This is the first study to estimate the validity of OUD ICD codes and develop validated EHR-based OUD identification algorithms. This work will inform future research on early intervention and prevention of OUD.
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- 2022
39. PP297 [Quality and Safety » Data Management (EHR, documentation)]: IMPLEMENTING 'ADULT COVID-19' ELECTRONIC ORDER SETS IN A CHILDREN’S HOSPITAL
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S. Gray, S. Silver, W. Seto, S. Pong, A. Theissen, P. Chan, S. Carey, A. Chmietewski, E. Gilfoyle, K. Jessa, and N. K. Mckinnon
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Pediatrics, Perinatology and Child Health ,Critical Care and Intensive Care Medicine - Published
- 2022
40. Synthesis of 1-Chloronaloxone and 2-Chloronaloxone
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Christopher J. Lovell, James Brailey-Partridge, George M. Taylor, and John S. Carey
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Chemistry ,Organic Chemistry ,Physical and Theoretical Chemistry - Published
- 2021
41. 306 GERIATRICIAN-LED COMPREHENSIVE GERIATRIC ASSESSMENT IN THE EMERGENCY DEPARTMENT: A COST-EFFECTIVE SERVICE APPROVED BY PATIENTS
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S Magner, S Carey, G Harrington, L Ward, H Smyth, R Purcell, L Callaly, C O'Caheny, C Pender, B Buckley, R Laguna, R Riches, M Mitchell, N Carrabine, V Ramiah, and C Byrne
- Subjects
Aging ,General Medicine ,Geriatrics and Gerontology - Abstract
Background Many older people are brought to the Emergency Department (ED) who do not require acute hospital admission but there are risks to these patients if this occurs. The Frailty Intervention Team (FIT) are an interdisciplinary team based in the ED including physiotherapy, occupational therapy, speech and language therapy, dietetics, pharmacy, advanced nurse practitioners, and a geriatric registrar and consultant. They assess frail older patients and suggest alternative care pathways to admission. We aimed to investigate the impact of FIT on admission avoidance, bed days saved and to obtain patient feedback on their experience. Methods Routinely collected data from May 2021 to April 2022 was reviewed retrospectively. An anonymous patient feedback questionnaire was posted to 40 patients randomised from the FIT worklist between January to May 2022. Results 2,025 Comprehensive Geriatric Assessments (CGA) were completed between May 2021 and April 2022. 38% percent of patients were discharged home, 45% of this number had follow-up arranged. 104 patients were transferred directly to an offsite bed, mostly rehabilitation. We estimate we avoided 51 admissions to the acute hospital per month, almost half of these were patients admitted to the hospital and, who we discharged to alternative care pathways or home. The average length of stay in April 2022 was 22 days – by avoiding 615 admissions between May 2021 and April 2022 we have saved 13,530 bed days at an estimated cost saving of almost €11 million. 15 completed questionnaires were returned. 73% were very satisfied with their experience. 87% felt the FIT team helped facilitate their discharge from ED. The main themes identified from open ended questions included thorough assessment, patient centred care and satisfaction with early intervention and discharge. Conclusion A Frailty Intervention Team is a cost effective and patient centred way of avoiding unnecessary admissions for older people presenting to the ED.
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- 2022
42. 37 RE-AUDIT OF VITAMIN D SUPPLEMENTATION IN FRAIL OLDER ADULTS PRESENTING TO AN IRISH LEVEL 5 EMERGENCY DEPARTMENT
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C Pender, C O'Caheny, C Byrne, S Magner, S Carey, N Carrabine, M Mitchell, R Laguna, G Harrington, B Buckley, and H Smyth
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Aging ,General Medicine ,Geriatrics and Gerontology - Abstract
Background The Department of Health published new guidance in November 2020 “Vitamin D advice for people aged 65 and older” which recommended that all adults ≥65 years should be supplemented with 15micrograms of Vitamin D daily. 55.5% of adults ≥65 years have insufficient/deficient vitamin D levels in winter (TILDA 2020). The Frailty Intervention Team (FIT) assess frail adults ≥65 years in the Emergency Department using medication review and Comprehensive Geriatric Assessment to identify vitamin D supplementation. The audit aim was to determine if compliance with the new guideline improved since the initial audit in January 2021. Methods All patients who had a medicine reconciliation completed by the FIT Pharmacist in January 2022 were included in a retrospective audit. Patients were identified from the pharmacist’s worklist. Data was collected from a Hospital Clinical System using a Microsoft Excel®. The data recorded included: Age, Sex, Rockwood Clinical Frailty Score (CFS) and vitamin D supplementation. Results The FIT Pharmacist completed 66 medicine reconciliations in January 2022. The mean age (+/-SD) was 82.4 (+/-7.6) years.The male to female ratio was 1:1.75The median CFS was 5 (mildly/moderately frail) with an IQR of 1. 68% (n=45) were prescribed vitamin D. Of those 89% (n=40) were prescribed a supplement containing at least 15micrograms of vitamin D. 32% (n=21) were not prescribed any vitamin D supplementation. 8% (n=5) were prescribed doses lower than 15micrograms of vitamin D. Conclusion Compliance with the new guideline was 61% (n=40) in comparison to 65% (n=39) in the initial audit. The results are reflective of adherence to the new guideline in the community. The policy update and education provided post the initial audit has possibly influenced the prescribing of vitamin D in the acute setting which unless patients are re-presenting will not have been captured in the outcome of this re-audit.
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- 2022
43. 269 PHARMACIST INTERVENTIONS WITHIN A MULTIDISCIPLINARY CARE TEAM FOR FRAIL OLDER ADULTS PRESENTING TO A LEVEL 4 EMERGENCY DEPARTMENT
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C O'Caheny, L Dillon, H Smyth, R Riches, R Laguna, S Magner, C Pender, N Carrabine, B Buckley, S Carey, G Harrington, M Mitchell, J Brown, E Callaly, R Purcell, V Ramiah, and C Byrne
- Subjects
Aging ,General Medicine ,Geriatrics and Gerontology - Abstract
Background Inappropriate polypharmacy and ‘Potentially Inappropriate Prescriptions’ (PIP) are associated with increased morbidity and hospitalisation, in particular among frail older persons. A structured medication review, in conjunction with a Comprehensive Geriatric Assessment (CGA), can address PIP. The aim of the study was to review Frail Intervention Team (FIT) pharmacist interventions for frail, older adults presenting to the Emergency Department (ED) and experiencing medication compliance difficulties, polypharmacy and PIP. Methods Patients identified for medication review included those experiencing polypharmacy or medication compliance issues, presenting with a fall, delirium and/or frailty syndromes or complex comorbidities. The medication review process involved completion of medicines reconciliation and medication appropriateness review in accordance with the 7-Steps Medication Review Model (Scottish Government Polypharmacy Model of Care Group, 2018). Pharmacist optimisation recommendations were reviewed by a Consultant Geriatrician or Registrar and discussed with the patient prior to implementation. Results The FIT Pharmacist completed medication reviews for 765 patients between May 2021 and April 2022. The mean age (+/-SD) was 83.1 (+/-7.0) years with a median Clinical Frailty Score (CFS) of 5 (mildly/moderately frail). Medication Optimisation recommendations were actioned in 63% (n=483) of patients reviewed. The most commonly encountered PIP’s included: excessive anti-hypertensive/diuretic therapy, long-term acid-suppression therapy, anticholinergics and long-term prophylactic antimicrobials. Prescribing opportunities identified included: bone protection, laxatives and pain management. Conclusion FIT pharmacist review, in conjunction with the CGA, led to medication optimisation interventions in the frail older adult cohort presenting to the ED. Future studies should examine the impact of medication review on patient outcomes post-discharge.
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- 2022
44. Laboratory Curing Protocols to Replicate Thermomechanical Behavior of High-Strength Concrete in Mass Placements
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Ashley S. Carey, Isaac L. Howard, Jay Shannon, Dylan A. Scott, and Brad Songer
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Mechanics of Materials ,General Materials Science ,Building and Construction ,Civil and Structural Engineering - Published
- 2022
45. Repairable reinforced composites of 1D TiO2 lepidocrocite mesoparticles and thiol-yne click networks via alkylborane-initiated in situ polymerization
- Author
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Olivia R. Wilson, Michael S. Carey, Jacob H. Cope, Hussein O. Badr, Jacob M. Nantz, Tarek A. ElMelegy, Michel W. Barsoum, and Andrew J.D. Magenau
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General Energy ,General Engineering ,General Physics and Astronomy ,General Materials Science ,General Chemistry - Published
- 2023
46. Michigan ZoomIN: Validating Crowd‐Sourcing to Identify Mammals from Camera Surveys
- Author
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Justin Schell, Rumaan Malhotra, Nyeema C. Harris, Gabriel I. Gadsden, and Tiffany S. Carey
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0106 biological sciences ,education.field_of_study ,Computer science ,Population ,Endangered species ,Wildlife ,010603 evolutionary biology ,01 natural sciences ,Popularity ,Data science ,010601 ecology ,Workflow ,Crowd sourcing ,Citizen science ,Camera trap ,education - Abstract
Camera trap studies have become a popular medium to assess many ecological phenomena including population dynamics, patterns of biodiversity, and monitoring of endangered species. In conjunction with the benefit to scientists, camera traps present an unprecedented opportunity to involve the public in scientific research via image classifications. However, this engagement strategy comes with a myriad of complications. Volunteers vary in their familiarity with wildlife, and thus, the accuracy of user-derived classifications may be biased by the commonness or popularity of species and user-experience. From an extensive multi-site camera trap study across Michigan U.S.A, images were compiled and identified through a public science platform called Michigan ZoomIN. We aggregated responses from 15 independent users per image using multiple consensus methods to assess accuracy by comparing to species identification completed by wildlife experts. We also evaluated how different factors including consensus algorithms, study area, wildlife species, user support, and camera type influenced the accuracy of user-derived classifications. Overall accuracy of user-derived classification was 97%; although, several canid (e.g., Canis lupus, Vulpes vulpes) and mustelid (e.g., Neovison vison) species were repeatedly difficult to identify by users and had lower accuracy. When validating user-derived classification, we found that study area, consensus method, and user support best explained accuracy. To continue to overcome stigma associated with data from untrained participants, we demonstrated their value by showing the accuracy from volunteers was comparable to experts when classifying North American mammals. Our hierarchical workflow that integrated multiple consensus methods lead to more image classifications without extensive training and even when the expertise of the volunteer was unknown. Ultimately, adopting such an approach can harness broader participation, expedite future camera trap data synthesis, and improve allocation of resources by scholars to enhance performance of public participants and increase accuracy of user-derived data.
- Published
- 2021
47. Multiwavelength Light Curves of Two Remarkable Sagittarius A* Flares
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G. G. Fazio, J. L. Hora, G. Witzel, S. P. Willner, M. L. N. Ashby, F. Baganoff, E. Becklin, S. Carey, D. Haggard, C. Gammie, A. Ghez, M. A. Gurwell, J. Ingalls, D. Marrone, M. R. Morris, and H. A. Smith
- Subjects
Astrophysics - Abstract
Sgr A* , the supermassive black hole (SMBH) at the center of our Milky Way Galaxy, is known to be a variable source of X-ray, near-infrared (NIR), and submillimeter radiation and therefore a prime candidate to study the electromagnetic radiation generated by mass accretion flow onto a black hole and/or a related jet. Disentangling the power source and emission mechanisms of this variability is a central challenge to our understanding of accretion flows around SMBHs. Simultaneous multiwavelength observations of the flux variations and their time correlations can play an important role in obtaining a better understanding of possible emission mechanisms and their origin. This paper presents observations of two flares that both apparently violate the previously established patterns in the relative timing of submillimeter/NIR/X-ray flares from Sgr A* . One of these events provides the first evidence of coeval structure between NIR and submillimeter flux increases, while the second event is the first example of the sequence of submillimeter/X-ray/NIR flux increases all occurring within ∼1 hr. Each of these two events appears to upend assumptions that have been the basis of some analytic models of flaring in Sgr A* . However, it cannot be ruled out that these events, even though unusual, were just coincidental. These observations demonstrate that we do not fully understand the origin of the multiwavelength variability of Sgr A* and show that there is a continued and important need for long-term, coordinated, and precise multiwavelength observations of Sgr A* to characterize the full range of variability behavior
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- 2018
- Full Text
- View/download PDF
48. Variability Timescale and Spectral Index of Sgr A* in the Near Infrared: Approximate Bayesian Computation Analysis of the Variability of the Closest Supermassive Black Hole
- Author
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G. Witzel, G. Martinez, J. Hora, S. P. Willner, M. R. Morris, C. Gammie, E. E. Becklin, M. L. N. Ashby, F. Baganoff, S. Carey, T. Do, G. G. Fazio, A. Ghez, W. J. Glaccum, D. Haggard, R. Herrero-Illana, J. Ingalls, R. Narayan, and H. A. Smith
- Subjects
Astrophysics - Abstract
Sagittarius A* (Sgr A* ) is the variable radio, near-infrared (NIR), and X-ray source associated with accretion onto the Galactic center black hole. We present an analysis of the most comprehensive NIR variability data set of Sgr A* to date: eight 24 hr epochs of continuous monitoring of Sgr A* at 4.5 μm with the IRAC instrument on the Spitzer Space Telescope, 93 epochs of 2.18 μm data from Naos Conica at the Very Large Telescope, and 30 epochs of 2.12 μm data from the NIRC2 camera at the Keck Observatory, in total 94,929 measurements. A new approximate Bayesian computation method for fitting the first-order structure function extracts information beyond current fast Fourier transformation (FFT) methods of power spectral density (PSD) estimation. With a combined fit of the data of all three observatories, the characteristic coherence timescale of Sgr A* is b 243 57 82 t = - + minutes (90% credible interval). The PSD has no detectable features on timescales down to 8.5 minutes (95% credible level), which is the ISCO orbital frequency for a dimensionless spin parameter a = 0.92. One light curve measured simultaneously at 2.12 and 4.5 μm during a low flux-density phase gave a spectral index αs = 1.6 ± 0.1 (F µ n s n -a ). This value implies that the Sgr A* NIR color becomes bluer during higher flux-density phases. The probability densities of flux densities of the combined data sets are best fit by log-normal distributions. Based on these distributions, the Sgr A* spectral energy distribution is consistent with synchrotron radiation from a nonthermal electron population from below 20 GHz through the NIR.
- Published
- 2018
- Full Text
- View/download PDF
49. A serpiginous eruption
- Author
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S. Carey, K. Courtney, E. Rudd, S. Walsh, Jon Salisbury, and M. Berovic
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medicine.medical_specialty ,Lung Neoplasms ,business.industry ,Dermatology ,Adenocarcinoma ,Middle Aged ,Adrenal Cortex Hormones ,Erythema ,Serpiginous eruption ,medicine ,Humans ,Female ,business - Published
- 2021
50. Understanding Patients’ Decisions to Obtain Unplanned, High-Resource Health Care After Colorectal Surgery
- Author
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Karyn B. Stitzenberg, Timothy S. Carey, Alessandro Fichera, Paul Mihas, Stephanie T Lumpkin, and Eileen Harvey
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Adult ,caregivers ,medicine.medical_specialty ,emergency care ,health seeking ,Aftercare ,users’ experiences ,Patient Readmission ,health behavior ,determinants of health ,Health care ,Humans ,Medicine ,Prospective Studies ,Social determinants of health ,crisis management ,Prospective cohort study ,Research Articles ,Surgical team ,behavior ,business.industry ,Information seeking ,Public Health, Environmental and Occupational Health ,health ,decision-making ,Emergency department ,information seeking ,medicine.disease ,health care ,Southeastern United States ,Patient Discharge ,Colorectal surgery ,Stratified sampling ,crisis ,qualitative ,caretaking ,Medical emergency ,Emergency Service, Hospital ,business ,Colorectal Surgery ,Delivery of Health Care - Abstract
Readmissions and emergency department (ED) visits after colorectal surgery (CRS) are common, burdensome, and costly. Effective strategies to reduce these unplanned postdischarge health care visits require a nuanced understanding of how and why patients make the decision to seek care. We used a purposefully stratified sample of 18 interview participants from a prospective cohort of adult CRS patients. Thirteen (72%) participants had an unplanned postdischarge health care visit. Participant decision-making was classified by methodology (algorithmic, guided, or impulsive), preexisting rationale, and emotional response to perceived health care needs. Participants voiced clear mental algorithms about when to visit an ED. In addition, participants identified facilitators and barriers to optimal health care use. They also identified tangible targets for health care utilization reduction efforts, such as improved care coordination with streamlined discharge instructions and improved communication with the surgical team. Efforts should be directed at improving postdischarge communication and care coordination to reduce CRS patients’ high-resource health care utilization.
- Published
- 2021
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