118 results on '"Stober, C."'
Search Results
2. A multicentre, randomised trial comparing schedules of G-CSF (filgrastim) administration for primary prophylaxis of chemotherapy-induced febrile neutropenia in early stage breast cancer
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Clemons, M., Fergusson, D., Simos, D., Mates, M., Robinson, A., Califaretti, N., Zibdawi, L., Bahl, M., Raphael, J., Ibrahim, M.F.K., Fernandes, R., Pitre, L., Aseyev, O., Stober, C., Vandermeer, L., Saunders, D., Hutton, B., Mallick, R., Pond, G.R., Awan, A., and Hilton, J.
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- 2020
- Full Text
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3. Taxane acute pain syndrome (TAPS) in patients receiving chemotherapy for breast or prostate cancer: a prospective multi-center study
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Fernandes, R., Mazzarello, S., Joy, A. A., Pond, G. R., Hilton, J., Ibrahim, M. F. K., Canil, C., Ong, M., Stober, C., Vandermeer, L., Hutton, B., da Costa, M., Damaraju, S., and Clemons, Mark
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- 2018
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4. Gaps and complex structurally variant loci in phased genome assemblies
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Porubsky, D., Vollger, M.R., Harvey, W.T., Rozanski, A.N., Ebert, P., Hickey, G., Hasenfeld, P., Sanders, A.D., Stober, C., Korbel, J.O., Paten, B., Marschall, T., and Eichler, E.E.
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Cancer Research - Abstract
There has been tremendous progress in phased genome assembly production by combining long-read data with parental information or linked-read data. Nevertheless, a typical phased genome assembly generated by trio-hifiasm still generates more than 140 gaps. We perform a detailed analysis of gaps, assembly breaks, and misorientations from 182 haploid assemblies obtained from a diversity panel of 77 unique human samples. Although trio-based approaches using HiFi are the current gold standard, chromosome-wide phasing accuracy is comparable when using Strand-seq instead of parental data. Importantly, the majority of assembly gaps cluster near the largest and most identical repeats (including segmental duplications [35.4%], satellite DNA [22.3%], or regions enriched in GA/AT-rich DNA [27.4%]). Consequently, 1513 protein-coding genes overlap assembly gaps in at least one haplotype, and 231 are recurrently disrupted or missing from five or more haplotypes. Furthermore, we estimate that 6-7 Mbp of DNA are misorientated per haplotype irrespective of whether trio-free or trio-based approaches are used. Of these misorientations, 81% correspond to bona fide large inversion polymorphisms in the human species, most of which are flanked by large segmental duplications. We also identify large-scale alignment discontinuities consistent with 11.9 Mbp of deletions and 161.4 Mbp of insertions per haploid genome. Although 99% of this variation corresponds to satellite DNA, we identify 230 regions of euchromatic DNA with frequent expansions and contractions, nearly half of which overlap with 197 protein-coding genes. Such variable and incompletely assembled regions are important targets for future algorithmic development and pangenome representation.
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- 2023
5. Nitrogen Uptake Processes in Roots and Mycorrhizas
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Wallenda, T., Stober, C., Högbom, L., Schinkel, H., George, E., Högberg, P., Read, D. J., Caldwell, M. M., editor, Heldmaier, G., editor, Lange, O. L., editor, Mooney, H. A., editor, Schulze, E.-D., editor, Sommer, U., editor, and Schulze, Ernst-Detlef, editor
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- 2000
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6. Root Growth and Response to Nitrogen
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Stober, C., George, E., Persson, H., Caldwell, M. M., editor, Heldmaier, G., editor, Lange, O. L., editor, Mooney, H. A., editor, Schulze, E.-D., editor, Sommer, U., editor, and Schulze, Ernst-Detlef, editor
- Published
- 2000
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7. Semi-automated assembly of high-quality diploid human reference genomes
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Jarvis, E.D., Formenti, G., Rhie, A., Guarracino, A., Yang, C., Wood, J., Tracey, A., Thibaud-Nissen, F., Vollger, M.R., Porubsky, D., Cheng, H., Asri, M., Logsdon, G.A., Carnevali, P., Chaisson, M.J.P., Chin, C.S., Cody, S., Collins, J., Ebert, P., Escalona, M., Fedrigo, O., Fulton, R.S., Fulton, L.L., Garg, S., Gerton, J.L., Ghurye, J., Granat, A., Green, R.E., Harvey, W., Hasenfeld, P., Hastie, A., Haukness, M., Jaeger, E.B., Jain, M., Kirsche, M., Kolmogorov, M., Korbel, J.O., Koren, S., Korlach, J., Lee, J., Li, D., Lindsay, T., Lucas, J., Luo, F., Marschall, T., Mitchell, M.W., McDaniel, J., Nie, F., Olsen, H.E., Olson, N.D., Pesout, T., Potapova, T., Puiu, D., Regier, A., Ruan, J., Salzberg, S.L., Sanders, A.D., Schatz, M.C., Schmitt, A., Schneider, V.A., Selvaraj, S., Shafin, K., Shumate, A., Stitziel, N.O., Stober, C., Torrance, J., Wagner, J., Wang, J., Wenger, A., Xiao, C., Zimin, A.V., Zhang, G., Wang, T., Li, H., Garrison, E., Haussler, D., Hall, I., Zook, J.M., Eichler, E.E., Phillippy, A.M., Paten, B., Howe, K., and Miga, K.H.
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Cancer Research ,Haplotypes ,Genome, Human ,Humans ,Chromosome Mapping ,High-Throughput Nucleotide Sequencing ,Chromosomes, Human ,Genetic Variation ,Sequence Analysis, DNA ,Genomics ,Reference Standards ,Diploidy - Abstract
The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has benefitted societysup1,2/sup. However, it still has many gaps and errors, and does not represent a biological genome as it is a blend of multiple individualssup3,4/sup. Recently, a high-quality telomere-to-telomere reference, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a nearly homozygous genomesup5/sup. To address these limitations, the Human Pangenome Reference Consortium formed with the goal of creating high-quality, cost-effective, diploid genome assemblies for a pangenome reference that represents human genetic diversitysup6/sup. Here, in our first scientific report, we determined which combination of current genome sequencing and assembly approaches yield the most complete and accurate diploid genome assembly with minimal manual curation. Approaches that used highly accurate long reads and parent-child data with graph-based haplotype phasing during assembly outperformed those that did not. Developing a combination of the top-performing methods, we generated our first high-quality diploid reference assembly, containing only approximately four gaps per chromosome on average, with most chromosomes within ±1% of the length of CHM13. Nearly 48% of protein-coding genes have non-synonymous amino acid changes between haplotypes, and centromeric regions showed the highest diversity. Our findings serve as a foundation for assembling near-complete diploid human genomes at scale for a pangenome reference to capture global genetic variation from single nucleotides to structural rearrangements.
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- 2021
8. Decision Strategies while Intoxicated relate to Alcohol-Impaired Driving Attitudes and Intentions
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Denis M. McCarthy, Sara D McMullin, Clintin P. Davis-Stober, Laura E. Hatz, Courtney A. Motschman, and Stober C
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Impaired driving ,Psychology ,Clinical psychology - Abstract
Objective: Approximately 28 million individuals engage in alcohol-impaired driving (AID) every year. This study investigated individuals’ AID decision making strategies under intoxication, their variability across the breath alcohol concentration curve (BrAC), and the association between strategy and AID attitudes and intentions. Method: 79 adults (23.9 years, 57% women) who drank alcohol ≥2 days per week and lived >2 miles away from their typical drinking locations completed an alcohol administration protocol and AID decision making task. AID attitudes, intentions, and behaviors were assessed repeatedly across the BrAC curve. Bayesian cognitive modeling identified decision strategies used by individuals on the AID decision making task, revealing whether alcohol consumption level and/or ride service cost factored into individuals’ decisions to drive while impaired or obtain a ride. Additional analyses tested whether AID attitudes and intentions were related to individuals’ decision strategies. Results: Two decision strategies were examined on the ascending and descending limb of the BrAC curve: compensatory (both consumption level and ride service cost factored into AID decisions) and non-compensatory (only consumption level factored into AID decisions). Switching to a compensatory strategy on the descending limb was associated with lower perceived intoxication, perceiving AID as less dangerous, and being willing to drive above the legal BrAC limit. Conclusions: Results suggest that risk for engaging in AID is higher for those using a cost-sensitive, compensatory strategy when making AID decisions under intoxication. Future research is needed to test whether AID countermeasures (e.g., subsidized ride services) are differentially effective according to decision strategy type.
- Published
- 2021
9. The use of different soil nitrogen sources by young Norway spruce plants
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George, E., Stober, C., and Seith, B.
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- 1999
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10. Characterisation of novel anti-human IgE monoclonal antibodies: 2. Effects on interaction of IgE with FcϵRII
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Stober, C., Lamont, A. G., and Hewitt, E. L.
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- 1999
11. a survey of oncology nurses and physicians
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LeVasseur, N., Stober, C., Daigle, K., Robinson, A., McDiarmid, S., Mazzarello, S., Hutton, B., Joy, A., Fergusson, D., Hilton, J., McInnes, M., and Clemons, M.
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physician surveys ,vascular access ,nurse surveys ,Early-stage breast cancer - Abstract
Despite advances in systemic therapy choices for patients with early-stage breast cancer, optimal practices for intravenous (IV) access remain unknown. That lack of knowledge holds particularly true for the use of central venous access devices (cvads) such as peripherally inserted central catheters (piccs) and implanted vascular access devices (ports). Using a survey of Canadian oncologists and oncology nurses responsible for the care of breast cancer patients, we evaluated current access practices, perceptions of complications, and perceptions of risk, and we estimated complication rates and evaluated perceived risk factors for lymphedema. Survey responses were received from 25 physicians and 57 oncology nurses. Administration of trastuzumab or an anthracycline was associated with a higher likelihood of a cvad being recommended. Other factors associated with recommendation of a cvad included prior difficult IV access and a recommendation from the chemotherapy nurse. Although the complication rates perceived to be associated with the use of piccs and ports remained high, respondents felt that cvads might improve patient quality of life. Risk factors perceived to be associated with the risk of lymphedema were axillary lymph node dissection, radiation to the axilla, and line-associated infection. Factors known to be unrelated to lymphedema risk (specifically, blood draws and blood pressure measurement) continue to be perceived as posing a higher risk. Despite widespread use of chemotherapy for patients with breast cancer, the type of venous access used for treatment varies significantly, as do perceptions about the risks of cvad use and the risk for lymphedema development. Further prospective studies are needed to identify best-practice strategies.
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- 2018
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12. A pragmatic, randomised, multicentre trial comparing 4-weekly vs. 12-weekly administration of bone-targeted agents (denosumab, zoledronate or pamidronate) in patients with bone metastases
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Clemons, M., primary, Stober, C., additional, Mates, M., additional, Joy, A.A., additional, Robinson, A., additional, Hilton, J., additional, Blanchette, P., additional, Aseyev, O., additional, Pond, G., additional, and Fergusson, D., additional
- Published
- 2019
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13. A prospective, multicentre, randomized trial comparing vascular access strategies for patients receiving non-trastuzumab containing chemotherapy for early stage breast cancer
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Awan, A.A., primary, Basulaiman, B., additional, Robinson, A., additional, Stober, C., additional, Fergusson, D., additional, Joy, A.A., additional, Vandermeer, L., additional, Mallick, R., additional, Saunders, D., additional, and Clemons, M., additional
- Published
- 2019
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14. A cost-utility analysis of administration schedules of G-CSF for primary prophylaxis of chemotherapy-induced febrile neutropenia in early stage breast cancer: Economic evaluation alongside the REaCT-G trial
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Basulaiman, B., primary, Awan, A.A., additional, Hilton, J., additional, Fergusson, D., additional, Stober, C., additional, Vandermeer, L., additional, Saunders, D., additional, Clemons, M., additional, and Thavorn, K., additional
- Published
- 2019
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15. INVESTIGATION OF THE ROLE OF PHOSPHOLIPASE D (PLD) IN ATP/P2Z RECEPTOR-MEDIATED KILLING OF INTRACELLULAR MYCOBACTERIA WITHIN MURINE AND HUMAN MACROPHAGES.
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Stober, C. B., Powner, D., Lammas, D. A., Ben-Smith, A., Wakelam, M. J.O., and Kumararatne, D. S.
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- 1998
16. Testing probabilistic models of choice using column generation
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Smeulders, B., Davis-Stober, C., Regenwetter, M., Spieksma, F.C.R., Smeulders, B., Davis-Stober, C., Regenwetter, M., and Spieksma, F.C.R.
- Abstract
In so-called random preference models of probabilistic choice, a decision maker chooses according to an unspecified probability distribution over preference states. The most prominent case arises when preference states are linear orders or weak orders of the choice alternatives. The literature has documented that actually evaluating whether decision makers’ observed choices are consistent with such a probabilistic model of choice poses computational difficulties. This severely limits the possible scale of empirical work in behavioral economics and related disciplines. We propose a family of column generation based algorithms for performing such tests. We evaluate our algorithms on various sets of instances. We observe substantial improvements in computation time and conclude that we can efficiently test substantially larger data sets than previously possible.
- Published
- 2018
17. out of office&rdquo
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Clemons, M., Joy, A.A., Hilton, J., Arnaout, A., Brackstone, M., Wheatley-Price, P., Stober, C., Dinniwell, R., Mazzarello, S., Costa, M. da, and Hutton, B.
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- 2017
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18. Optimal sequence of adjuvant endocrine and radiation therapy in early-stage breast cancer – A systematic review
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McGee, S.F., primary, Mazzarello, S., additional, Caudrelier, J.M., additional, Lima, M.A.G., additional, Hutton, B., additional, Sienkiewicz, M., additional, Stober, C., additional, Fernandes, R., additional, Ibrahim, M.F.K., additional, Vandermeer, L., additional, Hilton, J., additional, Shorr, R., additional, Fergusson, D., additional, and Clemons, M., additional
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- 2018
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19. Optimizing Vascular Access for Patients Receiving Intravenous Systemic Therapy for Early-Stage Breast Cancer—A Survey of Oncology Nurses and Physicians
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LeVasseur, N., primary, Stober, C., additional, Daigle, K., additional, Robinson, A., additional, McDiarmid, S., additional, Mazzarello, S., additional, Hutton, B., additional, Joy, A., additional, Fergusson, D., additional, Hilton, J., additional, McInnes, M., additional, and Clemons, M., additional
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- 2018
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20. Perceptions of Vascular Access for Intravenous Systemic Therapy and Risk Factors for Lymphedema in Early-Stage Breast Cancer—A Patient Survey
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LeVasseur, N., primary, Stober, C., additional, Ibrahim, M., additional, Gertler, S., additional, Hilton, J., additional, Robinson, A., additional, McDiarmid, S., additional, Fergusson, D., additional, Mazzarello, S., additional, Hutton, B., additional, Joy, A.A., additional, McInnes, M., additional, and Clemons, M., additional
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- 2018
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21. SAT0449 Sex, metabolic co-morbidities and line of therapy predict tnf-inhibitor therapy persistence in psoriatic arthritis: a retrospective cohort study
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Ye, W, primary, Guruparan, T, additional, Stober, C, additional, Htut, EEP, additional, and Jadon, DR, additional
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- 2017
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22. Physician "Out of Office" Alert: Does It Work?
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Clemons, Mark, primary, Joy, A. A., additional, Hilton, J., additional, Arnaout, A., additional, Brackstone, M., additional, Wheatley-Price, P., additional, Stober, C., additional, Dinniwell, R., additional, Mazzarello, S., additional, da Costa, M., additional, and Hutton, B., additional
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- 2017
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23. FRI0452 Are Gm-Csf-Producing Th17 Cells Important in The Pathogenesis of Psoriatic Arthritis?
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Stober, C., primary, Goodall, J., additional, and Gaston, H., additional
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- 2016
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24. The Reliability, Validity, and Responsiveness in an Elderly Population
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GLOTHIII, F, primary, SCHEVE, A, additional, STOBER, C, additional, CHOW, S, additional, and PROSSER, J, additional
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- 2001
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25. Functional Pain Scale
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Gloth, F. Michael, primary, Scheve, A. A., additional, Stober, C. V., additional, Chow, Selina, additional, and Prosser, Jane, additional
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- 2001
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26. ATP-Induced Killing of Mycobacteria by Human Macrophages Is Mediated by Purinergic P2Z(P2X7) Receptors
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Lammas, D.A., primary, Stober, C., additional, Harvey, C.J., additional, Kendrick, N., additional, Panchalingam, S., additional, and Kumararatne, D.S., additional
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- 1997
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27. LBA 3 A pragmatic, randomised, multicentre trial comparing 4-weekly vs. 12-weekly administration of bone-targeted agents (denosumab, zoledronate or pamidronate) in patients with bone metastases.
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Clemons, M, Stober, C, Mates, M, Joy, A A, Robinson, A, Hilton, J, Blanchette, P, Aseyev, O, Pond, G, and Fergusson, D
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- *
BONE metastasis , *METASTATIC breast cancer , *EXPERIMENTAL medicine , *DENOSUMAB - Published
- 2019
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28. 211P A cost-utility analysis of administration schedules of G-CSF for primary prophylaxis of chemotherapy-induced febrile neutropenia in early stage breast cancer: Economic evaluation alongside the REaCT-G trial.
- Author
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Basulaiman, B, Awan, A A, Hilton, J, Fergusson, D, Stober, C, Vandermeer, L, Saunders, D, Clemons, M, and Thavorn, K
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- *
FEBRILE neutropenia , *COST effectiveness , *BREAST cancer , *PREVENTIVE medicine , *PUBLIC hospitals - Published
- 2019
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29. 205P A prospective, multicentre, randomized trial comparing vascular access strategies for patients receiving non-trastuzumab containing chemotherapy for early stage breast cancer.
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Awan, A A, Basulaiman, B, Robinson, A, Stober, C, Fergusson, D, Joy, A A, Vandermeer, L, Mallick, R, Saunders, D, and Clemons, M
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- *
SURGICAL arteriovenous shunts , *BREAST cancer , *CANCER chemotherapy , *MEDICAL sciences , *WOMEN'S hospitals - Published
- 2019
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30. A randomised trial comparing 6-monthly adjuvant zoledronate with a single one-time dose in patients with early breast cancer.
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Awan AA, Stober C, Pond GR, Machado I, Clemons L, Conter H, Simos D, Dhesy-Thind S, Mates M, Kumar V, Hilton J, Savard MF, Fergusson D, Vandermeer L, and Clemons M
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- Humans, Female, Middle Aged, Aged, Chemotherapy, Adjuvant methods, Chemotherapy, Adjuvant adverse effects, Drug Administration Schedule, Treatment Outcome, Neoplasm Staging, Aged, 80 and over, Prospective Studies, Adult, Diphosphonates administration & dosage, Diphosphonates adverse effects, Diphosphonates therapeutic use, Zoledronic Acid administration & dosage, Zoledronic Acid therapeutic use, Zoledronic Acid adverse effects, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Quality of Life, Bone Density Conservation Agents administration & dosage, Bone Density Conservation Agents adverse effects, Bone Density Conservation Agents therapeutic use
- Abstract
Purpose: While adjuvant bisphosphonate use in early breast cancer (EBC) is associated with improvements in breast cancer-specific outcomes, questions remain around optimal bisphosphonate type, dose and scheduling. We evaluated a single zoledronate infusion in a prospective randomised trial., Methods: Postmenopausal patients with EBC were randomised to receive a single infusion of zoledronate (4 mg IV) or 6-monthly treatment for 3 years. Outcomes measured were; Quality of Life (QoL; EQ-5D-5L), bisphosphonate-related toxicities, including acute phase reactions (APRs), recurrence-free survival (RFS), bone metastasis-free survival (BMFS) and overall survival (OS)., Results: 211 patients were randomized to either a single infusion (n = 107) or six-monthly treatment (n = 104). After 3 years of follow up there were no significant differences between the arms for QoL and most toxicity endpoints. APRs following zoledronate occurred in 81% (171/211) of patients (77.6% in single infusion arm and 84.6% in the 6-monthly group). While the frequency of APRs decreased over 3 years in the 6-monthly arm, they still remain common. Of 34/104 (32.7%) patients who discontinued zoledronate early in the 6-monthly treatment group, the most common reason was APRs (16/34, 47%). At the 3 year follow up, there were no differences between arms for RFS, BMFS or OS., Conclusion: A single infusion of zoledronate was associated with increased patient convenience, less toxicity, and lower rates of treatment discontinuation. Despite the common clinical impression that APRs decrease with time, this was not observed when patients were specifically questioned. While the study is not powered for non-inferiority, longer-term follow-up for confirmation of RFS and OS rates is ongoing., (© 2024. The Author(s).)
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- 2024
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31. Cell-type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells.
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Grimes K, Jeong H, Amoah A, Xu N, Niemann J, Raeder B, Hasenfeld P, Stober C, Rausch T, Benito E, Jann JC, Nowak D, Emini R, Hoenicka M, Liebold A, Ho A, Shuai S, Geiger H, Sanders AD, and Korbel JO
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- Humans, Middle Aged, Adult, Single-Cell Analysis methods, Aged, Female, Male, Aging genetics, Aged, 80 and over, Stem Cells metabolism, Genetic Variation, Hematopoietic Stem Cells metabolism, Hematopoietic Stem Cells cytology, Mosaicism
- Abstract
The functional impact and cellular context of mosaic structural variants (mSVs) in normal tissues is understudied. Utilizing Strand-seq, we sequenced 1,133 single-cell genomes from 19 human donors of increasing age, and discovered the heterogeneous mSV landscapes of hematopoietic stem and progenitor cells. While mSVs are continuously acquired throughout life, expanded subclones in our cohort are confined to individuals >60. Cells already harboring mSVs are more likely to acquire additional somatic structural variants, including megabase-scale segmental aneuploidies. Capitalizing on comprehensive single-cell micrococcal nuclease digestion with sequencing reference data, we conducted high-resolution cell-typing for eight hematopoietic stem and progenitor cells. Clonally expanded mSVs disrupt normal cellular function by dysregulating diverse cellular pathways, and enriching for myeloid progenitors. Our findings underscore the contribution of mSVs to the cellular and molecular phenotypes associated with the aging hematopoietic system, and establish a foundation for deciphering the molecular links between mSVs, aging and disease susceptibility in normal tissues., (© 2024. The Author(s).)
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- 2024
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32. Smarter in the city? Lizards from urban and semi-natural habitats do not differ in a cognitive task in two syntopic species.
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Damas-Moreira I, Szabo B, Drosopoulos G, Stober C, Lisičić D, and Caspers BA
- Abstract
Urbanization occurs at a global scale, imposing dramatic and abrupt environmental changes that lead to biodiversity loss. Yet, some animal species can handle these changes, and thrive in such artificial environments. One possible explanation is that urban individuals are equipped with better cognitive abilities, but most studies have focused on birds and mammals and yielded varied results. Reptiles have received much less attention, despite some lizard species being common city dwellers. The Italian wall lizard, Podarcis siculus , and the common wall lizard, Podarcis muralis , are two successful lizards in anthropogenic habitats that thrive in urban locations. To test for differences in a cognitive skill between urban and semi-natural environments, we investigated inhibitory control through a detour task in syntopic populations of the two species, across 249 lizards that were tested in partially artificial field settings. Sophisticated inhibitory control is considered essential for higher degrees of cognitive flexibility and other higher-level cognitive abilities. In this task, we confronted lizards with a transparent barrier, separating them from a desired shelter area that they could only reach by controlling their impulse to go straight and instead detour the barrier. We found no differences between lizards in urban and semi-natural environments, nor between species, but females overall performed better than males. Moreover, 48% of the lizards in our study did not perform a correct trial in any of the 5 trials, hinting at the difficulty of the task for these species. This study is among the first to address lizard cognition, through their inhibitory control, as a potential explanation for success in cities and highlights one should be careful with assuming that urban animals generally have enhanced cognitive performance, as it might be taxa, task, or condition dependent., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Editorial Office, Current Zoology.)
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- 2024
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33. Impact on patient outcomes of spondyloarthritis-inflammatory bowel disease multi-disciplinary meetings.
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Sayers S, Lam D, Shah Q, Evans J, Parkes M, Stober C, Rimmer J, Clunie G, Gudu TE, Rosembert D, Subramanian S, Brookes-Jones S, Moss S, Raine T, and Jadon D
- Abstract
Objectives: To assess the impact on patient outcomes of the spondyloarthritis (SpA) and inflammatory bowel disease (IBD) multidisciplinary team (MDT) meetings in a large university hospital., Methods: A single-centre retrospective observational case-note review was conducted assessing the outcome of all 226 cases discussed at the SpA-IBD MDT meetings in a large UK university hospital between 2017-2022., Results: A total of 226 patients were discussed. It was deemed that 97% of MDT meetings helped to improve communication between teams, and 100% were educational. A total of 57% of discussions led to an instant change of disease management, while 40% of discussions resulted in a treatment plan that avoided the use of dual advanced therapy. This improved patient safety by reducing immunosuppression. The MDT meetings were highly cost and time efficient; 125 referrals between specialists were avoided, and in 51 cases there was a significant chance of reducing future drug costs. A timely investigation or appointment was arranged following 50% of MDT discussions, helping to clarify the diagnosis and optimise patient care. 9% of meetings enabled drugs to be prescribed to patients that are not yet licenced for the other speciality, thereby improving treatment options available in the management of complex cases., Conclusion: The MDT meetings have been beneficial for patients, the clinical team and the institution. This approach might be considered by other rheumatology and gastroenterology departments., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2024
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34. A Multi-Centre Randomized Study Comparing Two Standard of Care Chemotherapy Regimens for Lower-Risk HER2-Positive Breast Cancer.
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Fernandes R, Ng TL, Alzahrani MJ, Raphael J, Blanchette P, Black M, Stober C, Pond GR, Cella D, Vandermeer L, Ibrahim M, and Clemons M
- Subjects
- Humans, Female, Quality of Life, Standard of Care, Chemotherapy, Adjuvant, Trastuzumab therapeutic use, Breast Neoplasms drug therapy
- Abstract
Background: Neither paclitaxel plus trastuzumab (P-H) nor docetaxel-cyclophosphamide plus trastuzumab (TC-H) have been prospectively compared in HER2-positive early-stage breast cancer (EBC). A randomized trial was performed to assess the feasibility of a larger study., Methods: Lower-risk HER2-positive EBC patients were randomized to either P-H or TC-H treatment arms. The co-primary feasibility outcomes were: ≥75% patient acceptability rate, active trial participation of ≥50% of medical oncologists, ≥75% and ≥90% treatment completion, and receipt rate of planned cycles of chemotherapy, respectively., Secondary Outcomes: Febrile neutropenia (FN) rate, treatment-related hospitalizations, health-related quality of life (HR-QoL) questionnaires. Analyses were performed by per protocol and intention-to-treat., Results: Between May 2019 and March 2021, 49 of 52 patients agreed to study participation (94% acceptability rate). Fifteen (65%) of 23 medical oncologists approached patients. Rates of FN were higher (8.3% vs. 0%) in the TC-H vs. P-H arm. Median (IQR) changes in scores from baseline in FACT-Taxane Trial Outcome Index at 24 weeks were -4 (-10, -1) vs. -6.5 (-15, -2) for TC-H and P-H arms, respectively., Conclusions: A randomized trial comparing P-H and TC-H was feasible. Expansion to a larger trial would be feasible to explore patient-reported outcomes of these adjuvant HER2 chemotherapy regimens.
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- 2023
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35. Gaps and complex structurally variant loci in phased genome assemblies.
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Porubsky D, Vollger MR, Harvey WT, Rozanski AN, Ebert P, Hickey G, Hasenfeld P, Sanders AD, Stober C, Korbel JO, Paten B, Marschall T, and Eichler EE
- Subjects
- Humans, Haplotypes, Segmental Duplications, Genomic, Sequence Analysis, DNA, DNA, Satellite genetics, Polymorphism, Genetic
- Abstract
There has been tremendous progress in phased genome assembly production by combining long-read data with parental information or linked-read data. Nevertheless, a typical phased genome assembly generated by trio-hifiasm still generates more than 140 gaps. We perform a detailed analysis of gaps, assembly breaks, and misorientations from 182 haploid assemblies obtained from a diversity panel of 77 unique human samples. Although trio-based approaches using HiFi are the current gold standard, chromosome-wide phasing accuracy is comparable when using Strand-seq instead of parental data. Importantly, the majority of assembly gaps cluster near the largest and most identical repeats (including segmental duplications [35.4%], satellite DNA [22.3%], or regions enriched in GA/AT-rich DNA [27.4%]). Consequently, 1513 protein-coding genes overlap assembly gaps in at least one haplotype, and 231 are recurrently disrupted or missing from five or more haplotypes. Furthermore, we estimate that 6-7 Mbp of DNA are misorientated per haplotype irrespective of whether trio-free or trio-based approaches are used. Of these misorientations, 81% correspond to bona fide large inversion polymorphisms in the human species, most of which are flanked by large segmental duplications. We also identify large-scale alignment discontinuities consistent with 11.9 Mbp of deletions and 161.4 Mbp of insertions per haploid genome. Although 99% of this variation corresponds to satellite DNA, we identify 230 regions of euchromatic DNA with frequent expansions and contractions, nearly half of which overlap with 197 protein-coding genes. Such variable and incompletely assembled regions are important targets for future algorithmic development and pangenome representation., (© 2023 Porubsky et al.; Published by Cold Spring Harbor Laboratory Press.)
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- 2023
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36. Semi-automated assembly of high-quality diploid human reference genomes.
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Jarvis ED, Formenti G, Rhie A, Guarracino A, Yang C, Wood J, Tracey A, Thibaud-Nissen F, Vollger MR, Porubsky D, Cheng H, Asri M, Logsdon GA, Carnevali P, Chaisson MJP, Chin CS, Cody S, Collins J, Ebert P, Escalona M, Fedrigo O, Fulton RS, Fulton LL, Garg S, Gerton JL, Ghurye J, Granat A, Green RE, Harvey W, Hasenfeld P, Hastie A, Haukness M, Jaeger EB, Jain M, Kirsche M, Kolmogorov M, Korbel JO, Koren S, Korlach J, Lee J, Li D, Lindsay T, Lucas J, Luo F, Marschall T, Mitchell MW, McDaniel J, Nie F, Olsen HE, Olson ND, Pesout T, Potapova T, Puiu D, Regier A, Ruan J, Salzberg SL, Sanders AD, Schatz MC, Schmitt A, Schneider VA, Selvaraj S, Shafin K, Shumate A, Stitziel NO, Stober C, Torrance J, Wagner J, Wang J, Wenger A, Xiao C, Zimin AV, Zhang G, Wang T, Li H, Garrison E, Haussler D, Hall I, Zook JM, Eichler EE, Phillippy AM, Paten B, Howe K, and Miga KH
- Subjects
- Humans, Haplotypes genetics, High-Throughput Nucleotide Sequencing methods, High-Throughput Nucleotide Sequencing standards, Sequence Analysis, DNA methods, Sequence Analysis, DNA standards, Reference Standards, Chromosomes, Human genetics, Genetic Variation genetics, Chromosome Mapping standards, Diploidy, Genome, Human genetics, Genomics methods, Genomics standards
- Abstract
The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has benefitted society
1,2 . However, it still has many gaps and errors, and does not represent a biological genome as it is a blend of multiple individuals3,4 . Recently, a high-quality telomere-to-telomere reference, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a nearly homozygous genome5 . To address these limitations, the Human Pangenome Reference Consortium formed with the goal of creating high-quality, cost-effective, diploid genome assemblies for a pangenome reference that represents human genetic diversity6 . Here, in our first scientific report, we determined which combination of current genome sequencing and assembly approaches yield the most complete and accurate diploid genome assembly with minimal manual curation. Approaches that used highly accurate long reads and parent-child data with graph-based haplotype phasing during assembly outperformed those that did not. Developing a combination of the top-performing methods, we generated our first high-quality diploid reference assembly, containing only approximately four gaps per chromosome on average, with most chromosomes within ±1% of the length of CHM13. Nearly 48% of protein-coding genes have non-synonymous amino acid changes between haplotypes, and centromeric regions showed the highest diversity. Our findings serve as a foundation for assembling near-complete diploid human genomes at scale for a pangenome reference to capture global genetic variation from single nucleotides to structural rearrangements., (© 2022. The Author(s).)- Published
- 2022
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37. A hold-and-feed mechanism drives directional DNA loop extrusion by condensin.
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Shaltiel IA, Datta S, Lecomte L, Hassler M, Kschonsak M, Bravo S, Stober C, Ormanns J, Eustermann S, and Haering CH
- Subjects
- Cryoelectron Microscopy, Nucleic Acid Conformation, Single Molecule Imaging, Adenosine Triphosphatases chemistry, DNA chemistry, DNA-Binding Proteins chemistry, Multiprotein Complexes chemistry
- Abstract
Structural maintenance of chromosomes (SMC) protein complexes structure genomes by extruding DNA loops, but the molecular mechanism that underlies their activity has remained unknown. We show that the active condensin complex entraps the bases of a DNA loop transiently in two separate chambers. Single-molecule imaging and cryo-electron microscopy suggest a putative power-stroke movement at the first chamber that feeds DNA into the SMC-kleisin ring upon adenosine triphosphate binding, whereas the second chamber holds on upstream of the same DNA double helix. Unlocking the strict separation of "motor" and "anchor" chambers turns condensin from a one-sided into a bidirectional DNA loop extruder. We conclude that the orientation of two topologically bound DNA segments during the SMC reaction cycle determines the directionality of DNA loop extrusion.
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- 2022
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38. Proceedings of the 2021 GRAPPA-Collaborative Research Network (CRN) Meeting.
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Stober C, McInnes IB, Raychaudhuri S, Mease PJ, Pennington SR, Scher JU, Chandran V, Armstrong AW, Wit M, Cauli A, Jadon DR, Löve TJ, Ogdie A, O'Sullivan D, van Mens LJJ, Ritchlin CT, and FitzGerald O
- Subjects
- Humans, Organizations, Pilot Projects, Arthritis, Psoriatic, Psoriasis, Rheumatology
- Abstract
At the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-Collaborative Research Network (CRN) annual meeting, the GRAPPA-CRN group presented a number of project updates, including a pilot investigator-initiated study to evaluate liquid and tissue biomarkers associated with axial involvement in psoriatic arthritis (PsA). The GRAPPA-CRN session updated progress made with 3 parallel international research initiatives based on 3 previously defined unmet needs in PsA. The Health Initiatives in Psoriasis and PsOriatic arthritis ConsoRTium European States (HIPPOCRATES) is a European research consortium formed to address unmet clinical needs in PsA. The Preventing Arthritis in a multicenter Psoriasis At-Risk Population (PAMPA) is a US-based organization that has defined consensus terminology for preclinical phases of PsA and is interested in the transition process from psoriasis to PsA. An overview of the Accelerating Medicines Partnership Autoimmune and Immune-Mediated Diseases (AMP AIM) program 2.0, a consortium including GRAPPA-CRN members that addressed these 3 unmet needs in PsA, was also presented., (Copyright © 2022 by The Journal of Rheumatology.)
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- 2022
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39. Symptomatic skeletal-related events in patients receiving longer term bone-modifying agents for bone metastases from breast and castration resistant prostate cancers.
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Alzahrani M, Stober C, Liu M, Awan A, Ng TL, Pond G, Alshamsan B, Vandermeer L, and Clemons M
- Subjects
- Adult, Aged, Aged, 80 and over, Castration, Humans, Male, Middle Aged, Retrospective Studies, Zoledronic Acid therapeutic use, Bone Neoplasms drug therapy, Bone Neoplasms secondary, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Background: The effect of longer-term use of bone-modifying agent (BMA) on symptomatic skeletal event (SSE) rates in patients with bone metastases remains unclear. This retrospective study of a cohort of patients in a randomized controlled trial evaluated SSEs in patients receiving BMAs at a single cancer center., Methods: Data from patients with metastatic breast and castration-resistant prostate cancer (CRPC) were interrogated to evaluate the effects of longer-term use of BMAs on incidence, type, and risk factors for SSEs., Results: Of 162 patients, 109 (67%) had breast cancer (BC) and 53 (33%) CRPC. Median age at diagnosis of bone metastases was 61.9 years (range 27.5-97.2) for BC patients and 72.1 (range 37.0-92.2) for CRPC patients. Median duration of BMA use was 2.3 years (range 0.1-9.9 years) for BC and 3.8 years (range 1.5-9.4) for CRPC patients. The initial BMAs in BC patients were pamidronate (46.8%), denosumab (31.2%), and zoledronate (22%). All CRPC patients received denosumab. During follow-up, 59% of BC and 75% of CRPC patients had at least one SSE. The number of patients experiencing ≥ 1 SSE per year was higher in the first year after bone metastasis diagnosis (63/162; 38.9%) compared with that in the second (26/149; 17.5%) and third years (30/123; 24.4%). Neither age, visceral disease, multiple bone metastases, nor biological markers for BC had a significant impact on time to first SSE., Conclusions: The risk for SSEs was greatest in the first year after diagnosis of bone metastasis. Studies evaluating de-escalation and even stopping of BMAs with longer-term use may therefore be warranted., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2022
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40. Oral magnesium supplements for cancer treatment-induced hypomagnesemia: Results from a pilot randomized trial.
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Awan A, Basulaiman B, Stober C, Clemons M, Fergusson D, Hilton J, Al Ghareeb W, Goodwin R, Ibrahim M, Hutton B, Vandermeer L, Mallick R, and Vickers MM
- Abstract
Background and Aims: Optimal management of cancer treatment-induced hypomagnesemia (hMg) is not known. We assessed the feasibility of using a novel pragmatic clinical trials model to compare two commonly used oral Mg replacement strategies., Methods: Patients with grade 1 to 3 hMg while receiving either platinum-based chemotherapy or epidermal growth factor receptor inhibitors (EGFRI) were randomized to oral magnesium oxide (MgOx) or oral magnesium citrate (MgCit). The trial methodology utilized the integrated consent model. Feasibility would be successful if; accrual rate was ≥5 patients a month and if measures of patient and physician engagement, were > 50%. Secondary endpoints included; comparison of Mg levels, cardiac arrhythmias, and rates of treatment delay/hospitalizations., Results: From July 2016 to December 2017, an average of 1 patient a month was accrued. All 15 eligible and approached patients consented to participate in the study (100% engagement) and 7/15 were randomized to MgOx and 8/15 to MgCit. The percentage of physicians who approached patients for the study was 4 of 6 (66.6% engagement). The mean slope of change in Mg (mmol/L/day) was 0.0022 (95% CI: -0.0001 to 0.0044) for MgOx and 0.0006 (95% CI, -0.0012 to 0.0024) for MgCit ( P = .2123). Three patients (20%) required IV magnesium while on the study (2 MgCit and 1 MgOx). Grade 1 diarrhea occurred in 3 patients in the MgCit arm., Conclusion: Despite oral magnesium tolerability and meeting most of its feasibility endpoints, this study did not meet its target accrual rate. Alternative designs would be necessary for a definitive efficacy study., Competing Interests: AA reports participating in the Novartis Canada Advisory Board on the use of Ribociclib, BH consults for Cornerstore Research, not related to this research project. All other authors have nothing to disclose., (© 2021 The Authors. Health Science Reports published by Wiley Periodicals LLC.)
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- 2021
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41. A Randomized Trial Comparing 3- versus 4-Monthly Cardiac Monitoring in Patients Receiving Trastuzumab-Based Chemotherapy for Early Breast Cancer.
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Dent S, Fergusson D, Aseyev O, Stober C, Pond G, Awan AA, McGee SF, Ng TL, Simos D, Vandermeer L, Saunders D, Hilton JF, Hutton B, and Clemons M
- Subjects
- Female, Humans, Receptor, ErbB-2, Stroke Volume, Trastuzumab adverse effects, Ventricular Function, Left, Breast Neoplasms complications, Breast Neoplasms drug therapy
- Abstract
Purpose: The optimal frequency for cardiac monitoring of left ventricular ejection fraction (LVEF) in patients receiving trastuzumab-based therapy for early breast cancer (EBC) is unknown. We conducted a randomized controlled trial comparing 3- versus 4-monthly cardiac monitoring., Patients and Method: Patients scheduled to receive trastuzumab-containing cancer therapy for EBC with normal (>53%) baseline LVEF were randomized to undergo LVEF assessments every 3 or 4 months. The primary outcome was the change in LVEF from baseline. Secondary outcomes included the rate of cardiac dysfunction (defined as a decrease in the LVEF of ≥10 percentage points, to a value <53%), delays in or discontinuation of trastuzumab therapy, and cardiology referral., Results: Of the 200 eligible and enrolled patients, 100 (50%) were randomized to 3-monthly and 100 (50%) to 4-monthly cardiac monitoring. Of these patients, 98 and 97 respectively underwent at least one cardiac scan. The estimated mean difference in LVEF from baseline was -0.94% (one-sided 95% lower bound: -2.14), which exceeded the pre-defined non-inferiority margin of -4%. There were also no significant differences between the two study arms for any of the secondary endpoints. The rate of detection of cardiac dysfunction was 16.3% (16/98) and 12.4% (12/97) in the 3- and 4-monthly arms, respectively (95% CI: 4.0 [-5.9, 13.8])., Conclusions: Cardiac monitoring every 4 months was deemed non-inferior to that every 3 months in patients with HER2-positive EBC being treated with trastuzumab-based therapy. Given its costs and inconvenience, cardiac monitoring every 4 months should be considered standard practice. Registration: NCT02696707, 18 February 2016.
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- 2021
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42. Two-year results of a randomised trial comparing 4- versus 12-weekly bone-targeted agent use in patients with bone metastases from breast or castration-resistant prostate cancer.
- Author
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Clemons M, Liu M, Stober C, Pond G, Jemaan Alzahrani M, Ong M, Ernst S, Booth C, Mates M, Abraham Joy A, Aseyev O, Blanchette P, Vandermeer L, Tu M, Thavorn K, and Fergusson D
- Abstract
Background: We present the 2-year results of a randomised trial comparing 4- versus 12-weekly bone-targeting agents (BTAs) in patients with bone metastases from breast or castration-resistant prostate cancer (CRPC)., Patients and Methods: Patients with bone metastases from breast or CRPC, who were going to start or were already receiving BTAs, were randomised to 4- or 12-weekly BTA treatment for 2 years. The endpoints were: symptomatic skeletal events (SSE) rates, time to SSEs, toxicity and cost-effectiveness., Results: Of 263 patients (160 breast cancer, 103 CRPC), 133 (50.6%) and 130 (49.4%) were randomised to the 4- and 12-weekly groups, respectively. BTAs included denosumab (56.3%), zoledronate (24.0%) and pamidronate (19.8%). After 2 years, the cumulative incidence rate (95% CI) of SSEs was 32.7% (24.6% to 41.1%) and 28.1% (20.3% to 36.4%) for the 4- and 12-weekly intervention groups respectively. The hazard ratio for time to first SSE was 0.96 (95% CI = 0.63 to 1.47). However, in a post hoc analysis, those patients who had an on-study SSE, there was a small non-statistical increased risk of subsequent SSEs among patients on the 12-weekly dosing arm (HR = 1.14; 95% CI - 0.90-1.44). BTA-related toxicity rates were similar between study arms. A cost-utility analysis showed that 12-weekly BTA is cost-effective from a public payer's perspective., Conclusion: These results in addition to those previously reported for de-escalating zoledronate, would support that de-escalation of commonly used BTAs is a reasonable and economically valid treatment option. While not statistically significant, the increase in subsequent SSEs in the 12-weekly arm requires further exploration., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier GmbH.)
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- 2021
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43. De-escalating adjuvant therapies in older patients with lower risk estrogen receptor-positive breast cancer treated with breast-conserving surgery: A systematic review and meta-analysis.
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Savard MF, Clemons M, Hutton B, Jemaan Alzahrani M, Caudrelier JM, Vandermeer L, Liu M, Saunders D, Sienkiewicz M, Stober C, Cole K, Shorr R, Arnaout A, and Chang L
- Subjects
- Age Factors, Antineoplastic Agents, Hormonal, Breast Neoplasms metabolism, Breast Neoplasms surgery, Chemotherapy, Adjuvant, Clinical Trials, Phase III as Topic, Female, Humans, Mastectomy, Segmental methods, Radiotherapy, Adjuvant, Randomized Controlled Trials as Topic, Risk Factors, Breast Neoplasms therapy, Receptors, Estrogen metabolism
- Abstract
Purpose: Radiation therapy (RT) and endocrine therapy (ET) are standard treatments for hormone receptor-positive (HR+) breast cancer after breast-conserving surgery (BCS). However, many older patients are at greater risk of treatment-related toxicities and non-cancer related death, and less likely to benefit from these standard treatments. A systematic review was performed evaluating outcomes of omitting RT or ET in older patients aged ≥50 treated with BCS for lower-risk breast cancer., Methods: Medline, Embase, and the Cochrane Register of Controlled Trials were queried from 1980 to April 30th, 2020 for randomized controlled studies (RCTs) and prospective cohort studies (PCSs) evaluating omission of RT and/or ET compared to RT plus ET in patients. Meta-analysis was performed using random-effects models with findings reported as risk ratios (RR) with 95% confidence intervals (CI)., Results: From 3860 citations, 10 prospective studies met eligibility criteria. Omission of RT alone was evaluated in 7 RCTs (n = 4604) and one PCS (n = 667); omission of ET alone was assessed in 1 PCS (n = 271); and omission of either ET or RT was compared to ET plus RT in 1 RCT (n = 495). Adjuvant RT compared to no RT reduced 5- and 10-year in-breast tumor recurrence [5-year: RR 0.16, 95 %CI 0.09-0.27 l 10-year: 0.28, 95 %CI 0.16-0.5], but had no effect on survival [5-year: RR 0.94, 95 %CI 0.77-1.15; 10-year: 1.01, 95 %CI 0.9-1.12]., Conclusion: The current body of evidence suggests that RT can be omitted in older patients with lower-risk disease. However, more trials on the omission of ET are required to better inform treatment decisions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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44. The COVID-19 pandemic: An opportunity to rethink and harmonise the frequency of follow-up visits for patients with early stage breast cancer.
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Surujballi J, Shah H, Hutton B, Alzahrani M, Beltran-Bless AA, Shorr R, Larocque G, McGee S, Cole K, Ibrahim MFK, Fernandes R, Arnaout A, Stober C, Liu M, Sienkiewicz M, Saunders D, Vandermeer L, and Clemons M
- Subjects
- Breast Neoplasms virology, COVID-19 virology, Female, Follow-Up Studies, Humans, Prospective Studies, Randomized Controlled Trials as Topic, Breast Neoplasms therapy, COVID-19 complications, Quality of Life, SARS-CoV-2 isolation & purification
- Abstract
Purpose: While routine, in-person follow-up of early-stage breast cancer patients (EBC) after completion of initial treatment is common, the COVID-19 pandemic has resulted in unprecedented changes in clinical practice. A systematic review was performed to evaluate the evidence supporting different frequencies of routine follow-up., Methods: MEDLINE and the Cochrane Collaboration Library were searched from database inception to July 16, 2020 for randomized controlled trials (RCTs) and prospective cohort studies (PCS) evaluating different frequencies of routine follow-up. Citations were assessed by pairs of independent reviewers. Risk of Bias (RoB) was assessed using the Cochrane RoB tool for RCTs and the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies. Findings were summarized narratively., Results: The literature search identified 3316 studies, of which 7 (6 RCTs and 1 PCS) were eligible. Study endpoints included; quality of life (QoL; 5 RCTs and 1 PCS), disease free survival (DFS) (1 RCT), overall survival (OS) (1 RCT) and cost-effectiveness (1 RCT). The results showed reduction in follow-up frequency had no adverse effect on: QoL (6 studies, n = 920), DFS (1 trial, n = 472) or OS (1 trial, n = 472), but improved cost-effectiveness (1 trial, n = 472). Four RCTs specifically examined follow-up on-demand versus scheduled follow-up visits and found no statistically significant differences in QoL (n = 544)., Conclusion: While no evidence-based guidelines suggest that follow-up of EBC patients improves DFS or OS, routinely scheduled in-person assessment is common. RCT data suggests that reduced frequency of follow-up has no adverse effects., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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45. A randomized clinical trial comparing physician-directed or fixed-dose steroid replacement strategies for incomplete dexamethasone dosing prior to docetaxel chemotherapy.
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Hsu T, Fergusson D, Stober C, Daigle K, Moledina N, Vandermeer L, Pond G, Hilton J, Hutton B, and Clemons M
- Subjects
- Antineoplastic Combined Chemotherapy Protocols pharmacology, Dexamethasone pharmacology, Docetaxel pharmacology, Female, Glucocorticoids pharmacology, Humans, Male, Middle Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Dexamethasone therapeutic use, Docetaxel therapeutic use, Drug Administration Schedule, Glucocorticoids therapeutic use, Premedication methods
- Abstract
Purpose: Prior to docetaxel chemotherapy, incomplete dosing of steroid premedication is common. The lack of standardized steroid replacement strategies can lead to variability in care and delays in starting docetaxel., Methods: This randomized trial compared physician-directed with fixed-dose dexamethasone. Patients who had missed at least one dose of steroid premedication were randomized to physician-directed replacement (any choice of steroid, dose or route) or to dexamethasone 8 mg oral before starting docetaxel. The primary outcome was time from randomization to starting docetaxel. Secondary outcomes included rates of acute and delayed hypersensitivity reactions, fluid retention and skin toxicity., Results: Of 60 eligible patients, 30 (50%) and 30 (50%) were randomized to physician-directed and fixed-dose arms, respectively. Overall tumour types: breast (42 [70%]), gastrointestinal (7 [12%]), prostate (7 [12%]) and lung (3 [7%]). Dexamethasone was most commonly incompletely taken with cycles 1 (28 [48%]) and 2 (13 [22%]) of docetaxel. Seven different replacement strategies were used in the physician-choice arm. Patients in the fixed-dose arm received docetaxel a mean of 21.2 (95% CI for the difference is 2.1 to 44.6) minutes earlier than the physician-choice arm (p = 0.033 Wilcoxon rank sum test or p = 0.073 two-sample t test). Median time to docetaxel was 47.5 vs 61 min (mean 62.2 vs 83.4 min) by arm, respectively. No significant difference in toxicity rates was observed., Conclusion: While not meeting our predefined criteria of improving the time from randomization to starting docetaxel by 30 min, the fixed-dose replacement strategy reduced both the time to starting docetaxel and treatment variability. Fixed dosing with oral dexamethasone 8 mg should be the preferred standard of care. REGISTRATION: www.clinicaltrials.gov NCT02815319 REGISTRATION DATE: June 28, 2016.
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- 2021
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46. Pathogenesis of psoriatic arthritis.
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Stober C
- Subjects
- Humans, Inflammation, Arthritis, Psoriatic diagnosis, Arthritis, Psoriatic etiology, Enthesopathy, Psoriasis
- Abstract
Psoriatic arthritis (PsA) is a heterogenous systemic inflammatory disorder which affects peripheral joints (PsA) and skin (psoriasis (Ps)), but also causes inflammation at entheseal sites, digits (dactylitis) and the axial skeleton. Over the past decade, there have been considerable advances both in our understanding of the pathogenesis of PsA and in the treatment of its diverse manifestations. This article reviews our current knowledge of the pathogenesis of PsA, and how genetic pre-disposition coupled with mechanical stress may influence the development of the pathognomonic features of PsA including enthesitis and osteoproliferation, with concomitant osteoporosis and erosive disease. We consider factors that influence the development of PsA in patients with Ps, and how improving our knowledge of the phenotypes of PsA may ultimately facilitate our goal of precision medicine, a key unmet need as defined by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)
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- 2021
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47. Proceedings of the 2020 GRAPPA Collaborative Research Network (CRN) Meeting.
- Author
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Stober C, Jadon DR, Armstrong AW, Chandran V, de Wit M, Helliwell PS, Mease PJ, Ogdie A, O'Sullivan D, Pennington SR, Löve T, Cauli A, van Mens L, Waxman R, Scher JU, Barton A, Ritchlin CT, and FitzGerald O
- Subjects
- Biomarkers, Europe, Humans, Research Personnel, Arthritis, Psoriatic diagnosis, Arthritis, Psoriatic drug therapy, Psoriasis
- Abstract
At the 2020 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-Collaborative Research Network (CRN) annual meeting, the GRAPPA-CRN group presented a pilot investigator-initiated study protocol to test electronic case report forms (eCRFs) and proposed Standardized Operating Procedures (SOPs) to evaluate biomarkers of psoriatic arthritis (PsA) associated with axial disease. The progress on 3 studies was also presented: BioDAM PsA (Biomarkers as Predictors of structural DAMage in PsA; to validate soluble biomarkers as predictors of structural damage in PsA), PreventPsA (examining the development of PsA and risk factors among patients with psoriasis and no arthritis), and PredictORPsA (Predicting Treatment respOnse in patients with eaRly PsA; in collaboration with Pfizer using samples from the Oral Psoriatic Arthritis TriaL [OPAL], to identify biomarkers of treatment response). GRAPPA-CRN funding partnerships and applications are also underway with both the Innovative Medicines Initiative (IMI) in Europe and Accelerating Medicines Partnerships (AMP) 2.0 in the USA, and the progress of these applications and associated objectives were presented., (Copyright © 2021 by The Journal of Rheumatology.)
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- 2021
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48. Cost-Effectiveness Analysis of 12-Versus 4-Weekly Administration of Bone-Targeted Agents in Patients with Bone Metastases from Breast and Castration-Resistant Prostate Cancer.
- Author
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Tu MM, Clemons M, Stober C, Jeong A, Vandermeer L, Mates M, Blanchette P, Joy AA, Aseyev O, Pond G, Fergusson D, Ng TL, and Thavorn K
- Subjects
- Canada, Cost-Benefit Analysis, Humans, Male, Quality-Adjusted Life Years, Bone Neoplasms drug therapy, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
A cost-utility analysis was performed based on the Rethinking Clinical Trials (REaCT) bone-targeted agents (BTA) clinical trial that compared 12-weekly (once every 12 weeks) ( n = 130) versus 4-weekly (once every 4 weeks) ( n = 133) BTA dosing for metastatic breast and castration-resistant prostate (CRPC) cancer. Using a decision tree model, we calculated treatment and symptomatic skeletal event (SSE) costs as well as quality-adjusted life-years (QALYs) for each treatment option. Deterministic and probabilistic sensitivity analyses were performed to assess the robustness of the study findings. The total cost of BTA treatment in Canadian dollars (C$) and estimated QALYs was C$8965.03 and 0.605 QALY in the 4-weekly group versus C$5669.95 and 0.612 QALY in the 12-weekly group, respectively. De-escalation from 4-weekly to 12-weekly BTA reduces cost (C$3293.75) and improves QALYs by 0.008 unit, suggesting that 12-weekly BTA dominates 4-weekly BTA in breast and CRPC patients with bone metastases. Sensitivity analysis suggests high levels of uncertainty in the cost-effectiveness findings. De-escalation of bone-targeted agents is cost-effective from the Canadian public payer's perspective.
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- 2021
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49. Baricitinib set to join the Covid-19 therapeutic arsenal?
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Gudu T, Stober C, Cope AP, Cheriyan J, Galloway J, Wilkinson IB, Kostapanos M, Jayne D, and Hall F
- Subjects
- Antiviral Agents immunology, Antiviral Agents pharmacology, Clinical Trials as Topic, Humans, Immunologic Factors pharmacology, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Janus Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Treatment Outcome, Azetidines immunology, Azetidines pharmacology, COVID-19 immunology, Purines immunology, Purines pharmacology, Pyrazoles immunology, Pyrazoles pharmacology, SARS-CoV-2 drug effects, Sulfonamides immunology, Sulfonamides pharmacology, COVID-19 Drug Treatment
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- 2021
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50. Adjuvant bisphosphonate use in patients with early stage breast cancer: Patient perspectives on treatment acceptability and potential de-escalation.
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McGee S, AlZahrani M, Stober C, Ng TL, Cole K, Larocque G, Awan A, Sehdev S, Hilton J, Vandermeer L, Hutton B, Pond G, Saunders D, and Clemons M
- Abstract
Background: Despite the increasing use of adjuvant bisphosphonates for early stage breast cancer (EBC), little is known about the patient experience with such treatments. A patient survey was performed to identify current prescribing practices, perceptions around the role of treatment, the impact of treatment on patients' quality of life, and future trial designs., Methods: EBC patients who had either completed or were currently receiving adjuvant bisphosphonates were sent an anonymized survey. The survey collected information on patient and disease characteristics, bisphosphonate scheduling, compliance, and tolerance. Questions also assessed patient interest in trials of de-escalated bisphosphonate therapy., Results: A total of 255 patients were contacted, with 164 eligible respondents (eligible response rate 164/255, 64.3%). Median patient age was 52 years (range 28 to 82 years). The majority (111/163, 68.1%) were postmenopausal at the time of diagnosis, 23.3% (38/163) were premenopausal, and 7.4% (12/163) were perimenopausal. Most patients (78%) had received chemotherapy. Zoledronate was the most commonly used bisphosphonate (92%), with the majority receiving treatment every 6 months for 3 years (73%). While 66% (107/161) of respondents had experienced side effects with treatment, most had, or expected to, complete treatment (154/163, 94%). Provided there was no detriment in breast cancer outcomes, there was strong interest in future studies of de-escalating adjuvant bisphosphonate therapy., Conclusion: While most patients tolerate their treatment, there is interest in performing trials of de-escalation of these agents., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SMG reports receipt of honorarium from Novartis for insights on management of breast cancer patients. AAA reports Advisory board: Eli Lily, Exact Sciences, Exactis, Novartis, Pfizer, Honoraria: Apotex, Roche, Travel: Roche. BH and MC reports consulting fees from Cornerstone Research, outside the submitted work. GP reports consulting fees from Merck, Astra-Zeneca, Profound Medical, outside of submitted work; honorarium for DSMB membership from Takeda outside of submitted work; a close family member works for Roche Canada Ltd and owns stock in Roche Ltd. All other authors declare no competing interests., (© 2021 The Authors.)
- Published
- 2021
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