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1. Ultra hypercyclicity

Author

Liu, Martin, Walmsley, David, and Xue, James

Subjects
Mathematics - Functional Analysis
Abstract

Recently, new topological properties that an operator acting on a topological vector space can have were introduced: strong hypercyclicity and hypermixing. We introduce a new property called ultra hypercyclicity, and we compare it to the other common topological properties, including the new ones. For the family of weighted backward shifts on $c_0$ and $\ell^p$, we prove the existence of a strongly hypercyclic weighted backward shift which is not ultra hypercyclic., Comment: arXiv admin note: text overlap with arXiv:2304.02073

Published
2023

2. Strong topological transitivity, hypermixing, and their relationships with other dynamical properties

Author

Curtis, Ian, Griswold, Sean, Halverson, Abigail, Stilwell, Eric, Teske, Sarah, Walmsley, David, and Wang, Shaozhe

Subjects
Mathematics - Functional Analysis, 47A16 (Primary) 37B02 (Secondary)
Abstract

Recently, two stronger versions of dynamical properties have been introduced and investigated: strong topological transitivity, which is a stronger version of the topological transitivity property, and hypermixing, which is a stronger version of the mixing property. We continue the investigation of these notions with two main results. First, we show there are dynamical systems which are strongly topologically transitive but not weakly mixing. We then show that on $\ell^p$ or $c_0$, there is a weighted backward shift which is strongly topologically transitive but not mixing.

Published
2023

3. Offering you a glimpse into Canada’s underexposed corners

Author

Walmsley, David

Subjects
Canada
Abstract

With a new documentary photo series, The Globe and Mail takes the portrait of a nation, showcasing the extraordinary lives of ordinary citizens, David Walmsley is The Globe and Mail’s Editor-in-Chief. Today, The Globe and Mail is proud to launch a year-long photo project dedicated to telling the stories of our massive, varied [...]

Published
2024

4. Two Families of Hypercyclic Non-Convolution Operators

Author

Myers, Alex, Odinaev, Muhammadyusuf, and Walmsley, David

Subjects
Mathematics - Functional Analysis
Abstract

Let $H(\mathbb{C})$ be the set of all entire functions endowed with the topology of uniform convergence on compact sets. Let $\lambda,b\in\mathbb{C}$, let $C_{\lambda,b}:H(\mathbb{C})\to H(\mathbb{C})$ be the composition operator $C_{\lambda,b} f(z)=f(\lambda z+b)$, and let $D$ be the derivative operator. We extend results on the hypercyclicity of the non-convolution operators $T_{\lambda,b}=C_{\lambda,b} \circ D$ by showing that whenever $|\lambda|\geq 1$, the collection of operators \begin{align*} \{\psi(T_{\lambda,b}): \psi(z)\in H(\mathbb{C}), \psi(0)=0 \text{ and } \psi(T_{\lambda,b}) \text{ is continuous}\} \end{align*} forms an algebra under the usual addition and multiplication of operators which consists entirely of hypercyclic operators (i.e., each operator has a dense orbit). We also show that the collection of operators \begin{align*} \{C_{\lambda,b}\circ\varphi(D): \varphi(z) \text{ is an entire function of exponential type with } \varphi(0)=0\} \end{align*} consists entirely of hypercyclic operators.

Published
2020
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5. Linear Factorization of Hypercyclic Functions for Differential Operators

Author

Chan, Kit C., Hofstad, Jakob, and Walmsley, David

Subjects
Mathematics - Functional Analysis
Abstract

On the Fr\'{e}chet space of entire functions $H(\mathbb{C})$, we show that every nonscalar continuous linear operator $L:H(\mathbb{C})\to H(\mathbb{C})$ which commutes with differentiation has a hypercyclic vector $f(z)$ in the form of the infinite product of linear polynomials: \[ f(z) = \prod_{j=1}^\infty \, \left( 1-\frac{z}{a_j}\right), \] where each $a_j$ is a nonzero complex number.

Published
2019

9. Bringing you the news from Windsor

Author

Walmsley, David

Abstract

A new bureau emerges, Updated: December 08, 2023 David Walmsley is The Globe and Mail’s Editor-in-Chief. This weekend sees the launch of our latest pop-up bureau, this time bringing focus to events in Windsor, [...]

Published
2023

13. Art and the Historic Environment: A Teacher's Guide. Education on Site.

Author

English Heritage Education Service, London (England)., Lockey, Malcolm, and Walmsley, David

Abstract

This teacher's guide gives practical and realistic ideas for teaching and learning about art. Creating artwork need not be seen as an activity in isolation but can be used to reinforce historical understanding or to support cross-curricular work. The aim of the guide is to help teachers recognize the potential of the historic environment to: extend students' powers of perception and expression by exposing them to new environments; introduce them to different cultures and world influences, and their reflection in the buildings of the past; and support a cross-curricular approach to historical learning. The book will help teachers plan structured art-based visits to historic sites; prepare students in school for experiences and work on site; recognize the formal graphic elements within the historic environment; collect and record visual information on site; use sketches taken on site to stimulate creative artwork; and develop ideas in school using different techniques and materials. The illustrated guide contains a variety of case studies, used by teachers, which give more detailed approaches. It is divided into the following sections: "About This Book"; "Recognizing the Formal Elements"; "Choosing Materials"; "Checklists"; "Practicing Skills"; "Looking at Buildings"; "Looking at Decorative Features"; "Planning a Project"; and "Case Studies." Contains a bibliography and resources section. (BT)

Published
1999

14. Primary History: Using the Evidence of the Historic Environment. A Teacher's Guide.

Author

English Heritage Education Service, London (England)., Corbishley, Mike, Fordham, Jennie, Gay, Susan, Hollinshead, Liz, Spicer, Suzanne, and Walmsley, David

Abstract

This guide aims to help busy elementary teachers make the best use of a whole range of evidence for teaching history in schools today, covering areas of study at both Key Stages 1 and 2 (in the British school system). The guide includes: clear, richly illustrated explanatory text for the non-expert, with practical advice and project ideas; how to ask the right questions, teach key skills, use objects, games, documents, and interpretations of the past; ideas for Key Stage 1, from looking at houses or famous people or events, to using stories and timelines; the Romans in Britain; the Anglo-Saxons and the Vikings; Tudor life; Victoria's England and Britain since 1930; case studies of places relating to each period; and reproducible activity sheets for classroom use or on site visits. Contains a list of selected annotated resources for further reading. (BT)

Published
1999

15. Letter from the editor

Author

Walmsley, David

Subjects
Disclosure of information -- Laws, regulations and rules -- Political aspects, Freedom of information -- Political aspects -- Laws, regulations and rules, Government regulation, General interest, News, opinion and commentary
Abstract

Byline: David Walmsley; Staff Transparency is a crucial pillar of democracy: The public has a right to know how decisions are being made, and by whom, at all levels of [...]

Published
2023

20. On World News Day, let's remember that access to information is a human right

Author

Walmsley, David

Subjects
Journalists -- Practice -- Social aspects, Disclosure of information -- Social aspects, Human rights -- Social aspects, Current events -- Social aspects -- Access control, General interest, News, opinion and commentary
Abstract

Byline: DAVID WALMSLEY; Staff Editor-in-chief of The Globe and Mail and founder of World News Day Making a positive difference to someone's life is the greatest gift a journalist can [...]

Published
2022

22. Targeting DYRK1A/B kinases to modulate p21‐cyclin D1‐p27 signalling and induce anti‐tumour activity in a model of human glioblastoma

Author

Mike Burbridge, Andrew Massey, Walmsley David, K Benwell, and András Kotschy

Subjects
Cyclin-Dependent Kinase Inhibitor p21, DYRK1B, kinase inhibitor, DNA damage, Protein Serine-Threonine Kinases, Mice, Cyclin D1, In vivo, Cell Line, Tumor, Animals, Humans, Protein Kinase Inhibitors, Chemistry, Cell growth, Kinase, Cell Cycle, glioblastoma, Original Articles, DYRK1A, Cell Biology, Protein-Tyrosine Kinases, Cell cycle, Disease Models, Animal, Cancer cell, Cancer research, Molecular Medicine, Female, Original Article, Cyclin-Dependent Kinase Inhibitor p27, Signal Transduction
Abstract

The dual‐specificity tyrosine‐regulated kinases DYRK1A and DYRK1B play a key role in controlling the quiescence‐proliferation switch in cancer cells. Serum reduction of U87MG 2D cultures or multi‐cellular tumour spheroids induced a quiescent like state characterized by increased DYRK1B and p27, and decreased pRb and cyclin D1. VER‐239353 is a potent, selective inhibitor of the DYRK1A and DYRK1B kinases identified through fragment and structure‐guided drug discovery. Inhibition of DYRK1A/B by VER‐239353 in quiescent U87MG cells increased pRb, DYRK1B and cyclin D1 but also increased the cell cycle inhibitors p21 and p27. This resulted in exit from G0 but subsequent arrest in G1. DYRK1A/B inhibition reduced the proliferation of U87MG cells in 2D and 3D culture with greater effects observed under reduced serum conditions. Paradoxically, the induced re‐expression of cell cycle proteins by DYRK1A/B inhibition further inhibited cell proliferation. Cell growth arrest induced in quiescent cells by DYRK1A/B inhibition was reversible through the addition of growth‐promoting factors. DYRK inhibition‐induced DNA damage and synergized with a CHK1 inhibitor in the U87MG spheroids. In vivo, DYRK1A/B inhibition‐induced tumour stasis in a U87MG tumour xenograft model. These results suggest that further evaluation of VER‐239353 as a treatment for glioblastoma is therefore warranted.

Published
2021

23. The Agrodiversity Experiment: three years of data from a multisite study in intensively managed grasslands

Author

Kirwan, Laura, Connolly, John, Brophy, Caroline, Baadshaug, Ole, Belanger, Gilles, Black, Alistair, Carnus, Tim, Čollins, Rosemary, Cop, Jure, Delgado, Ignacio, De Vliegher, Alex, Elgersma, Anjo, Frankow-Lindberg, Bodil, Golinski, Piotr, Grieu, Philippe, Gustavsson, Anne-Maj, Helgadóttir, Áslaug, Höglind, Mats, Huguenin-Elie, Olivier, Jørgensen, Marit, Kadžiulienè, Žydrè, Lunnan, Tor, Lüscher, Andreas, Kurki, Päivi, Porqueddu, Claudio, Sebastia, M.-Teresa, Thumm, Ulrich, Walmsley, David, and Finn, John

Published
2014

24. Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B

Author

András Kotschy, Allan E. Surgenor, Andrea Fiumana, James Brooke Murray, Andrew Massey, Thomas Edmonds, Nicolas Foloppe, Didier Demarles, Pawel Dokurno, Mike Burbridge, Francisco Cruzalegui, K Benwell, Roderick E. Hubbard, Stuart C. Ray, Walmsley David, and Julia Smith

Subjects
Models, Molecular, DYRK1B, DYRK1A, Cellular differentiation, Mice, Nude, Antineoplastic Agents, Mice, SCID, Protein Serine-Threonine Kinases, 01 natural sciences, Metastasis, Serine, Mice, Structure-Activity Relationship, 03 medical and health sciences, In vivo, Cell Line, Tumor, Drug Discovery, medicine, Animals, Humans, Protein Kinase Inhibitors, Cell Proliferation, 030304 developmental biology, Mice, Inbred BALB C, 0303 health sciences, Dose-Response Relationship, Drug, Molecular Structure, Brain Neoplasms, Kinase, Chemistry, Neoplasms, Experimental, Protein-Tyrosine Kinases, medicine.disease, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Apoptosis, Cancer research, Molecular Medicine, Female, Drug Screening Assays, Antitumor
Abstract

The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down's syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.

Published
2021

25. A letter to readers about our Ukraine coverage

Author

Walmsley, David

Subjects
The Globe and Mail Inc. -- Services, Russian Invasion of Ukraine, 2022- -- Media coverage, Journalists -- Practice, Newspaper publishing -- Services, Military maneuvers -- Political aspects -- International relations -- Social aspects -- Media coverage, General interest, News, opinion and commentary
Abstract

Byline: David Walmsley; Staff There is something about journalism that makes those observers of the human spirit head toward danger and not away from it. In the weeks leading up [...]

Published
2022

30. Correction to:Provenance- and life-history stage-specific responses of the dwarf shrub Calluna vulgaris to elevated vapour pressure deficit (Plant Ecology, (2020), 221, 12, (1219-1232), 10.1007/s11258-020-01076-3)

Author

Ibe, Karin, Walmsley, David, Fichtner, Andreas, Coners, Heinz, Leuschner, Christoph, and Härdtle, Werner

Subjects
Ecosystems Research, Biology
Abstract

The article ‘‘Provenance- and life-history stage-specific responses of the dwarf shrub Calluna vulgaris to elevated vapour pressure deficit’’, written by ‘‘Karin Ibe, David Walmsley, Andreas Fichtner, Heinz Coners, Christoph Leuschner and Werner Ha¨rdtle’’, was originally published Online First without Open Access. After publication in volume 221, issue 12, page 1219–1232 the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to

Published
2022

37. Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2): The Exploratory Health-Related Quality of Life and Patient-Reported Functional Outcomes of a Multi-Centre 2 × 2 Factorial Randomized Controlled Pilot Trial in Young Femoral Neck Fracture Patients

Author

Slobogean, Gerard P., primary, Sprague, Sheila, additional, Bzovsky, Sofia, additional, Scott, Taryn, additional, Thabane, Lehana, additional, Heels-Ansdell, Diane, additional, O'Toole, Robert V., additional, Howe, Andrea, additional, Gaski, Greg E., additional, Hill, Lauren C., additional, Brown, Krista M., additional, Viskontas, Darius, additional, Zomar, Mauri, additional, Della Rocca, Gregory J., additional, O'Hara, Nathan N., additional, Bhandari, Mohit, additional, Malekzadeh, A. Stephen, additional, Nauth, Aaron, additional, Perdue, Aaron, additional, Mamun, Abdullah, additional, Wasim, Abeer, additional, Klein, Adam, additional, Brandon, Adrienne, additional, Theriault, Aimee, additional, Garibaldi, Alisha, additional, Liew, Allan, additional, Atrey, Amit, additional, Lialios-Ramfos, Anastasia, additional, Spiguel, André, additional, Howe, Andrea L., additional, Furey, Andrew, additional, Marcantonio, Andrew J., additional, Pollak, Andrew N., additional, Schmidt, Andrew, additional, Dowbenka, Ann, additional, Mak, Anne, additional, Sorkin, Anthony T., additional, Sivananthan, Araby, additional, Buck, Ashley, additional, Okocha, Benita, additional, Frye, Benjamin, additional, Perey, Bertrand, additional, Mohan, Bindu, additional, Eyberg, Blake, additional, Sumner, Bonnie, additional, Fan, Brenda Chen, additional, Lindsey, Brock, additional, Schoonover, Carrie, additional, Schwartzbach, Cary C., additional, Lieder, Charles, additional, Koenig, Chris, additional, Boulton, Christina, additional, LeBrun, Christopher, additional, Jones, Clifford B., additional, Barber, Collin, additional, Donahue, Craig, additional, Ventry, Cyndi, additional, Carter, Cynthia, additional, Williams, Dale, additional, Richardson, Damien, additional, Connelly, Daniel, additional, Mascarenhas, Daniel, additional, Squire, Daniel, additional, Whelan, Daniel, additional, Dias, Danyella, additional, Roffey, Darren M., additional, Hubbard, David, additional, Stephen, David J.G., additional, Shearer, David, additional, Teague, David, additional, Templeman, David, additional, Walmsley, David, additional, Malish, Dean, additional, Sietsema, Debra L., additional, Nam, Diane, additional, Marinos, Dimitrius, additional, Boyer, Dory, additional, McDonough, E. Barry, additional, Bogoch, Earl, additional, Westrick, Edward, additional, Pullenayegum, Eleanor M., additional, Berhaneselase, Eleni, additional, Agustin, Elizabeth, additional, Schemitsch, Emil H., additional, Meinberg, Eric, additional, Baker, Erin, additional, Moola, Farhad, additional, Adamsahib, Fathima, additional, Howells, Fiona, additional, Wells, Garrett, additional, Bal, George K., additional, Reahl, George, additional, Slobogean, Gerard P., additional, Ramonas, Gitana, additional, Guyatt, Gordon, additional, Rocca, Gregory J. Della, additional, Mueller, Gudrun Mirick, additional, Lemke, H. Michael, additional, Kreder, Hans J., additional, Grant, Heather, additional, Ahn, Henry, additional, Broekhuyse, Henry, additional, Leung, Irene, additional, Goulet, James, additional, Waddell, James, additional, Lowe, Jason, additional, Nascone, Jason W., additional, Schulman, Jeff E., additional, Potter, Jeffrey, additional, Hagen, Jennifer, additional, Hidy, Jennifer T., additional, Westberg, Jerald R., additional, Hall, Jeremy A., additional, Burns, Jessica, additional, Peattie, Jessica, additional, Goodwin, Jill, additional, Gagnier, Joel J., additional, France, John, additional, Iazzetta, John, additional, Lubicky, John P., additional, Garfi, John S., additional, Kwong, Johnathan, additional, Walker, Joseph, additional, Hustedt, Joshua, additional, Rudnicki, Joshua, additional, Foxall, Julia, additional, Robbins, Julie, additional, Sadasivan, Kalia, additional, Ryan, Karen, additional, Walsh, Karen, additional, Moon, Karyn, additional, Polihronidis, Katerina, additional, Ordonio, Katherine, additional, Hatzifilalithis, Katrina, additional, Milner, Katrine, additional, Au, Keegan, additional, Apostle, Kelly, additional, Lefaivre, Kelly, additional, Madden, Kim, additional, Swasey, Krystal, additional, Jeray, Kyle, additional, Deeter, Lakye, additional, Fine, Landon, additional, Parsons, Laura, additional, Kempton, Laurence B., additional, Buckingham, Lisa, additional, Sutton, Lisa Giblin, additional, Ramsey, Lolita, additional, Swiontkowski, Marc, additional, Sciadini, Marcus F., additional, Hake, Mark, additional, Richardson, Mark, additional, Nousiainen, Markku, additional, Bernaus, Martí, additional, Heetveld, Martin J., additional, Dietz, Matthew, additional, Menon, Matthew, additional, Patrick, Matthew, additional, MacNevin, Melanie, additional, Johnson, Melissa, additional, Fuerst, Merryjessica, additional, McKee, Michael D., additional, Duran, Michael, additional, Holzman, Michael, additional, Lucero, Michael, additional, Kain, Michael S.H., additional, Bramer, Michelle A., additional, Vogt, Michelle, additional, Vicente, Milena R., additional, Kunz, Monica, additional, Pekmezci, Murat, additional, Harris, Nicole, additional, Simunovic, Nicole, additional, Sultana, Nigar, additional, Dehghan, Niloofar, additional, Clovis, Nina, additional, Chutkan, Norman, additional, Suthar, Paril, additional, Henry, Patrick, additional, Knaus, Paul, additional, Muccino, Paul, additional, Toogood, Paul, additional, Berger, Peter, additional, O'Brien, Peter, additional, Rockwood, Peter, additional, Johnson, Pierce, additional, Guy, Pierre, additional, Blachut, Piotr, additional, Devereaux, PJ, additional, Pritchard (Moon), Raely, additional, Johal, Raman, additional, Tuazon, Ravianne, additional, Pensy, Raymond, additional, Zaidi, Raza, additional, Jenkinson, Richard J., additional, Hymes, Robert A., additional, McCormack, Robert, additional, O'Toole, RobertV., additional, Walker, Robert, additional, Natoli, Roman, additional, Meldrum, Russell, additional, Bicknell, Ryan, additional, DiGiovanni, Ryan, additional, Montalvo, Ryan, additional, Shelhamer, Ryan, additional, Morshed, Saam, additional, McFarland, Sara, additional, Anthony, Sarah, additional, Ward, Sarah, additional, Ahmed, Sarim, additional, Daffner, Scott, additional, Karr, Sean, additional, Mitchell, Sean, additional, Haaser, Sharon, additional, Rye, Sheila, additional, Davis, Sherri, additional, Weir, Sherry, additional, Brisbane, Sonya, additional, Papp, Steven, additional, Beltz, Susan, additional, Liew, Susan, additional, Mauro, Susan, additional, Murphy, T. Ryan, additional, Moore, Tara, additional, Dykes, Taylor, additional, Manson, Theodore, additional, DiPasquale, Thomas, additional, Belaye, Tigist, additional, Daniels, Timothy, additional, Carter, Tina, additional, Oliver, Todd M., additional, McKinley, Todd O., additional, Salopek, Traci, additional, Stone, Trevor, additional, Caron, Troy, additional, Tufescu, Tudor V., additional, Leviton, Tzivia, additional, Keough, Valisha, additional, Jones, Vicki, additional, Eglseder Jr., W. Andrew, additional, Gofton, Wade, additional, Virkus, Walter W., additional, Ghent, Wesley, additional, Degani, Yasmin, additional, Hannaford, Zeta, additional, and Murdoch, Zoe, additional

Published
2021
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39. Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors

Author

Attila Paczal, Thomas Edmonds, Nicolas Foloppe, Andrew Massey, András Kotschy, Mike Burbridge, Francisco Cruzalegui, Pawel Dokurno, Didier Demarles, Roderick E. Hubbard, Csaba Wéber, Sipos Melinda, Balázs Bálint, Vilibald Kun, K Benwell, James Murray, Walmsley David, and Alain Bruno

Subjects
DYRK1A, Cell Survival, Drug Evaluation, Preclinical, Mice, Nude, Protein Serine-Threonine Kinases, 01 natural sciences, 03 medical and health sciences, Mice, Structure-Activity Relationship, Adenosine Triphosphate, In vivo, Cell Line, Tumor, Drug Discovery, Animals, Humans, Protein Isoforms, Phosphorylation, Protein Kinase Inhibitors, 030304 developmental biology, Ovarian Neoplasms, 0303 health sciences, Binding Sites, Chemistry, Kinase, Drug discovery, Protein-Tyrosine Kinases, Cyclin-Dependent Kinase 9, 0104 chemical sciences, Molecular Docking Simulation, 010404 medicinal & biomolecular chemistry, Pyrimidines, Biochemistry, Cell culture, Drug Design, Molecular Medicine, Tumor growth inhibition, Female, Selectivity
Abstract

The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.

Published
2021

40. Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B

Author

Lee Walmsley, David, primary, Murray, James B., additional, Dokurno, Pawel, additional, Massey, Andrew J., additional, Benwell, Karen, additional, Fiumana, Andrea, additional, Foloppe, Nicolas, additional, Ray, Stuart, additional, Smith, Julia, additional, Surgenor, Allan E., additional, Edmonds, Thomas, additional, Demarles, Didier, additional, Burbridge, Mike, additional, Cruzalegui, Francisco, additional, Kotschy, Andras, additional, and Hubbard, Roderick E., additional

Published
2021
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41. Effect of surgeon fatigue on hip and knee arthroplasty

Author

Peskun, Christopher, Walmsley, David, Waddell, James, and Schemitsch, Emil

Subjects
Arthroplasty -- Health aspects, Fatigue -- Risk factors, Arthritis -- Care and treatment, Physicians -- Health aspects, Health, Health care industry
Abstract

Background: There is growing support in the literature that patient outcomes are adversely affected by physician fatigue in operator-dependent cognitive and technical tasks. Recent increases in total joint arthroplasty caseloads have resulted in longer operative days and increased surgeon fatigue. We sought to determine if time of day predicts perioperative complications and outcomes in total joint arthroplasty. Methods: The records of all total hip and knee arthroplasties (THA; TKA) performed for primary osteoarthritis in one calendar year at one large university hospital were retrospectively reviewed. Demographic data, surgery start time and duration, intraoperative complications, radiographic component alignment and functional outcome scores (SF-12 and Western Ontario and McMaster Universities Osteoarthritis Index) were collected and analyzed using linear and nonparametric rank correlation statistics. Data were corrected for sex, body mass index, surgeon and postcall operating days. Results: In the THA cohort (n = 341), a later surgery start time was significantly related to duration of surgery (p = 0.004, mean difference -7.1 min). There was a trend toward significance between a later surgery start time and intraoperative femur fracture (p = 0.05). Postoperative complications, component alignment and functional outcome scores were not significantly affected by surgery start time. There were no significant findings for any of the intraoperative or postoperative outcomes in the TKA cohort (n = 292). Conclusion: Duration of surgery and incidence of intraoperative complications for THA may increase with later surgery start time; however, the relatively small statistical differences observed imply that they likely are not clinically significant. Contexte: On reconnait de plus en plus dans les publications scientifiques que dans l'execution de taches cognitives et techniques tributaires de l'intervenant, la fatigue des medecins a un effet indesirable sur les resultats des patients. Des augmentations recentes du nombre de cas d'arthroplastie totale d'une articulation ont allonge les journees en salle d'operation et aggrave la fatigue des chirurgiens. Nous avons cherche a determiner si l'heure du jour est un predicteur de complications peroperatoires et des resultats d'une arthroplastie totale d'une articulation. Methodes: Nous avons effectue une analyse retrospective des dossiers de toutes les arthroplasties de la hanche et du genou (ATH; ATG) pratiquees a cause d'une arthrose primitive au cours d'une annee civile dans un grand hopital universitaire. Nous avons recueilli les donnees demographiques, l'heure du debut de l'intervention chirurgicale et sa duree, les complications intraoperatoires, l'alignement radiographique des pieces et les resultats fonctionnels (SF-12 et les donnees sur l'indice de l'arthrose des universites Western Ontario et McMaster) et nous les avons analysees en etablissant des statistiques de correlation lineaire et non parametrique. Nous avons corrige les donnees en fonction du sexe, de l'indice de masse corporelle, du chirurgien et du nombre de jours de chirugie apres l'appel. Resultats: Dans la cohorte des ATH (n = 341), on a etabli un lien important entre l'heure plus tardive du debut de l'intervention chirurgicale et sa duree (p = 0,004, difference moyenne -7,1 min). On a constate une tendance a l'importance du lien entre le debut de l'intervention chirurgicale a une heure plus tardive et une fracture intraoperatoire du femur (p = 0,05). L'heure du debut de la chirurgie n'a pas eu d'effet significatif sur les complications postoperatoires, l'alignement des pieces et le resultat fonctionnel. Il n'y a eu aucune constatation significative dans le cas d'aucun des resultats intraoperatoires ou postoperatoires dans la cohorte des ATG (n = 292). Conclusion: La duree de l'intervention chirurgicale et l'incidence de complications intraoperatoires dans les cas d'ATH peuvent augmenter en fonction de l'heure plus tardive du debut de l'intervention chirurgicale. Les differences statistiques relativement faibles observees indiquent toutefois qu'elles ne sont probablement pas cliniquement significatives., In an effort to reduce wait times associated with joint replacement surgery, the overall arthroplasty caseload in the province in Ontario has increased by more than 50% in the past [...]

Published
2012
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42. A covalent fragment-based strategy targeting a novel cysteine to inhibit activity of mutant EGFR kinaseElectronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3md00439b

Author

Kuki, Naoki, Walmsley, David L., Kanai, Kazuo, Takechi, Sho, Yoshida, Masao, Murakami, Ryo, Takano, Kohei, Tominaga, Yuichi, Takahashi, Mizuki, Ito, Shuichiro, Nakao, Naoki, Angove, Hayley, Baker, Lisa M., Carter, Edward, Dokurno, Pawel, Le Strat, Loic, Macias, Alba T., Molyneaux, Carrie-Anne, Murray, James B., Surgenor, Allan E., Hamada, Tomoaki, and Hubbard, Roderick E.

Abstract

Several generations of ATP-competitive anti-cancer drugs that inhibit the activity of the intracellular kinase domain of the epidermal growth factor receptor (EGFR) have been developed over the past twenty years. The first-generation of drugs such as gefitinib bind reversibly and were followed by a second-generation such as dacomitinib that harbor an acrylamide moiety that forms a covalent bond with C797 in the ATP binding pocket. Resistance emerges through mutation of the T790 gatekeeper residue to methionine, which introduces steric hindrance to drug binding and increases the Kmfor ATP. A third generation of drugs, such as osimertinib were developed which were effective against T790M EGFR in which an acrylamide moiety forms a covalent bond with C797, although resistance has emerged by mutation to S797. A fragment-based screen to identify new starting points for an EGFR inhibitor serendipitously identified a fragment that reacted with C775, a previously unexploited residue in the ATP binding pocket for a covalent inhibitor to target. A number of acrylamide containing fragments were identified that selectively reacted with C775. One of these acrylamides was optimized to a highly selective inhibitor with sub-1 μM activity, that is active against T790M, C797S mutant EGFR independent of ATP concentration, providing a potential new strategy for pan-EGFR mutant inhibition.

Published
2023
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43. Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors

Author

Weber, Csaba, primary, Sipos, Melinda, additional, Paczal, Attila, additional, Balint, Balazs, additional, Kun, Vilibald, additional, Foloppe, Nicolas, additional, Dokurno, Pawel, additional, Massey, Andrew J., additional, Walmsley, David Lee, additional, Hubbard, Roderick E., additional, Murray, James, additional, Benwell, Karen, additional, Edmonds, Thomas, additional, Demarles, Didier, additional, Bruno, Alain, additional, Burbridge, Mike, additional, Cruzalegui, Francisco, additional, and Kotschy, Andras, additional

Published
2021
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45. Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity

Author

Yuya Ogata, Harumi Kanazawa, Macias Alba, Norikazu Ohtake, Allan E. Surgenor, Iichiro Takata, Hajime Takashima, Walmsley David, Kiyoko Fujita, Hayley Angove, Kunihiko Iwamoto, Masashi Mima, Hiroyuki Sugiyama, Fumihito Ushiyama, Junya Yamagishi, Yousuke Yamada, Alan P. Robertson, Kosuke Hitaka, Koichiro Nakano, Hayato Watanabe, Atsushi Okada, Yohei Matsuda, Roderick E. Hubbard, Nozomi Tanaka-Yamamoto, Toru Yamaguchi-Sasaki, Risa Kurimoto-Tsuruta, Lisa Baker, Akihiro Tanaka, and R. Harris

Subjects
Stereochemistry, chemistry.chemical_element, Zinc, Microbial Sensitivity Tests, 01 natural sciences, Amidohydrolases, Lipid A, 03 medical and health sciences, chemistry.chemical_compound, Minimum inhibitory concentration, Structure-Activity Relationship, Biosynthesis, Bacterial Proteins, Piperidines, Drug Discovery, Escherichia coli, Moiety, Chelation, Anilides, Enzyme Inhibitors, 030304 developmental biology, Chelating Agents, chemistry.chemical_classification, 0303 health sciences, Molecular Structure, Imidazoles, 0104 chemical sciences, Anti-Bacterial Agents, 010404 medicinal & biomolecular chemistry, Enzyme, chemistry, Pseudomonas aeruginosa, Molecular Medicine, Antibacterial activity
Abstract

UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation. A series was evolved from a fragment where a glycine moiety complexes zinc, which achieved low nanomolar potency in an enzyme functional assay but poor antibacterial activity on cell cultures. A second series was based on a fragment that chelated zinc through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)-imidazole derivative exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 μg/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.

Published
2020

50. Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity

Author

Yamada, Yousuke, primary, Takashima, Hajime, additional, Walmsley, David Lee, additional, Ushiyama, Fumihito, additional, Matsuda, Yohei, additional, Kanazawa, Harumi, additional, Yamaguchi-Sasaki, Toru, additional, Tanaka-Yamamoto, Nozomi, additional, Yamagishi, Junya, additional, Kurimoto-Tsuruta, Risa, additional, Ogata, Yuya, additional, Ohtake, Norikazu, additional, Angove, Hayley, additional, Baker, Lisa, additional, Harris, Richard, additional, Macias, Alba, additional, Robertson, Alan, additional, Surgenor, Allan, additional, Watanabe, Hayato, additional, Nakano, Koichiro, additional, Mima, Masashi, additional, Iwamoto, Kunihiko, additional, Okada, Atsushi, additional, Takata, Iichiro, additional, Hitaka, Kosuke, additional, Tanaka, Akihiro, additional, Fujita, Kiyoko, additional, Sugiyama, Hiroyuki, additional, and Hubbard, Roderick E., additional

Published
2020
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