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55,336 results on '"Dennis, J."'

103. Longitudinal profiling in patients undergoing cardiac surgery reveals postoperative changes in DNA methylation.

Author

Fischer, Matthew A, Chapski, Douglas J, Soehalim, Elizabeth, Montoya, Dennis J, Grogan, Tristan, Pellegrini, Matteo, Cai, Hua, Shemin, Richard J, and Vondriska, Thomas M

Subjects
Humans, Postoperative Complications, Cardiac Surgical Procedures, Longitudinal Studies, DNA Methylation, Gene Expression Regulation, Atrial fibrillation, Cardiac surgery, DNA methylation, Precision medicine, Clinical Research, Cardiovascular, Heart Disease, Genetics, 2.1 Biological and endogenous factors, Aetiology, Clinical Sciences, Paediatrics and Reproductive Medicine
Abstract

BackgroundCardiac surgery and cardiopulmonary bypass induce a substantial immune and inflammatory response, the overactivation of which is associated with significant pulmonary, cardiovascular, and neurologic complications. Commensurate with the immune and inflammatory response are changes in the heart and vasculature itself, which together drive postoperative complications through mechanisms that are poorly understood. Longitudinal DNA methylation profiling has the potential to identify changes in gene regulatory mechanisms that are secondary to surgery and to identify molecular processes that predict and/or cause postoperative complications. In this study, we measure DNA methylation in preoperative and postoperative whole blood samples from 96 patients undergoing cardiac surgery on cardiopulmonary bypass.ResultsWhile the vast majority of DNA methylation is unchanged by surgery after accounting for changes in cell-type composition, we identify several loci with statistically significant postoperative changes in methylation. Additionally, two of these loci are associated with new-onset postoperative atrial fibrillation, a significant complication after cardiac surgery. Paired statistical analysis, use of FACS data to support sufficient control of cell-type heterogeneity, and measurement of IL6 levels in a subset of patients add rigor to this analysis, allowing us to distinguish cell-type variability from actual changes in methylation.ConclusionsThis study identifies significant changes in DNA methylation that occur immediately after cardiac surgery and demonstrates that these acute alterations in DNA methylation have the granularity to identify processes associated with major postoperative complications. This research also establishes methods for controlling for cell-type variability in a large human cohort that may be useful to deploy in other longitudinal studies of epigenetic marks in the setting of acute and chronic disease.

Published
2022

110. Contributors

Author

Aleman, Brayann O., primary, Azizzadeh, Babak, additional, Cabin, Jonathan, additional, Chen, Ruonan, additional, Cohen, Steven R., additional, Davila, Armando Augusto, additional, Derakhshan, Adeeb, additional, Devgan, Lara, additional, Francoisse, Caitlin, additional, Hurwitz, Dennis J., additional, Ibrahim, Omer, additional, Ishii, Lisa E., additional, Jacob, Carolyn I., additional, Lee, Linda N., additional, Leong, Tracy, additional, Liscano, Esteban, additional, Martinez-Diaz, Gabriel J., additional, Nahai, Farzad R., additional, Obagi, Suzan, additional, Paiewonsky, Briana, additional, Ross, E. Victor, additional, Saad, Ahmad N., additional, Sarhaddi, Deniz, additional, Shridharani, Sachin M., additional, Tisch, Grace M., additional, and Triana, Lina, additional

Published
2024
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111. Accumulation of alkyl-lysophosphatidylcholines in Niemann-Pick disease type C1

Author

Sonali Mishra, Pamela Kell, David Scherrer, Dennis J. Dietzen, Charles H. Vite, Elizabeth Berry-Kravis, Cristin Davidson, Stephanie M. Cologna, Forbes D. Porter, Daniel S. Ory, and Xuntian Jiang

Subjects
alkyl-lysophosphatidylcholine, Niemann-Pick disease type C, biomarker, mass spectrometry, structural identification, Biochemistry, QD415-436
Abstract

Lysosomal function is impaired in Niemann-Pick disease type C1 (NPC1), a rare and inherited neurodegenerative disorder, resulting in late endosomal/lysosomal accumulation of unesterified cholesterol. The precise pathogenic mechanism of NPC1 remains incompletely understood. In this study, we employed metabolomics to uncover secondary accumulated substances in NPC1. Our findings unveiled a substantial elevation in the levels of three alkyl-lysophosphatidylcholine [alkyl-LPC, also known as lyso-platelet activating factor (PAF)] species in NPC1 compared to controls across various tissues, including brain tissue from individuals with NPC1, liver, spleen, cerebrum, cerebellum, and brain stem from NPC1 mice, as well as in both brain and liver tissue from NPC1 cats. The three elevated alkyl-LPC species were as follows: LPC O-16:0, LPC O-18:1, and LPC O-18:0. However, the levels of PAF 16:0, PAF 18:1, and PAF 18:0 were not altered in NPC1. In the NPC1 feline model, the brain and liver alkyl-LPC levels were reduced following 2-hydroxypropyl-β-cyclodextrin (HPβCD) treatment, suggesting that alkyl-LPCs are secondary storage metabolites in NPC1 disease. Unexpectedly, cerebrospinal fluid (CSF) levels of LPC O-16:0 and LPC O-18:1 were decreased in individuals with NPC1 compared to age-appropriate comparison samples, and their levels were increased in 80% of participants 2 years after intrathecal HPβCD treatment. The fold increases in CSF LPC O-16:0 and LPC O-18:1 levels were more pronounced in responders compared to nonresponders. This study identified alkyl-LPC species as secondary storage metabolites in NPC1 and indicates that LPC O-16:0 and LPC O-18:1, in particular, could serve as potential biomarkers for tracking treatment response in NPC1 patients.

Published
2024
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112. Gravidity influences distinct transcriptional profiles of maternal and fetal placental macrophages at term

Author

Nida Ozarslan, Joshua F. Robinson, Sirirak Buarpung, M. Yvonne Kim, Megan R. Ansbro, Jason Akram, Dennis J. Montoya, Moses R. Kamya, Abel Kakuru, Grant Dorsey, Philip J. Rosenthal, Genhong Cheng, Margaret E. Feeney, Susan J. Fisher, and Stephanie L. Gaw

Subjects
placenta, myeloid cells, monocyte, Hofbauer cell, pregnancy, gravidity, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionMaternal intervillous monocytes (MIMs) and fetal Hofbauer cells (HBCs) are myeloid-derived immune cells at the maternal-fetal interface. Maternal reproductive history is associated with differential risk of pregnancy complications. The molecular phenotypes and roles of these distinct monocyte/macrophage populations and the influence of gravidity on these phenotypes has not been systematically investigated.MethodsHere, we used RNA sequencing to study the transcriptional profiles of MIMs and HBCs in normal term pregnancies.ResultsOur analyses revealed distinct transcriptomes of MIMs and HBCs. Genes involved in differentiation and cell organization pathways were more highly expressed in MIMs vs. HBCs. In contrast, HBCs had higher expression of genes involved in inflammatory responses and cell surface receptor signaling. Maternal gravidity influenced monocyte programming, as expression of pro-inflammatory molecules was significantly higher in MIMs from multigravidae compared to primigravidae. In HBCs, multigravidae displayed enrichment of gene pathways involved in cell-cell signaling and differentiation.DiscussionOur results demonstrated that MIMs and HBCs have highly divergent transcriptional signatures, reflecting their distinct origins, locations, functions, and roles in inflammatory responses. Furthermore, maternal gravidity influences the gene signatures of MIMs and HBCs, potentially modulating the interplay between tolerance and trained immunity. The phenomenon of reproductive immune memory may play a novel role in the differential susceptibility of primigravidae to pregnancy complications.

Published
2024
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113. The Ludii Game Description Language is Universal

Author

Soemers, Dennis J. N. J., Piette, Éric, Stephenson, Matthew, and Browne, Cameron

Subjects
Computer Science - Artificial Intelligence, Computer Science - Computer Science and Game Theory
Abstract

There are several different game description languages (GDLs), each intended to allow wide ranges of arbitrary games (i.e., general games) to be described in a single higher-level language than general-purpose programming languages. Games described in such formats can subsequently be presented as challenges for automated general game playing agents, which are expected to be capable of playing any arbitrary game described in such a language without prior knowledge about the games to be played. The language used by the Ludii general game system was previously shown to be capable of representing equivalent games for any arbitrary, finite, deterministic, fully observable extensive-form game. In this paper, we prove its universality by extending this to include finite non-deterministic and imperfect-information games., Comment: Accepted for publication in the Proceedings of the 2024 IEEE Conference on Games

Published
2022

114. Free groups as end homogeneity groups of $3$-manifolds

Author

Garity, Dennis J. and Repovš, Dušan D.

Subjects
Mathematics - Geometric Topology, Mathematics - General Topology, Primary 54E45, 57M30, 57N12, Secondary 57N10, 54F65
Abstract

For every finitely generated free group $F$, we construct an irreducible open $3$-manifold $M_F$ whose end set is homeomorphic to a Cantor set, and with the end homogeneity group of $M_F$ isomorphic to $F$. The end homogeneity group is the group of all self-homeomorphisms of the end set that extend to homeomorphisms of the entire $3$-manifold. This extends an earlier result that constructs, for each finitely generated abelian group $G$, an irreducible open $3$-manifold $M_G$ with end homogeneity group $G$. The method used in the proof of our main result also shows that if $G$ is a group with a Cayley graph in $\mathbb{R}^3$ such that the graph automorphisms have certain nice extension properties, then there is an irreducible open $3$-manifold $M_G$ with end homogeneity group $G$.

Published
2022
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115. Targeting CDK4 and 6 in Cancer Therapy: Emerging Preclinical Insights Related to Abemaciclib

Author

Wander, Seth A, O’Brien, Neil, Litchfield, Lacey M, O’Dea, Declan, Guimaraes, Claudia Morato, Slamon, Dennis J, and Goel, Shom

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Estrogen, Breast Cancer, Cancer, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Aminopyridines, Benzimidazoles, Breast Neoplasms, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Estrogens, Female, Humans, Mitogens, Protein Kinase Inhibitors, Tumor Suppressor Proteins, abemaciclib, antitumor, breast neoplasms, CDK4 and 6, preclinical, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 and 6) are approved for the treatment of subsets of patients with hormone receptor positive (HR+) breast cancer (BC). In metastatic disease, strategies involving endocrine therapy combined with CDK4 and 6 inhibitors (CDK4 and 6i) improve clinical outcomes in HR+ BCs. CDK4 and 6i prevent retinoblastoma tumor suppressor protein phosphorylation, thereby blocking the transcription of E2F target genes, which in turn inhibits both mitogen and estrogen-mediated cell proliferation. In this review, we summarize preclinical data pertaining to the use of CDK4 and 6i in BC, with a particular focus on several of the unique chemical, pharmacologic, and mechanistic properties of abemaciclib. As research efforts elucidate the novel mechanisms underlying abemaciclib activity, potential new applications are being identified. For example, preclinical studies have demonstrated abemaciclib can exert antitumor activity against multiple tumor types and can cross the blood-brain barrier. Abemaciclib has also demonstrated distinct activity as a monotherapeutic in the treatment of BC. Accordingly, we also discuss how a greater understanding of mechanisms related to CDK4 and 6 blockade highlight abemaciclib's unique in-class properties, and could pave new avenues for enhancing its therapeutic efficacy.

Published
2022

116. Genome-Wide Association Study of Pregnancy in Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study.

Author

Rotz, Seth J, Worley, Sarah, Hu, Bo, Bazeley, Peter, Baedke, Jessica L, Hudson, Melissa M, Kuo, Dennis J, Oeffinger, Kevin C, Robison, Leslie L, Sahoo, Debashis, Wang, Fan, Yasui, Yutaka, Armstrong, Gregory T, and Bhatia, Smita

Subjects
Contraception/Reproduction, Genetics, Human Genome, Pediatric, Pediatric Cancer, Prevention, Cancer, Infertility, 2.1 Biological and endogenous factors, Aetiology, Reproductive health and childbirth, Cancer Survivors, Child, Cohort Studies, Female, Genome-Wide Association Study, Humans, Neoplasms, Pregnancy, Quality of Life, Medical and Health Sciences, Epidemiology
Abstract

BackgroundGonadotoxic treatment-related infertility has a significant impact on quality of life in childhood cancer survivors. Genome-wide association analyses to delineate the risk of infertility in childhood cancer survivors have not been previously reported.MethodsLeveraging genotype data from a large survivor cohort, the Childhood Cancer Survivor Study (CCSS), we investigated the role of SNPs on future pregnancy or siring a pregnancy in survivors without pelvic, testicular, or brain radiation who had ever been married. We calculated sex-stratified hazard ratios, using Cox proportional hazards modeling, adjusting for birth cohort (before 1965 vs. 1965 or later) and doses of relevant chemotherapies; replication was attempted in the independent St. Jude Lifetime Cohort study (SJLIFE).ResultsIn the CCSS cohort, nine SNPs were found to be suggestive (P < 10-7) or statistically significantly (P < 5 × 10-8) associated with pregnancy, however, none of the SNPs were replicated in SJLIFE. Cohorts differed based on the overall pregnancy rate, frequency of sterilizing procedures, and birth cohort.ConclusionsWe were not able to replicate our findings of SNPs associated with pregnancy in childhood cancer survivors.ImpactFuture attempts at replication should be considered in cohorts treated in a comparable era. In addition, understanding the role of genetics in fertility in childhood cancer survivors may be better approached using more advanced sequencing techniques.

Published
2022

121. γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Author

Aguillon, David, Allegri, Ricardo F., Aschenbrenner, Andrew J., Baker, Bryce, Barthelemy, Nicolas, Bechara, Jacob A., Berman, Sarah B., Brooks, William S., Cash, David M., Chen, Allison, Chrem Mendez, Patricio, Courtney, Laura, Cruchaga, Carlos, Daniels, Alisha J., Fagan, Anne M., Flores, Shaney, Fox, Nick C., Franklin, Erin, Goate, Alison M., Graber-Sultan, Susanne, Graff-Radford, Neill R., Gremminger, Emily, Herries, Elizabeth, Hofmann, Anna, Holtzman, David M., Hornbeck, Russ, Huey, Edward D., Ibanez, Laura, Ikeuchi, Takeshi, Ikonomovic, Snezana, Jackson, Kelley, Jarman, Steve, Jerome, Gina, Johnson, Erik C.B, Kasuga, Kensaku, Keefe, Sarah, Koudelis, Deborah, Kuder-Buletta, Elke, Laske, Christoph, Leon, Yudy Milena, Levey, Allan I., Li, Yan, Llibre-Guerra, Jorge J., Lopera, Francisco, Lu, Ruijin, Marsh, Jacob, Martins, Ralph, Massoumzadeh, Parinaz, Masters, Colin, McCullough, Austin, McKay, Nicole, Minton, Matthew, Mori, Hiroshi, Morris, John C., Nadkarni, Neelesh K., Nicklaus, Joyce, Niimi, Yoshiki, Noble, James M., Obermueller, Ulrike, Picarello, Danielle M., Pulizos, Christine, Ramirez, Laura, Renton, Alan E., Ringman, John, Rizzo, Jacqueline, Roedenbeck, Yvonne, Roh, Jee Hoon, Rosa-Neto, Pedro, Ryan, Natalie S., Sabaredzovic, Edita, Salloway, Stephen, Sanchez-Valle, Raquel, Scott, Jalen, Seyfried, Nicholas T., Simmons, Ashlee, Smith, Jennifer, Smith, Hunter, Stauber, Jennifer, Stout, Sarah, Supnet-Bell, Charlene, Surace, Ezequiel, Vazquez, Silvia, Vöglein, Jonathan, Wang, Guoqiao, Wang, Qing, Xu, Xiong, Xu, Jinbin, Schultz, Stephanie A, Liu, Lei, Schultz, Aaron P, Fitzpatrick, Colleen D, Levin, Raina, Bellier, Jean-Pierre, Shirzadi, Zahra, Joseph-Mathurin, Nelly, Chen, Charles D, Benzinger, Tammie L S, Day, Gregory S, Farlow, Martin R, Gordon, Brian A, Hassenstab, Jason J, Jack, Clifford R, Jr, Jucker, Mathias, Karch, Celeste M, Lee, Jae-Hong, Levin, Johannes, Perrin, Richard J, Schofield, Peter R, Xiong, Chengjie, Johnson, Keith A, McDade, Eric, Bateman, Randall J, Sperling, Reisa A, Selkoe, Dennis J, and Chhatwal, Jasmeer P

Published
2024
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122. Cognitive and psychiatric symptom trajectories 2–3 years after hospital admission for COVID-19: a longitudinal, prospective cohort study in the UK

Author

Lone, Nazir, Baillie, Kenneth, Pairo-Castineira, Erola, Avramidis, Nikos, Wain, Louise, Guillen-Guio, Beatriz, Leavy, Olivia, Jones, S, Armstrong, Lisa, Hairsine, Brigid, Henson, Helen, Kurasz, Claire, Shaw, Alison, Shenton, Liz, Dobson, Hannah, Dell, Amanda, Fairbairn, Sara, Hawkings, Nancy, Haworth, Jill, Hoare, Michaela, Lewis, Victoria, Lucey, Alice, Mallison, Georgia, Nassa, Heeah, Pennington, Chris, Price, Andrea, Price, Claire, Storrie, Andrew, Willis, Gemma, Young, Susan, Poinasamy, Krisnah, Walker, Samantha, Jarrold, Ian, Rawlik, Konrad, Sanderson, Amy, Chong-James, K, David, C, James, W Y, Pfeffer, Paul, Zongo, O, Martineau, Adrian, Manisty, C, Armour, Cherie, Brown, Vanessa, Busby, John, Connolly, Bronwen, Craig, Thelma, Drain, Stephen, Heaney, Liam, King, Bernie, Magee, Nick, Major, E, McAulay, Danny, McGarvey, Lorcan, McGinness, Jade, Peto, Tunde, Stone, Roisin, Bolger, Annette, Davies, Ffyon, Haggar, Ahmed, Lewis, Joanne, Lloyd, Arwel, Manley, R, McIvor, Emma, Menzies, Daniel, Roberts, K, Saxon, W, Southern, David, Subbe, Christian, Whitehead, Victoria, Bularga, Anda, Mills, Nicholas, Dawson, Joy, El-Taweel, Hosni, Robinson, Leanne, Brear, Lucy, Regan, Karen, Saralaya, Dinesh, Storton, Kim, Amoils, Shannon, Bermperi, Areti, Cruz, Isabel, Dempsey, K, Elmer, Anne, Fuld, Jonathon, Jones, H, Jose, Sherly, Marciniak, Stefan, Parkes, M, Ribeiro, Carla, Taylor, Jessica, Toshner, Mark, Watson, L, Worsley, J, Broad, Lauren, Evans, Teriann, Haynes, Matthew, Jones, L, Knibbs, Lucy, McQueen, Alison, Oliver, Catherine, Paradowski, Kerry, Sabit, Ramsey, Williams, Jenny, Jones, Ian, Milligan, Lea, Harris, Edward, Sampson, Claire, Davies, Ellie, Evenden, Cerys, Hancock, Alyson, Hancock, Kia, Lynch, Ceri, Rees, Meryl, Roche, Lisa, Stroud, Natalie, Thomas-Woods, T, Heller, Simon, Chalder, Trudie, Shah, Kamini, Robertson, Elizabeth, Young, Bob, Babores, Marta, Holland, Maureen, Keenan, Natalie, Shashaa, Sharlene, Wassall, Helen, Austin, Liam, Beranova, Eva, Cosier, Tracey, Deery, Joanne, Hazelton, Tracy, Price, Carly, Ramos, Hazel, Solly, Reanne, Turney, Sharon, Weston, Heather, Coughlan, Eamon, Ralser, Markus, Pearce, Lorraine, Pugmire, S, Stoker, Wendy, Wilson, Ann, McCormick, W, Fraile, Eva, Ugoji, Jacinta, Aguilar Jimenez, Laura, Arbane, Gill, Betts, Sarah, Bisnauthsing, Karen, Dewar, A, Hart, Nicholas, Kaltsakas, G, Kerslake, Helen, Magtoto, Murphy, Marino, Philip, Martinez, L M, Ostermann, Marlies, Rossdale, Jennifer, Solano, Teresa, Alvarez Corral, Maria, Arias, Ava Maria, Bevan, Emily, Griffin, Denise, Martin, Jane, Owen, J, Payne, Sheila, Prabhu, A, Reed, Annabel, Storrar, Will, Williams, Nick, Wrey Brown, Caroline, Burdett, Tracy, Featherstone, James, Lawson, Cathy, Layton, Alison, Mills, Clare, Stephenson, Lorraine, Ellis, Yvette, Atkin, Paul, Brindle, K, Crooks, Michael, Drury, Katie, Easom, Nicholas, Flockton, Rachel, Holdsworth, L, Richards, A, Sykes, D L, Thackray-Nocera, Susannah, Wright, C, Coetzee, S, Davies, Kim, Hughes, Rachel Ann, Loosley, Ronda, McGuinness, Heather, Mohamed, Abdelrahman, O'Brien, Linda, Omar, Zohra, Perkins, Emma, Phipps, Janet, Ross, Gavin, Taylor, Abigail, Tench, Helen, Wolf-Roberts, Rebecca, Burden, L, Calvelo, Ellen, Card, Bethany, Carr, Caitlin, Chilvers, Edwin, Copeland, Donna, Cullinan, P, Daly, Patrick, Evison, Lynsey, Fayzan, Tamanah, Gordon, Hussain, Haq, Sulaimaan, Jenkins, Gisli, King, Clara, Kon, Onn Min, March, Katherine, Mariveles, Myril, McLeavey, Laura, Mohamed, Noura, Moriera, Silvia, Munawar, Unber, Nunag, Jose Lloyd, Nwanguma, Uchechi, Orriss-Dib, Lorna, Ross, Alexandra, Roy, Maura, Russell, Emily, Samuel, Katherine, Schronce, J, Simpson, Neil, Tarusan, Lawrence, Thomas, David, Wood, Chloe, Yasmin, Najira, Altmann, Danny, Howard, Luke, Johnston, Desmond, Lingford-Hughes, Anne, Man, William, Mitchell, Jane, Molyneaux, Philip, Nicolaou, Christos, O'Regan, D P, Price, L, Quint, Jenni, Smith, David, Thwaites, Ryan, Valabhji, Jonathon, Walsh, Simon, Efstathiou, Claudia, Liew, Felicity, Frankel, Anew, Lightstone, Liz, McAdoo, Steve, Wilkins, Martin, Willicombe, Michelle, Touyz, R, Guerdette, Anne-Marie, Hewitt, Melanie, Reddy, R, Warwick, Katie, White, Sonia, McMahon, Aisling, Adeyemi, Oluwaseun, Adrego, Rita, Assefa-Kebede, Hosanna, Breeze, Jonathon, Byrne, S, Dulawan, Pearl, Hoare, Amy, Jolley, Caroline, Knighton, Abigail, Patale, Sheetal, Peralta, Ida, Powell, Natassia, Ramos, Albert, Shevket, K, Speranza, Fabio, Te, Amelie, Malim, M, Bramham, Kate, Brown, M, Ismail, Khalida, Nicholson, Tim, Pariante, Carmen, Sharpe, Claire, Wessely, Simon, Whitney, J, Shah, Ajay, Chiribiri, A, O'Brien, C, Hayday, A, Ashworth, Andrew, Beirne, Paul, Clarke, Jude, Coupland, C, Dalton, Matthhew, Favager, Clair, Glossop, Jodie, Greenwood, John, Hall, Lucy, Hardy, Tim, Humphries, Amy, Murira, Jennifer, Peckham, Dan, Plein, S, Rangeley, Jade, Saalmink, Gwen, Tan, Ai Lyn, Wade, Elaine, Whittam, Beverley, Window, Nicola, Woods, Janet, Coakley, G, Turtle, Lance, Allerton, Lisa, Allt, Ann Marie, Beadsworth, M, Berridge, Anthony, Brown, Jo, Cooper, Shirley, Cross, Andy, Defres, Sylviane, Dobson, S L, Earley, Joanne, French, N, Greenhalf, William, Hainey, Kera, Hardwick, Hayley, Hawkes, Jenny, Highett, Victoria, Kaprowska, Sabina, Key, Angela, Lavelle-Langham, Lara, Lewis-Burke, N, Madzamba, Gladys, Malein, Flora, Marsh, Sophie, Mears, Chloe, Melling, Lucy, Noonan, Matthew, Poll, L, Pratt, James, Richardson, Emma, Rowe, Anna, Semple, Calum, Shaw, Victoria, Tripp, K A, Wajero, Lilian, Williams-Howard, S A, Wootton, Dan, Wyles, J, Diwanji, Shalin, Gurram, Sambasivarao, Papineni, Padmasayee, Quaid, Sheena, Tiongson, Gerlynn, Watson, Ekaterina, Briggs, Andrew, Marks, Michael, Hastie, Claire, Rogers, Natalie, Smith, Nikki, Stensel, David, Bishop, Lettie, McIvor, Katherine, Rivera-Ortega, Pilar, Al-Sheklly, Bashar, Avram, Cristina, Blaikely, John, Buch, M, Choudhury, N, Faluyi, David, Felton, T, Gorsuch, T, Hanley, Neil, Horsley, Alex, Hussell, Tracy, Kausar, Zunaira, Odell, Natasha, Osbourne, Rebecca, Piper Hanley, Karen, Radhakrishnan, K, Stockdale, Sue, Kabir, Thomas, Scott, Janet, Stewart, Iain, Openshaw, Peter, Burn, David, Ayoub, A, Brown, J, Burns, G, Davies, Gareth, De Soyza, Anthony, Echevarria, Carlos, Fisher, Helen, Francis, C, Greenhalgh, Alan, Hogarth, Philip, Hughes, Joan, Jiwa, Kasim, Jones, G, MacGowan, G, Price, D, Sayer, Avan, Simpson, John, Tedd, H, Thomas, S, West, Sophie, Witham, M, Wright, S, Young, A, McMahon, Michael, Neill, Paula, Anderson, David, Basu, Neil, Bayes, Hannah, Brown, Ammani, Dougherty, Andrew, Fallon, K, Gilmour, L, Grieve, D, Mangion, K, Morrow, A, Sykes, R, Berry, Colin, McInnes, I B, Scott, Kathryn, Barrett, Fiona, Donaldson, A, Sage, Beth, Bell, Murdina, Brown, Angela, Hamil, R, Leitch, Karen, Macliver, L, Patel, Manish, Quigley, Jackie, Smith, Andrew, Welsh, B, Choudhury, Gaunab, Clohisey, S, Deans, Andrew, Docherty, Annemarie, Furniss, J, Harrison, Ewen, Kelly, S, Sheikh, Aziz, Chalmers, James, Connell, David, Deas, C, Elliott, Anne, George, J, Mohammed, S, Rowland, J, Solstice, AR, Sutherland, Debbie, Tee, Caroline, Bunker, Jenny, Gill, Rhyan, Nathu, Rashmita, Holmes, Katie, Adamali, H, Arnold, David, Barratt, Shaney, Dipper, A, Dunn, Sarah, Maskell, Nick, Morley, Anna, Morrison, Leigh, Stadon, Louise, Waterson, Samuel, Welch, H, Jayaraman, Bhagy, Light, Tessa, Vogiatzis, Ioannis, Almeida, Paula, Bolton, Charlotte, Hosseini, Akram, Matthews, Laura, Needham, Robert, Shaw, Karen, Thomas, Andrew, Bonnington, J, Chrystal, Melanie, Dupont, Catherine, Greenhaff, Paul, Gupta, Ayushman, Jang, W, Linford, S, Nikolaidis, Athanasios, Prosper, Sabrina, Burns, A, Kanellakis, N, Ferreira, V, Nikolaidou, C, Xie, C, Ainsworth, Mark, Alamoudi, Asma, Bloss, Angela, Carter, Penny, Cassar, M, Chen, Jin, Conneh, Florence, Dong, T, Evans, Ranuromanana, Fraser, Emily, Geddes, John, Gleeson, F, Harrison, Paul, Havinden-Williams, May, Ho, Ling Pei, Jezzard, P, Koychev, Ivan, Kurupati, Prathiba, McShane, H, Megson, Clare, Neubauer, Stefan, Nicoll, Debby, Ogg, G, Pacpaco, Edmund, Pavlides, M, Peng, Yanchun, Petousi, Nayia, Pimm, John, Rahman, Najib, Raman, Betty, Rowland, M J, Saunders, Kathryn, Sharpe, Michael, Talbot, Nick, Tunnicliffe, E M, Korszun, Ania, Kerr, Steven, Barker, R E, Cristiano, Daniele, Dormand, N, George, P, Gummadi, Mahitha, Kon, S, Liyanage, Kamal, Nolan, C M, Patel, B, Patel, Suhani, Polgar, Oliver, Shah, P, Singh, Suver, Walsh, J A, Gibbons, Michael, Ahmad, Shanaz, Brill, Simon, Hurst, John, Jarvis, Hannah, Lim, Lai, Mandal, S, Matila, Darwin, Olaosebikan, Olaoluwa, Singh, Claire, Laing, C, Baxendale, Helen, Garner, Lucie, Johnson, C, Mackie, J, Michael, Alice, Newman, J, Pack, Jamie, Paques, K, Parfrey, H, Parmar, J, Reddy, A, Halling-Brown, Mark, Dark, P, Diar-Bakerly, Nawar, Evans, D, Hardy, E, Harvey, Alice, Holgate, D, Knight, Sean, Mairs, N, Majeed, N, McMorrow, L, Oxton, J, Pendlebury, Jessica, Summersgill, C, Ugwuoke, R, Whittaker, S, Matimba-Mupaya, Wadzanai, Strong-Sheldrake, Sophia, Chowienczyk, Phillip, Bagshaw, J, Begum, M, Birchall, K, Butcher, Robyn, Carborn, H, Chan, Flora, Chapman, Kerry, Cheng, Yutung, Chetham, Luke, Clark, Cameron, Coburn, Zach, Cole, Joby, Dixon, Myles, Fairman, Alexandra, Finnigan, J, Foot, H, Foote, David, Ford, Amber, Gregory, Rebecca, Harrington, Kate, Haslam, L, Hesselden, L, Hockridge, J, Holbourn, Ailsa, Holroyd-Hind, B, Holt, L, Howell, Alice, Hurditch, E, Ilyas, F, Jarman, Claire, Lawrie, Allan, Lee, Ju Hee, Lee, Elvina, Lenagh, Rebecca, Lye, Alison, Macharia, Irene, Marshall, M, Mbuyisa, Angeline, McNeill, J, Megson, Sharon, Meiring, J, Milner, L, Misra, S, Newell, Helen, Newman, Tom, Norman, C, Nwafor, Lorenza, Pattenadk, Dibya, Plowright, Megan, Porter, Julie, Ravencroft, Phillip, Roddis, C, Rodger, J, Rowland-Jones, Sarah, Saunders, Peter, Sidebottom, J, Smith, Jacqui, Smith, Laurie, Steele, N, Stephens, G, Stimpson, R, Thamu, B, Thompson, A. A. Roger, Tinker, N, Turner, Kim, Turton, Helena, Wade, Phillip, Walker, S, Watson, James, Wilson, Imogen, Zawia, Amira, Allsop, Lynne, Bennett, Kaytie, Buckley, Phil, Flynn, Margaret, Gill, Mandy, Goodwin, Camelia, Greatorex, M, Gregory, Heidi, Heeley, Cheryl, Holloway, Leah, Holmes, Megan, Hutchinson, John, Kirk, Jill, Lovegrove, Wayne, Sewell, Terri Ann, Shelton, Sarah, Sissons, D, Slack, Katie, Smith, Susan, Sowter, D, Turner, Sarah, Whitworth, V, Wynter, Inez, Tomlinson, Johanne, Warburton, Louise, Painter, Sharon, Palmer, Sue, Redwood, Dawn, Tilley, Jo, Vickers, Carinna, Wainwright, Tania, Breen, G, Hotopf, M, Aul, Raminder, Forton, D, Ali, Mariam, Dunleavy, A, Mencias, Mark, Msimanga, N, Samakomva, T, Siddique, Sulman, Tavoukjian, Vera, Teixeira, J, Ahmed, Rubina, Francis, Richard, Connor, Lynda, Cook, Amanda, Davies, Gwyneth, Rees, Tabitha, Thaivalappil, Favas, Thomas, Caradog, McNarry, M, Williams, N, Lewis, Keir, Coulding, Martina, Jones, Heather, Kilroy, Susan, McCormick, Jacqueline, McIntosh, Jerome, Turner, Victoria, Vere, Joanne, Butt, Al-Tahoor, Savill, Heather, Kon, Samantha, Landers, G, Lota, Harpreet, Portukhay, Sofiya, Nasseri, Mariam, Daniels, Alison, Hormis, Anil, Ingham, Julie, Zeidan, Lisa, Chablani, Manish, Osborne, Lynn, Aslani, Shahab, Banerjee, Amita, Batterham, R, Baxter, Gabrielle, Bell, Robert, David, Anthony, Denneny, Emma, Hughes, Alun, Lilaonitkul, W, Mehta, P, Pakzad, Ashkan, Rangelov, Bojidar, Williams, B, Willoughby, James, Xu, Moucheng, Ahwireng, Nyarko, Bang, Dongchun, Basire, Donna, Brown, Jeremy, Chambers, Rachel, Checkley, A, Evans, R, Heightman, M, Hillman, T, Jacob, Joseph, Jastrub, Roman, Lipman, M, Logan, S, Lomas, D, Merida Morillas, Marta, Plant, Hannah, Porter, Joanna, Roy, K, Wall, E, Treibel, T, Ahmad Haider, N, Atkin, Catherine, Baggott, Rhiannon, Bates, Michelle, Botkai, A, Casey, Anna, Cooper, B, Dasgin, Joanne, Dawson, Camilla, Draxlbauer, Katharine, Gautam, N, Hazeldine, J, Hiwot, T, Holden, Sophie, Isaacs, Karen, Jackson, T, Kamwa, Vicky, Lewis, D, Lord, Janet, Madathil, S, McGee, C, Mcgee, K, Neal, Aoife, Newton-Cox, Alex, Nyaboko, Joseph, Parekh, Dhruv, Peterkin, Z, Qureshi, H, Ratcliffe, Liz, Sapey, Elizabeth, Short, J, Soulsby, Tracy, Stockley, J, Suleiman, Zehra, Thompson, Tamika, Ventura, Maximina, Walder, Sinead, Welch, Carly, Wilson, Daisy, Yasmin, S, Yip, Kay Por, Chaudhuri, N, Childs, Caroline, Djukanovic, R, Fletcher, S, Harvey, Matt, Jones, Mark, Marouzet, Elizabeth, Marshall, B, Samuel, Reena, Sass, T, Wallis, Tim, Wheeler, Helen, Steeds, R, Beckett, Paul, Dickens, Caroline, Nanda, Uttam, Aljaroof, M, Armstrong, Natalie, Arnold, H, Aung, Hnin, Bakali, Majda, Bakau, M, Baldry, E, Baldwin, Molly, Bourne, Charlotte, Bourne, Michelle, Brightling, Chris, Brunskill, Nigel, Cairns, P, Carr, Liesel, Charalambou, Amanda, Christie, C, Davies, Melanie, Daynes, Enya, Diver, Sarah, Dowling, Rachael, Edwards, Sarah, Edwardson, C, Elneima, Omer, Evans, H, Evans, Rachael, Finch, J, Glover, Sarah, Goodman, Nicola, Gooptu, Bibek, Greening, Neil, Hadley, Kate, Haldar, Pranab, Hargadon, Beverley, Harris, Victoria, Houchen-Wolloff, Linzy, Ibrahim, W, Ingram, L, Khunti, Kamlesh, Lea, A, Lee, D, McAuley, Hamish, McCann, Gerry, McCourt, P, Mcnally, Teresa, Mills, George, Monteiro, Will, Pareek, Manish, Parker, S, Prickett, Anne, Qureshi, I N, Rowland, A, Russell, Richard, Sereno, Marco, Shikotra, Aarti, Siddiqui, Salman, Singapuri, Ananga, Singh, Sally, Skeemer, J, Soares, M, Stringer, E, Thornton, T, Tobin, Martin, Ward, T J C, Woodhead, F, Yates, Tom, Yousuf, A J, Broome, Mattew, McArdle, Paul, Thickett, David, Upthegrove, Rachel, Wilkinson, Dan, Moss, Paul, Wraith, David, Evans, Jonathon, Bullmore, Ed, Heeney, Jonathon, Langenberg, Claudia, Schwaeble, William, Summers, Charlotte, Weir McCall, J, Adeloye, Davies, Newby, D E, Pius, Riinu, Rudan, Igor, Shankar-Hari, Manu, Sudlow, Catherine, Thorpe, Mat, Walmsley, Sarah, Zheng, Bang, Allan, Louise, Ballard, Clive, McGovern, Andrew, Dennis, J, Cavanagh, Jonathon, MacDonald, S, O'Donnell, Kate, Petrie, John, Sattar, Naveed, Spears, Mark, Guthrie, Elspeth, Henderson, Max, Allen, Richard, Bingham, Michelle, Brugha, Terry, Finney, Selina, Free, Rob, Jones, Don, Lawson, Claire, Lucy, Gardiner, Moss, Alistair, Mukaetova-Ladinska, Elizabeta, Novotny, Petr, Overton, Charlotte, Pearl, John, Plekhanova, Tatiana, Richardson, M, Samani, Nilesh, Sargant, Jack, Sharma, M, Steiner, Mike, Taylor, Chris, Terry, Sarah, Tong, C, Turner, E, Wormleighton, J, Zhao, Bang, Ntotsis, Kimon, Saunders, Ruth, Lozano-Rojas, Daniel, Goemans, Anne, Cuthbertson, D, Kemp, G, McArdle, Anne, Michael, Benedict, Reynolds, Will, Spencer, Lisa, Vinson, Ben, Ashworth, M, Abel, Kathryn, Chinoy, H, Deakin, Bill, Harvie, M, Miller, C A, Stanel, Stefan, Barran, Perdita, Trivedi, Drupad, McAllister-Williams, Hamish, Paddick, Stella-Maria, Rostron, Anthony, Taylor, John Paul, Baguley, David, Coleman, Chris, Cox, E, Fabbri, Laura, Francis, Susan, Hall, Ian, Hufton, E, Johnson, Simon, Khan, Fasih, Kitterick, Paaig, Morriss, Richard, Selby, Nick, Wright, Louise, Antoniades, Charalambos, Bates, A, Beggs, M, Bhui, Kamaldeep, Breeze, Katie, Channon, K M, Clark, David, Fu, X, Husain, Masud, Li, X, Lukaschuk, E, McCracken, Celeste, McGlynn, K, Menke, R, Motohashi, K, Nichols, T E, Ogbole, Godwin, Piechnik, S, Propescu, I, Propescu, J, Samat, A A, Sanders, Z B, Sigfrid, Louise, Webster, M, Kingham, Lucy, Klenerman, Paul, Lamlum, Hanan, Taquet, Maxime, Carson, G, Finnigan, L, Saunders, Laura, Wild, James, Calder, P C, Huneke, Nathan, Simons, Gemma, Baldwin, David, Bain, Steve, Daines, Luke, Bright, E, Crisp, P, Dharmagunawardena, Ruvini, Stern, M, Bailey, Elisabeth, Reddington, Anne, Wight, Andrew, Ashish, A, Cooper, Josh, Robinson, Emma, Broadley, Andrew, Barman, Laura, Brookes, Claire, Elliott, K, Griffiths, L, Guy, Zoe, Howard, Kate, Ionita, Diana, Redfearn, Heidi, Sarginson, Carol, Turnbull, Alison, Skorniewska, Zuzanna, De Deyn, Thomas, Hampshire, Adam, Trender, William R, Hellyer, Peter J, Chalmers, James D, Ho, Ling-Pei, Leavy, Olivia C, Richardson, Matthew, McAuley, Hamish J C, Singapuri, Amisha, Saunders, Ruth M, Harris, Victoria C, Greening, Neil J, Mansoori, Parisa, Harrison, Ewen M, Docherty, Annemarie B, Lone, Nazir I, Quint, Jennifer, Brightling, Christopher E, Wain, Louise V, Evans, Rachael A, Geddes, John R, and Harrison, Paul J

Published
2024
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124. Generation of G51D and 3D mice reveals decreased α-synuclein tetramer-monomer ratios promote Parkinson’s disease phenotypes

Author

Silke Nuber, Xiaoqun Zhang, Thomas D. McCaffery, Tim E. Moors, Marie-Alexandre Adom, Wolf N. Hahn, Dylan Martin, Maria Ericsson, Arati Tripathi, Ulf Dettmer, Per Svenningsson, and Dennis J. Selkoe

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Mutations in the α-Synuclein (αS) gene promote αS monomer aggregation that causes neurodegeneration in familial Parkinson’s disease (fPD). However, most mouse models expressing single-mutant αS transgenes develop neuronal aggregates very slowly, and few have dopaminergic cell loss, both key characteristics of PD. To accelerate neurotoxic aggregation, we previously generated fPD αS E46K mutant mice with rationally designed triple mutations based on the α-helical repeat motif structure of αS (fPD E46K→3 K). The 3 K variant increased αS membrane association and decreased the physiological tetramer:monomer ratio, causing lipid- and vesicle-rich inclusions and robust tremor-predominant, L-DOPA responsive PD-like phenotypes. Here, we applied an analogous approach to the G51D fPD mutation and its rational amplification (G51D → 3D) to generate mutant mice. In contrast to 3 K mice, G51D and 3D mice accumulate monomers almost exclusively in the cytosol while also showing decreased αS tetramer:monomer ratios. Both 1D and 3D mutant mice gradually accumulate insoluble, higher-molecular weight αS oligomers. Round αS neuronal deposits at 12 mos immunolabel for ubiquitin and pSer129 αS, with limited proteinase K resistance. Both 1D and 3D mice undergo loss of striatal TH+ fibers and midbrain dopaminergic neurons by 12 mos and a bradykinesia responsive to L-DOPA. The 3D αS mice have decreased tetramer:monomer equilibria and recapitulate major features of PD. These fPD G51D and 3D mutant mice should be useful models to study neuronal αS-toxicity associated with bradykinetic motor phenotypes.

Published
2024
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125. Spatial State-Action Features for General Games

Author

Soemers, Dennis J. N. J., Piette, Éric, Stephenson, Matthew, and Browne, Cameron

Subjects
Computer Science - Artificial Intelligence
Abstract

In many board games and other abstract games, patterns have been used as features that can guide automated game-playing agents. Such patterns or features often represent particular configurations of pieces, empty positions, etc., which may be relevant for a game's strategies. Their use has been particularly prevalent in the game of Go, but also many other games used as benchmarks for AI research. In this paper, we formulate a design and efficient implementation of spatial state-action features for general games. These are patterns that can be trained to incentivise or disincentivise actions based on whether or not they match variables of the state in a local area around action variables. We provide extensive details on several design and implementation choices, with a primary focus on achieving a high degree of generality to support a wide variety of different games using different board geometries or other graphs. Secondly, we propose an efficient approach for evaluating active features for any given set of features. In this approach, we take inspiration from heuristics used in problems such as SAT to optimise the order in which parts of patterns are matched and prune unnecessary evaluations. This approach is defined for a highly general and abstract description of the problem -- phrased as optimising the order in which propositions of formulas in disjunctive normal form are evaluated -- and may therefore also be of interest to other types of problems than board games. An empirical evaluation on 33 distinct games in the Ludii general game system demonstrates the efficiency of this approach in comparison to a naive baseline, as well as a baseline based on prefix trees, and demonstrates that the additional efficiency significantly improves the playing strength of agents using the features to guide search., Comment: Accepted for publication in the journal of Artificial Intelligence (AIJ)

Published
2022

127. Shuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo

Author

Katarina Kulhankova, Soumba Traore, Xue Cheng, Hadrien Benk-Fortin, Stéphanie Hallée, Mario Harvey, Joannie Roberge, Frédéric Couture, Sajeev Kohli, Thomas J. Gross, David K. Meyerholz, Garrett R. Rettig, Bernice Thommandru, Gavin Kurgan, Christine Wohlford-Lenane, Dennis J. Hartigan-O’Connor, Bradley P. Yates, Gregory A. Newby, David R. Liu, Alice F. Tarantal, David Guay, and Paul B. McCray

Subjects
Science
Abstract

Abstract Gene editing strategies for cystic fibrosis are challenged by the complex barrier properties of airway epithelia. We previously reported that the amphiphilic S10 shuttle peptide non-covalently combined with CRISPR-associated (Cas) ribonucleoprotein (RNP) enabled editing of human and mouse airway epithelial cells. Here, we derive the S315 peptide as an improvement over S10 in delivering base editor RNP. Following intratracheal aerosol delivery of Cy5-labeled peptide in rhesus macaques, we confirm delivery throughout the respiratory tract. Subsequently, we target CCR5 with co-administration of ABE8e-Cas9 RNP and S315. We achieve editing efficiencies of up-to 5.3% in rhesus airway epithelia. Moreover, we document persistence of edited epithelia for up to 12 months in mice. Finally, delivery of ABE8e-Cas9 targeting the CFTR R553X mutation restores anion channel function in cultured human airway epithelia. These results demonstrate the therapeutic potential of base editor delivery with S315 to functionally correct the CFTR R553X mutation in respiratory epithelia.

Published
2023
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133. Overall Survival With Palbociclib And Fulvestrant in Women With HR+/HER2- ABC: Updated Exploratory Analyses of PALOMA-3, a Double-Blind, Phase 3 Randomized Study

Author

Cristofanilli, Massimo, Rugo, Hope S, Im, Seock-Ah, Slamon, Dennis J, Harbeck, Nadia, Bondarenko, Igor, Masuda, Norikazu, Colleoni, Marco, DeMichele, Angela, Loi, Sherene, Iwata, Hiroji, O'Leary, Ben, André, Fabrice, Loibl, Sibylle, Bananis, Eustratios, Liu, Yuan, Huang, Xin, Kim, Sindy, Frean, Maria Jose Lechuga, and Turner, Nicholas C

Subjects
Clinical Research, Clinical Trials and Supportive Activities, Breast Cancer, Cancer, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Double-Blind Method, Female, Fulvestrant, Humans, Piperazines, Pyridines, Receptor, ErbB-2, Receptor, erbB-2, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeTo conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis by circulating tumor DNA (ctDNA).Patients and methodsPatients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/day; 3/1 week schedule) and fulvestrant (500 mg intramuscularly) or placebo and fulvestrant. This OS analysis was performed when 75% of enrolled patients died (393 events in 521 randomized patients). ctDNA analysis was performed among patients who provided consent.ResultsAt the data cutoff (August 17, 2020), 258 and 135 deaths occurred in the palbociclib and placebo groups, respectively. The median OS [95% confidence interval (CI)] was 34.8 months (28.8-39.9) in the palbociclib group and 28.0 months (23.5-33.8) in the placebo group (stratified hazard ratio, 0.81; 95% CI, 0.65-0.99). The 6-year OS rate (95% CI) was 19.1% (14.9-23.7) and 12.9% (8.0-19.1) in the palbociclib and placebo groups, respectively. Favorable OS with palbociclib plus fulvestrant compared with placebo plus fulvestrant was observed in most subgroups, particularly in patients with endocrine-sensitive disease, no prior chemotherapy for ABC and low circulating tumor fraction and regardless of ESR1, PIK3CA, or TP53 mutation status. No new safety signals were identified.ConclusionsThe clinically meaningful improvement in OS associated with palbociclib plus fulvestrant was maintained with >6 years of follow-up in patients with HR+/HER2- ABC, supporting palbociclib plus fulvestrant as a standard of care in these patients.

Published
2022

134. Pharmacokinetics of isavuconazole in healthy cats after oral and intravenous administration

Author

Woerde, Dennis J, Wittenburg, Luke A, and Dear, Jonathan D

Subjects
Veterinary Sciences, Agricultural, Veterinary and Food Sciences, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Administration, Intravenous, Administration, Oral, Animals, Area Under Curve, Biological Availability, Cats, Half-Life, Humans, Nitriles, Pyridines, Triazoles, antifungal, azole, bioavailability, blastomyces, cryptococcus, fungal, Veterinary sciences
Abstract

BackgroundIsavuconazole is a triazole antifungal drug that has shown good efficacy in human patients. Absorption and pharmacokinetics have not been evaluated in cats.ObjectivesTo determine the pharmacokinetics of isavuconazole in cats given a single IV or PO dose.AnimalsEight healthy, adult research cats.MethodsFour cats received 100 mg capsules of isavuconazole PO. Four cats received 5 mg/kg isavuconazole solution IV. Serum was collected at predetermined intervals for analysis using ultra-high performance liquid chromatography-tandem mass spectrometry. Data were analyzed using a 2-compartment uniform weighting pharmacokinetic analysis with lag time for PO administration and a 2 compartment, 1/y2 weighting for IV administration. Predicted 24 and 48-hour dosing intervals of 100 mg isavuconazole administered PO were modeled and in vitro plasma protein binding was assessed.ResultsBoth PO and IV drug administration resulted in high serum concentrations. Intravenous and PO formulations of isavuconazole appear to be able to be used interchangeably. Peak serum isavuconazole concentrations occurred 5 ± 3.8 hours after PO administration with an elimination rate half-life of 66.2 ± 55.3 hours. Intersubject variability was apparent in both the PO and IV groups. Two cats vomited 6 to 8 hours after PO administration. No adverse effects were observed in the IV group. Oral bioavailability was estimated to be approximately 88%. Serum protein binding was calculated to be approximately 99.0% ± 0.03%.Conclusions and clinical importanceIsavuconazole might prove to be useful in cats with fungal disease given its favorable pharmacokinetics. Additional studies on safety, efficacy, and tolerability of long-term isavuconazole use are needed.

Published
2022

135. Adapt It! Adapting Stories and Technology for Engagement in Geometry

Author

Karen L. Terrell, Dennis J. DeBay, and Valerie J. Spencer

Abstract

To fulfill the Standards for Mathematical Practice (National Governors Association Center for Best Practices & Council of Chief State School Officers [NGA Center & CCSSO], 2010), it is important for teachers to empower students to critique, revise, and expand their ideas as they solve problems. However, students often face challenges such as anxiety, frustration, and language proficiency issues when dealing with written contexts and mathematical concepts. To address these obstacles and to create an inclusive learning environment for all students--including those with disabilities and multilingual learners--it is crucial to explore strategies that engage students in revision cycles and foster perseverance. By incorporating technologies such as Desmos, students can use multiple means of representation, expression, and communication, enhancing their mathematical identity and taking ownership of their learning. This article delves into a story task that showcases how students can embrace these opportunities for critique, revision, and idea expansion while using Desmos as a powerful tool. The authors' focus on adaptations made with Desmos, including dividing the story, providing workspace, and offering a paper-and-pencil option through a scaffolding worksheet.

Published
2023
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136. Pre-Incentive Efficacy in Survey Response Rates in a Large Prospective Military Cohort

Author

Powell, Teresa M., Geronimo-Hara, Toni Rose, Tobin, Laura E., Donoho, Carrie J., Sheppard, Beverly D., Walstrom, Jennifer L., Rull, Rudolph P., and Faix, Dennis J.

Abstract

Declining survey response rates concern researchers aiming to ensure study validity. This article tested the effectiveness of multiple pre-incentives on increasing survey response to the Millennium Cohort Study. Participants consisted of U.S. military service members and veterans, and were randomly assigned to receive a $2 bill, $5 gift card, magnet, Apple iPad® lottery entry, or no pre-incentive. Participants who received the gift card or cash pre-incentive had the highest response rates and were significantly more likely to respond to the survey than those who did not receive a pre-incentive. There was no significant difference in survey response among the magnet or lottery entry groups compared to the no pre-incentive group. This study found that giving participants a monetary pre-incentive was an effective way to increase response rates, and thereby participant retention, in a hard-to-reach, highly mobile population, and re-engage participants who did not respond to a previous follow-up survey.

Published
2023
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138. General Board Geometry

Author

Browne, Cameron, Piette, Éric, Stephenson, Matthew, and Soemers, Dennis J. N. J.

Subjects
Computer Science - Artificial Intelligence
Abstract

Game boards are described in the Ludii general game system by their underlying graphs, based on tiling, shape and graph operators, with the automatic detection of important properties such as topological relationships between graph elements, directions and radial step sequences. This approach allows most conceivable game boards to be described simply and succinctly., Comment: Accepted at Advances in Computer Games (ACG) 2021

Published
2021

139. Optimised Playout Implementations for the Ludii General Game System

Author

Soemers, Dennis J. N. J., Piette, Éric, Stephenson, Matthew, and Browne, Cameron

Subjects
Computer Science - Artificial Intelligence
Abstract

This paper describes three different optimised implementations of playouts, as commonly used by game-playing algorithms such as Monte-Carlo Tree Search. Each of the optimised implementations is applicable only to specific sets of games, based on their rules. The Ludii general game system can automatically infer, based on a game's description in its general game description language, whether any optimised implementations are applicable. An empirical evaluation demonstrates major speedups over a standard implementation, with a median result of running playouts 5.08 times as fast, over 145 different games in Ludii for which one of the optimised implementations is applicable., Comment: Advances in Computer Games (ACG) 2021

Published
2021

140. Automatic Generation of Board Game Manuals

Author

Stephenson, Matthew, Piette, Eric, Soemers, Dennis J. N. J., and Browne, Cameron

Subjects
Computer Science - Artificial Intelligence
Abstract

In this paper we present a process for automatically generating manuals for board games within the Ludii general game system. This process requires many different sub-tasks to be addressed, such as English translation of Ludii game descriptions, move visualisation, highlighting winning moves, strategy explanation, among others. These aspects are then combined to create a full manual for any given game. This manual is intended to provide a more intuitive explanation of a game's rules and mechanics, particularly for players who are less familiar with the Ludii game description language and grammar., Comment: 12 Pages, 6 Figures

Published
2021

142. Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial

Author

Phan, Timmy, Selmes, Christine, Lees, Kennedy, Kaste, Markku, MacIsaac, Rachael, Wellings, Tom, Loiselle, Andre, Pepper, Elizabeth, Miteff, Ferdi, Krishnamurthy, Venkatesh, Ang, Timothy, Alanati, Khaled, Gangadharan, Shyam, Zareie, Hossein, Starling, Rita, Dunkerton, Sophie, He, Jiacheng, Datta, Raka, Royan, Angela, Kerr, Erin, Kaauwai, Lara, Belevski, Linda, Ormond, Sally, Johnson, Annalese, Evans, Malcolm, Lachapelle, Nicole, Ombelet, Fouke, Bladin, Chris, Dewey, Helen, Wong, Joseph, Park, Peter, Cody, Ross, Tan, Peter, Callaly, Edward, Senanayake, Channa, Thomas, Grace, Liu, Jennifer, Busch, Tessa, Stuart, Narelle, Chung, Malcohm, Yassi, Nawaf, Valente, Michael, Sharobeam, Angelos, Cooley, Regan, Zhao, Henry, Alemseged, Fana, Williams, Cameron, Ng, Jo Lyn, Balabanski, Anna, dos Santos, Angela, Williamson, John, Pavlin-Premrl, Davor, Beharry, James, Ma, Margaret, Park, Ashley, Yan, Bernard, Hand, Peter, Jackson, David, McDonald, Amy, Fisicchia, Laura, Parsons, Nicola, Olenko, Liudmyla, Johns, Hannah, Guha, Prodipta, Rokaha, Birendra, Dhimal, Niruta, Harvey, Jackson, Cagi, Lavenia, Chia, Nicholas, Goh, Rudy, Palanikumar, Log, El-Masri, Shaddy, Mahadevan, Joshua, Kuranawai, Craig, Waters, Michael, Vallat, Wilson, Cheong, Eddie, Drew, Roy, Cordato, Dennis, McDougall, Alan, Cappelen-Smith, Cecilia, Venkat, Abhay, Edwards, Leon, Blair, Christopher, Thomas, James, Helou, Jacob, Green, Daniel, Nguyen, Tram, Pham, Timmy, Khan, Jasmeen, Miller, Megan, Loubiere, Laurence, Buck, Brian, Butcher, Ken, Fairall, Paige, Butt, Asif, Kalashyan, Hayrapet, Nomani, Ali, Lloret, Mar, Mishra, Sachin, Thirunavukkarasu, Sibi, Sivakumar, Leka, D'Souza, Atlantic, Tsai, Chon-Haw, Tseng, Billy, Tai, Iris, Chiang, I-Husan, Kuan, Angela, Tsai, Vivian, Hsu, Alice, Hsu, Sammi, Alchin, Deborah, Sanjuan, Estela, Fink, John, Wilson, Duncan, Mason, Deborah, Berry-Norohna, Alexander, Winders, Joel, Eagle, Jane, Green, Rosemary, Bremner, Kathleen, Celestino, Sherisse, Lee, Jiunn-Tay, Chou, Chung-Hsing, Tsai, Chia-Kuang, Sung, Yueh-Feng, Tsai, Chia-Lin, Lin, Yu-Kai, Kao, Hung-Wen, Vuong, Jason, Thirugnanachandran, Tharani, Hervet, Marie Veronic, Simmons, Karen, Sabet, Arman, Bailey, Peter, Urbi, Berzenn, Kurakose, Sumole, Martinez-Majander, Nicolas, Räty, Silja, Tiainen, Marjaana, Sibolt, Gerli, Ivanoff, Terhi, Sanz, Ana Calleja, García, Elisa Cortijo, De Lera Alfonso, Mercedes C., Araque, Maria Ester Ramos, Gómez, Alicia Sierra, Peñacoba, Gonzalo Valle, Vicente, Beatriz Gómez, Muñoz, Javier Reyes, Muñoz Rubio, Pedro Luis, Shah, Darshan, Harrison, Emma, Bendall, Carol, Subramanian, Ganesh, Jeng, Jiann-Shing, Tang, Sung-Chun, Tsai, Li-Kai, Yeh, Shin-Joe, Chen, Chih-Hao, Chung, Tai-Chun, Wong, Andrew, Muller, Claire, Skinner, Genevieve, Gunathilagan, Gunaratnam, Natarajan, Indira, Coutts, Shelagh, Menon, Bijoy, Kenney, Carol, Clarke, Brian, Ghatala, Rita, Mudd, Paul, Chen, Chih-Hung, Lemmens, Robin, Demeestere, Jelle, Mahant, Neil, Sun, Mu-Chien, Parsons, Mark W, Yogendrakumar, Vignan, Churilov, Leonid, Garcia-Esperon, Carlos, Campbell, Bruce C V, Russell, Michelle L, Sharma, Gagan, Chen, Chushuang, Lin, Longting, Chew, Beng Lim, Ng, Felix C, Deepak, Akshay, Choi, Philip M C, Kleinig, Timothy J, Cordato, Dennis J, Wu, Teddy Y, Fink, John N, Ma, Henry, Phan, Thanh G, Markus, Hugh S, Molina, Carlos A, Strbian, Daniel, Meretoja, Atte, Arenillas, Juan F, Buck, Brian H, Devlin, Michael J, Brown, Helen, Butcher, Ken S, O'Brien, Billy, Wijeratne, Tissa, Bivard, Andrew, Grimley, Rohan S, Agarwal, Smriti, Munshi, Sunil K, Donnan, Geoffrey A, Davis, Stephen M, Miteff, Ferdinand, Spratt, Neil J, and Levi, Christopher R

Published
2024
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149. Cruising Speed: Our Journal's 10-Year Voyage

Author

Dennis J. Baumgardner and Joe Grundle

Subjects
patient-centered care, health research, clinical inquiry, scientific literature, patient engagement, Medicine
Abstract

In this invited editorial, two long-tenured editors for the Journal of Patient-Centered Research and Reviews recount the publication’s many impactful contributions to the medical literature over its first 10 years.

Published
2024
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