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1. Implementing stakeholder engagement to explore alternative models of consent: An example from the PREP-IT trials

Author

Guillermo Pechero, Jr., MD, Branden Pfaff, Mayank Rao, David Pogorzelski, Paula McKay, Ella Spicer, Andrea Howe, Haley K. Demyanovich, Debra L. Sietsema, Michael F. McTague, Lolita Ramsey, Martha Holden, Joshua Rudnicki, Jeff Wells, Michelle Medeiros, Gerard P. Slobogean, Sheila Sprague, Jeffrey Wells, Mohit Bhandari, Robert V. O'Toole, Jean-Claude D'Alleyrand, Andrew Eglseder, Aaron Johnson, Christopher Langhammer, Christopher Lebrun, Theodore Manson, Jason Nascone, Ebrahim Paryavi, Raymond Pensy, Andrew Pollak, Marcus Sciadini, Yasmin Degani, Nathan N. O'Hara, Katherine Joseph, Megan Camara, Anthony D. Harris, Daniel C. Mullins, Lehana Thabane, Amber Wood, Gregory J. Della Rocca, Joan Hebden, Kyle J. Jeray, Lucas Marchand, Lyndsay M. O'Hara, Robert Zura, Michael J. Gardner, Jenna Blasman, Jonah Davies, Stephen Liang, Monica Taljaard, P.J. Devereaux, Gordon H. Guyatt, Diane Heels-Ansdell, Debra Marvel, Jana Palmer, Jeff Friedrich, Ms Frances Grissom, I. Leah Gitajn, Saam Morshed, Bradley A. Petrisor, Franca Mossuto, Manjari G. Joshi, Justin Fowler, Jessica Rivera, Max Talbot, Shannon Dodds, Alisha Garibaldi, Silvia Li, Uyen Nguyen, Alejandra Rojas, Taryn Scott, Gina Del Fabbro, Olivia Paige Szasz, Haley Demyanovich, Kelly Little, C. Daniel Mullins, Eric Kettering, Diamond Hale, Brad A. Petrisor, Herman Johal, Bill Ristevski, Dale Williams, Matthew Denkers, Krishan Rajaratnam, Jamal Al-Asiri, Jordan Leonard, Francesc A. Marcano-Fernández, Jodi Gallant, Federico Persico, Marko Gjorgjievski, Annie George, Roman M. Natoli, Greg E. Gaski, Todd O. McKinley, Walter W. Virkus, Anthony T. Sorkin, Jan P. Szatkowski, Joseph R. Baele, Brian H. Mullis, Lauren C. Hill, Andrea Hudgins, Patrick Osborn, Sarah Pierrie, Eric Martinez, Joseph Kimmel, John D. Adams, Michael L. Beckish, Christopher C. Bray, Timothy R. Brown, Andrew W. Cross, Timothy Dew, Gregory K. Faucher, Richard W. Gurich, Jr., David E. Lazarus, S. John Millon, M. Jason Palmer, Scott E. Porter, Thomas M. Schaller, Michael S. Sridhar, John L. Sanders, L. Edwin Rudisill, Jr., Michael J. Garitty, Andrew S. Poole, Michael L. Sims, Clark M. Walker, Robert M. Carlisle, II, Erin Adams Hofer, Brandon S. Huggins, Michael D. Hunter, William A. Marshall, Shea Bielby Ray, Cory D. Smith, Kyle M. Altman, Julia C. Bedard, Markus F. Loeffler, Erin R. Pichiotino, Austin A. Cole, Ethan J. Maltz, Wesley Parker, T. Bennett Ramsey, Alex Burnikel, Michael Colello, Russell Stewart, Jeremy Wise, M. Christian Moody, Stephanie L. Tanner, Rebecca G. Snider, Christine E. Townsend, Kayla H. Pham, Abigail Martin, Emily Robertson, Theodore Miclau, Utku Kandemir, Meir Marmor, Amir Matityahu, R. Trigg McClellan, Eric Meinberg, David Shearer, Paul Toogood, Anthony Ding, Erin Donohoe, Jothi Murali, Tigist Belaye, Eleni Berhaneselase, Alexandra Paul, Kartik Garg, Joshua L. Gary, Stephen J. Warner, John W. Munz, Andrew M. Choo, Timothy S. Achor, Milton L. “Chip” Routt, Guillermo Pechero, Adam Miller, Jennifer E. Hagen, Matthew Patrick, Richard Vlasak, Thomas Krupko, Kalia Sadasivan, Chris Koenig, Daniel Bailey, Daniel Wentworth, Chi Van, Justin Schwartz, Niloofar Dehghan, Clifford B. Jones, J. Tracy Watson, Michael McKee, Ammar Karim, Michael Talerico, Alyse Williams, Tayler Dykes, William T. Obremskey, Amir Alex Jahangir, Manish Sethi, Robert Boyce, Daniel J. Stinner, Phillip Mitchell, Karen Trochez, Andres Rodriguez, Vamshi Gajari, Elsa Rodriguez, Charles Pritchett, Christina Boulton, Jason Lowe, Jason Wild, John T. Ruth, Michel Taylor, Andrea Seach, Sabina Saeed, Hunter Culbert, Alejandro Cruz, Thomas Knapp, Colin Hurkett, Maya Lowney, Michael Prayson, Indresh Venkatarayappa, Brandon Horne, Jennifer Jerele, Linda Clark, Francesc Marcano-Fernández, Montsant Jornet-Gibert, Laia Martínez-Carreres, David Martí-Garín, Jorge Serrano-Sanz, Joel Sánchez-Fernández, Matsuyama Sanz-Molero, Alejandro Carballo, Xavier Pelfort, Francesc Acerboni-Flores, Anna Alavedra-Massana, Neus Anglada-Torres, Alexandre Berenguer, Jaume Cámara-Cabrera, Ariadna Caparros-García, Ferran Fillat-Gomà, Ruben Fuentes-López, Ramona Garcia-Rodriguez, Nuria Gimeno-Calavia, Guillem Graells-Alonso, Marta Martínez-Álvarez, Patricia Martínez-Grau, Raúl Pellejero-García, Ona Ràfols-Perramon, Juan Manuel Peñalver, Mònica Salomó Domènech, Albert Soler-Cano, Aldo Velasco-Barrera, Christian Yela-Verdú, Mercedes Bueno-Ruiz, Estrella Sánchez-Palomino, Ernesto Guerra-Farfan, Jordi Tomas-Hernandez, Jordi Teixidor-Serra, Vicente Molero-Garcia, Jordi Selga-Marsa, Juan Antonio Porcel-Vasquez, Jose Vicente Andres-Peiro, Joan Minguell-Monyart, Yaiza Garcia-Sanchez, Jorge Nuñez-Camarena, Eladia Tauste-Rubio, Marta Gonzalez-Amigo, Nicholas M. Romeo, Heather A. Vallier, Mary A. Breslin, Joanne Fraifogl, Eleanor S. Wilson, Leanne K. Wadenpfuhl, Paul G. Halliday, Darius G. Viskontas, Kelly L. Apostle, Dory S. Boyer, Farhad O. Moola, Bertrand H. Perey, Trevor B. Stone, H. Michael Lemke, Mauri Zomar, Chen “Brenda” Fan, Kyrsten Payne, Kevin Phelps, Michael Bosse, Madhav Karunakar, Laurence Kempton, Stephen Sims, Joseph Hsu, Rachel Seymour, Christine Churchill, Claire Bartel, Robert Miles Mayberry, Maggie Brownrigg, Cara Girardi, Ada Mayfield, Robert A. Hymes, Cary C. Schwartzbach, Jeff E. Schulman, A. Stephen Malekzadeh, Michael A. Holzman, James S. Ahn, Farhanaz Panjshiri, Sharmistha Das, Antoinisha D. English, Sharon M. Haaser, Jaslynn A.N. Cuff, Holly Pilson, Eben A. Carroll, Jason J. Halvorson, Sharon Babcock, J. Brett Goodman, Martha B. Holden, Debra Bullard, Wendy Williams, Thomas F. Higgins, Justin M. Haller, David L. Rothberg, Lucas S. Marchand, Ashley Neese, Mark Russell, Zachary M. Olsen, Marcus Coe, Kevin Dwyer, Devin S. Mullin, Clifford A. Reilly, Peter DePalo, Amy E. Hall, Marilyn Heng, Mitchel B. Harris, R. Malcolm Smith, David W. Lhowe, John G. Esposito, Mira Bansal, Patrick F. Bergin, George V. Russell, Matthew L. Graves, John Morellato, Heather K. Champion, Leslie N. Johnson, Sheketha L. McGee, Eldrin L. Bhanat, Samir Mehta, Derek Donegan, Jaimo Ahn, Annamarie Horan, Mary Dooley, Ashley Kuczinski, Ashley Iwu, David Potter, Robert VanDemark, III, Troy Hollinsworth, Michael J. Weaver, Arvind G. von Keudell, Elizabeth M. Allen, Todd Jaeblon, Robert Beer, Mark J. Gage, Rachel M. Reilly, and Cindy Sparrow

Subjects
Cluster randomized crossover, Stakeholder engagement, Consent, Deferred consent, Trial design, Patient advisors, Medicine (General), R5-920
Abstract

Introduction: Cluster randomized crossover trials are often faced with a dilemma when selecting an optimal model of consent, as the traditional model of obtaining informed consent from participant's before initiating any trial related activities may not be suitable. We describe our experience of engaging patient advisors to identify an optimal model of consent for the PREP-IT trials. This paper also examines surrogate measures of success for the selected model of consent. Methods: The PREP-IT program consists of two multi-center cluster randomized crossover trials that engaged patient advisors to determine an optimal model of consent. Patient advisors and stakeholders met regularly and reached consensus on decisions related to the trial design including the model for consent. Patient advisors provided valuable insight on how key decisions on trial design and conduct would be received by participants and the impact these decisions will have. Results: Patient advisors, together with stakeholders, reviewed the pros and cons and the requirements for the traditional model of consent, deferred consent, and waiver of consent. Collectively, they agreed upon a deferred consent model, in which patients may be approached for consent after their fracture surgery and prior to data collection. The consent rate in PREP-IT is 80.7%, and 0.67% of participants have withdrawn consent for participation. Discussion: Involvement of patient advisors in the development of an optimal model of consent has been successful. Engagement of patient advisors is recommended for other large trials where the traditional model of consent may not be optimal.

Published
2021
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2. Information flow, cell types and stereotypy in a full olfactory connectome

Author

Philipp Schlegel, Alexander Shakeel Bates, Tomke Stürner, Sridhar R Jagannathan, Nikolas Drummond, Joseph Hsu, Laia Serratosa Capdevila, Alexandre Javier, Elizabeth C Marin, Asa Barth-Maron, Imaan FM Tamimi, Feng Li, Gerald M Rubin, Stephen M Plaza, Marta Costa, and Gregory S X E Jefferis

Subjects
connectomics, olfaction, stereotypy, neuroanatomy, synapses, Drosophila, Medicine, Science, Biology (General), QH301-705.5
Abstract

The hemibrain connectome provides large-scale connectivity and morphology information for the majority of the central brain of Drosophila melanogaster. Using this data set, we provide a complete description of the Drosophila olfactory system, covering all first, second and lateral horn-associated third-order neurons. We develop a generally applicable strategy to extract information flow and layered organisation from connectome graphs, mapping olfactory input to descending interneurons. This identifies a range of motifs including highly lateralised circuits in the antennal lobe and patterns of convergence downstream of the mushroom body and lateral horn. Leveraging a second data set we provide a first quantitative assessment of inter- versus intra-individual stereotypy. Comparing neurons across two brains (three hemispheres) reveals striking similarity in neuronal morphology across brains. Connectivity correlates with morphology and neurons of the same morphological type show similar connection variability within the same brain as across two brains.

Published
2021
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3. Managing work flow in high enrolling trials: The development and implementation of a sampling strategy in the PREPARE trial

Author

David Pogorzelski, Uyen Nguyen, Paula McKay, Lehana Thabane, Megan Camara, Lolita Ramsey, Rachel Seymour, J. Brett Goodman, Sheketha McGee, Joanne Fraifogl, Andrea Hudgins, Stephanie L. Tanner, Mohit Bhandari, Gerard P. Slobogean, Sheila Sprague, Jeffrey Wells, Jean-Claude D'Alleyrand, Anthony D. Harris, Daniel C. Mullins, Amber Wood, Gregory J. Della Rocca, Joan Hebden, Kyle J. Jeray, Lucas Marchand, Lyndsay M. O'Hara, Robert Zura, Michael J. Gardner, Jenna Blasman, Jonah Davies, Stephen Liang, Monica Taljaard, P.J. Devereaux, Gordon H. Guyatt, Diane Heels-Ansdell, Debra Marvel, Jana Palmer, Jeff Friedrich, Nathan N. O'Hara, Ms. Frances Grissom, I. Leah Gitajn, Saam Morshed, Robert V. O'Toole, Bradley A. Petrisor, Franca Mossuto, Manjari G. Joshi, Justin Fowler, Jessica Rivera, Max Talbot, Shannon Dodds, Alisha Garibaldi, Silvia Li, Alejandra Rojas, Taryn Scott, Gina Del Fabbro, Olivia Paige Szasz, Andrea Howe, Joshua Rudnicki, Haley Demyanovich, Kelly Little, C. Daniel Mullins, Michelle Medeiros, Eric Kettering, Diamond Hale, Andrew Eglseder, Aaron Johnson, Christopher Langhammer, Christopher Lebrun, Theodore Manson, Jason Nascone, Ebrahim Paryavi, Raymond Pensy, Andrew Pollak, Marcus Sciadini, Yasmin Degani, Haley K. Demyanovich, Katherine Joseph, Brad A. Petrisor, Herman Johal, Bill Ristevski, Dale Williams, Matthew Denkers, Krishan Rajaratnam, Jamal Al-Asiri, Jordan Leonard, Francesc A. Marcano-Fernández, Jodi Gallant, Federico Persico, Marko Gjorgjievski, Annie George, Roman M. Natoli, Greg E. Gaski, Todd O. McKinley, Walter W. Virkus, Anthony T. Sorkin, Jan P. Szatkowski, Joseph R. Baele, Brian H. Mullis, Lauren C. Hill, Patrick Osborn, Sarah Pierrie, Eric Martinez, Joseph Kimmel, John D. Adams, Michael L. Beckish, Christopher C. Bray, Timothy R. Brown, Andrew W. Cross, Timothy Dew, Gregory K. Faucher, Richard W. Gurich, Jr., David E. Lazarus, S. John Millon, M. Jason Palmer, Scott E. Porter, Thomas M. Schaller, Michael S. Sridhar, John L. Sanders, L. Edwin Rudisill, Jr., Michael J. Garitty, Andrew S. Poole, Michael L. Sims, Clark M. Walker, Robert M. Carlisle, II, Erin Adams Hofer, Brandon S. Huggins, Michael D. Hunter, William A. Marshall, Shea Bielby Ray, Cory D. Smith, Kyle M. Altman, Julia C. Bedard, Markus F. Loeffler, Erin R. Pichiotino, Austin A. Cole, Ethan J. Maltz, Wesley Parker, T. Bennett Ramsey, Alex Burnikel, Michael Colello, Russell Stewart, Jeremy Wise, M. Christian Moody, Rebecca G. Snider, Christine E. Townsend, Kayla H. Pham, Abigail Martin, Emily Robertson, Theodore Miclau, Utku Kandemir, Meir Marmor, Amir Matityahu, R. Trigg McClellan, Eric Meinberg, David Shearer, Paul Toogood, Anthony Ding, Erin Donohue, Tigist Belaye, Eleni Berhaneselase, Alexandra Paul, Kartik Garg, Joshua L. Gary, Stephen J. Warner, John W. Munz, Andrew M. Choo, Timothy S. Achor, Milton L. “Chip” Routt, Mayank Rao, Guillermo Pechero, Adam Miller, Jennifer E. Hagen, Matthew Patrick, Richard Vlasak, Thomas Krupko, Kalia Sadasivan, Chris Koenig, Daniel Bailey, Daniel Wentworth, Chi Van, Justin Schwartz, Niloofar Dehghan, Clifford B. Jones, J Tracy Watson, Michael McKee, Ammar Karim, Michael Talerico, Debra L. Sietsema, Alyse Williams, Tayler Dykes, William T. Obremskey, Amir Alex Jahangir, Manish Sethi, Robert Boyce, Daniel J. Stinner, Phillip Mitchell, Karen Trochez, Andres Rodriguez, Vamshi Gajari, Elsa Rodriguez, Charles Pritchett, Christina Boulton, Jason Lowe, Jason Wild, John T. Ruth, Michel Taylor, Andrea Seach, Sabina Saeed, Hunter Culbert, Alejandro Cruz, Thomas Knapp, Colin Hurkett, Maya Lowney, Michael Prayson, Indresh Venkatarayappa, Brandon Horne, Jennifer Jerele, Linda Clark, Francesc Marcano-Fernández, Montsant Jornet-Gibert, Laia Martínez-Carreres, David Martí-Garín, Jorge Serrano-Sanz, Joel Sánchez-Fernández, Matsuyama Sanz-Molero, Alejandro Carballo, Xavier Pelfort, Francesc Acerboni-Flores, Anna Alavedra-Massana, Neus Anglada-Torres, Alexandre Berenguer, Jaume Cámara-Cabrera, Ariadna Caparros-García, Ferran Fillat-Gomà, Ruben Fuentes-López, Ramona Garcia-Rodriguez, Nuria Gimeno-Calavia, Guillem Graells-Alonso, Marta Martínez-Álvarez, Patricia Martínez-Grau, Raúl Pellejero-García, Ona Ràfols-Perramon, Juan Manuel Peñalver, Mònica Salomó Domènech, Albert Soler-Cano, Aldo Velasco-Barrera, Christian Yela-Verdú, Mercedes Bueno-Ruiz, Estrella Sánchez-Palomino, Ernesto Guerra, Yaiza García, Nicholas M. Romeo, Heather A. Vallier, Mary A. Breslin, Eleanor S. Wilson, Leanne K. Wadenpfuhl, Paul G. Halliday, Darius G. Viskontas, Kelly L. Apostle, Dory S. Boyer, Farhad O. Moola, Bertrand H. Perey, Trevor B. Stone, H. Michael Lemke, Mauri Zomar, Ella Spicer, Chen “Brenda” Fan, Kyrsten Payne, Kevin Phelps, Michael Bosse, Madhav Karunakar, Laurence Kempton, Stephen Sims, Joseph Hsu, Christine Churchill, Claire Bartel, Robert Miles Mayberry, Maggie Brownrigg, Cara Girardi, Ada Mayfield, Robert A. Hymes, Cary C. Schwartzbach, Jeff E. Schulman, A. Stephen Malekzadeh, Michael A. Holzman, James S. Ahn, Farhanaz Panjshiri, Sharmistha Das, Antoinisha D. English, Sharon M. Haaser, Jaslynn A.N. Cuff, Holly Pilson, Eben A. Carroll, Jason J. Halvorson, Sharon Babcock, Martha B. Holden, Debra Bullard, Wendy Williams, Thomas F. Higgins, Justin M. Haller, David L. Rothberg, Ashley Neese, Mark Russell, Marcus Coe, Kevin Dwyer, Devin S. Mullin, Clifford A. Reilly, Peter DePalo, Amy E. Hall, Marilyn Heng, Mitchel B. Harris, R. Malcolm Smith, David W. Lhowe, John G. Esposito, Mira Bansal, Patrick F. Bergin, George V. Russell, Matthew L. Graves, John Morellato, Heather K. Champion, Leslie N. Johnson, Sheketha L. McGee, Eldrin L. Bhanat, Samir Mehta, Derek Donegan, Jaimo Ahn, Annamarie Horan, Mary Dooley, Ashley Kuczinski, Ashley Iwu, David Potter, Robert VanDemark, III, Branden Pfaff, Troy Hollinsworth, Michael J. Weaver, Arvind G. von Keudell, Michael F. McTague, Elizabeth M. Allen, Todd Jaeblon, Robert Beer, Mark J. Gage, Rachel M. Reilly, and Cindy Sparrow

Subjects
Sampling, Pragmatic, Cluster crossover, Sampling framework, Work flow, Sampling strategy, Medicine (General), R5-920
Abstract

Introduction: Pragmatic trials in comparative effectiveness research assess the effects of different treatment, therapeutic, or healthcare options in clinical practice. They are characterized by broad eligibility criteria and large sample sizes, which can lead to an unmanageable number of participants, increasing the risk of bias and affecting the integrity of the trial. We describe the development of a sampling strategy tool and its use in the PREPARE trial to circumvent the challenge of unmanageable work flow. Methods: Given the broad eligibility criteria and high fracture volume at participating clinical sites in the PREPARE trial, a pragmatic sampling strategy was needed. Using data from PREPARE, descriptive statistics were used to describe the use of the sampling strategy across clinical sites. A Chi-square test was performed to explore whether use of the sampling strategy was associated with a reduction in the number of missed eligible patients. Results: 7 of 20 clinical sites (35%) elected to adopt a sampling strategy. There were 1539 patients excluded due to the use of the sampling strategy, which represents 30% of all excluded patients and 20% of all patients screened for participation. Use of the sampling strategy was associated with lower odds of missed eligible patients (297/4545 (6.5%) versus 341/3200 (10.7%) p

Published
2021
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4. Structured sampling of olfactory input by the fly mushroom body

Author

Joseph Hsu, Tom Kazimiers, Peter H. Li, Matthew Nichols, Viren Jain, Feng Li, Corey B. Fisher, Steven A. Calle-Schuler, Lucia Kmecova, Zhihao Zheng, Najla Masoodpanah, Iqbal J. Ali, Davi D. Bock, Eric Perlman, and Nadiya Sharifi

Subjects
Neurons, Sensory system, Olfaction, Biology, Content-addressable memory, biology.organism_classification, General Biochemistry, Genetics and Molecular Biology, Smell, Drosophila melanogaster, Postsynaptic potential, Mushroom bodies, Connectome, Biological neural network, Animals, Drosophila, General Agricultural and Biological Sciences, Neuroscience, Mushroom Bodies
Abstract

Associative memory formation and recall in the adult fruit flyDrosophila melanogasteris subserved by the mushroom body (MB). Upon arrival in the MB, sensory information undergoes a profound transformation. Olfactory projection neurons (PNs), the main MB input, exhibit broadly tuned, sustained, and stereotyped responses to odorants; in contrast, their postsynaptic targets in the MB, the Kenyon cells (KCs), are nonstereotyped, narrowly tuned, and only briefly responsive to odorants. Theory and experiment have suggested that this transformation is implemented by random connectivity between KCs and PNs. However, this hypothesis has been challenging to test, given the difficulty of mapping synaptic connections between large numbers of neurons to achieve a unified view of neuronal network structure. Here we used a recent whole-brain electron microscopy (EM) volume of the adult fruit fly to map large numbers of PN- to-KC connections at synaptic resolution. Comparison of the observed connectome to precisely defined null models revealed unexpected network structure, in which a subset of food-responsive PN types converge on individual downstream KCs more frequently than expected. The connectivity bias is consistent with the neurogeometry: axons of the overconvergent PNs tend to arborize near one another in the MB main calyx, making local KC dendrites more likely to receive input from those types. Computational modeling of the observed PN-to-KC network showed that input from the overconvergent PN types is better discriminated than input from other types. These results suggest an ‘associative fovea’ for olfaction, in that the MB is wired to better discriminate more frequently occurring and ethologically relevant combinations of food-related odors.

Published
2022
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5. Information flow, cell types and stereotypy in a full olfactory connectome

Author

Sridhar R. Jagannathan, Asa Barth-Maron, Marta Costa, Gerald M. Rubin, Feng Li, Alexandre Javier, Philipp Schlegel, Stephen M. Plaza, Nikolas Drummond, Tomke Stürner, Joseph Hsu, Laia Serratosa Capdevila, Imaan F.M. Tamimi, Elizabeth C. Marin, Gregory S.X.E. Jefferis, Alexander Shakeel Bates, Schlegel, Philipp [0000-0002-5633-1314], Bates, Alexander Shakeel [0000-0002-1195-0445], Stürner, Tomke [0000-0003-4054-0784], Jagannathan, Sridhar R [0000-0002-2078-1145], Marin, Elizabeth C [0000-0001-6333-0072], Li, Feng [0000-0002-6658-9175], Rubin, Gerald M [0000-0001-8762-8703], Plaza, Stephen M [0000-0001-7425-8555], Costa, Marta [0000-0001-5948-3092], Jefferis, Gregory SXE [0000-0002-0587-9355], Apollo - University of Cambridge Repository, and Jefferis, Gregory S X E [0000-0002-0587-9355]

Subjects
0301 basic medicine, Olfactory system, Property (programming), Datasets as Topic, neuroscience, 0302 clinical medicine, Biology (General), 0303 health sciences, D. melanogaster, General Neuroscience, General Medicine, Olfactory Pathways, 3. Good health, medicine.anatomical_structure, Drosophila melanogaster, Mushroom bodies, Connectome, Medicine, Drosophila, Female, Research Article, olfaction, Cell type, Connectomics, QH301-705.5, neuroanatomy, Science, Olfaction, Biology, stereotypy, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Interneurons, medicine, Animals, connectomics, 030304 developmental biology, General Immunology and Microbiology, biology.organism_classification, Stereotypy (non-human), 030104 developmental biology, nervous system, Antennal lobe, synapses, Neuroscience, 030217 neurology & neurosurgery, Neuroanatomy
Abstract

The hemibrain connectome (Scheffer et al., 2020) provides large scale connectivity and morphology information for the majority of the central brain of Drosophila melanogaster. Using this data set, we provide a complete description of the most complex olfactory system studied at synaptic resolution to date, covering all first, second and third-order neurons of the olfactory system associated with the antennal lobe and lateral horn (mushroom body neurons are described in a parallel paper, Li et al., 2020). We develop a generally applicable strategy to extract information flow and layered organisation from synaptic resolution connectome graphs, mapping olfactory input to descending interneurons. This identifies a range of motifs including highly lateralised circuits in the antennal lobe and patterns of convergence downstream of the mushroom body and lateral horn. We also leverage a second data set (FAFB, Zheng et al., 2018) to provide a first quantitative assessment of inter- versus intra-individual stereotypy. Complete reconstruction of select developmental lineages in two brains (three brain hemispheres) reveals striking similarity in neuronal morphology across brains for >170 cell types. Within and across brains, connectivity correlates with morphology. Notably, neurons of the same morphological type show similar connection variability within one brain as across brains; this property should enable a rigorous quantitative approach to cell typing.

Published
2021

6. Author response: Information flow, cell types and stereotypy in a full olfactory connectome

Author

Imaan F.M. Tamimi, Marta Costa, Asa Barth-Maron, Philipp Schlegel, Gregory S.X.E. Jefferis, Alexander Shakeel Bates, Laia Serratosa Capdevila, Elizabeth C. Marin, Joseph Hsu, Feng Li, Stephen M. Plaza, Sridhar R. Jagannathan, Alexandre Javier, Gerald M. Rubin, Nikolas Drummond, and Tomke Stürner

Subjects
Cell type, Stereotypy (non-human), Connectome, Information flow, Biology, Neuroscience
Published
2021
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7. Patient and stakeholder engagement learnings: PREP-IT as a case study

Author

Michelle Medeiros, T Rosie Love, Gerard P. Slobogean, Sheila Sprague, Eleanor M. Perfetto, Nathan N. O'Hara, C. Daniel Mullins, Jeffrey Wells, Mohit Bhandari, Jean-Claude D'alleyrand, Anthony Harris, Daniel C. Mullins, Lehana Thabane, Amber Wood, Gregory J. Della Rocca, Joan Hebden, Kyle J. Jeray, Lucas Marchand, Lyndsay M. O'Hara, Robert Zura, Michael J. Gardner, Jenna Blasman, Jonah Davies, Stephen Liang, Monica Taljaard, PJ Devereaux, Gordon H. Guyatt, Dianne Heels-Ansdell, Debra Marvel, Jana Palmer, Jeff Friedrich, Nathan O'Hara, Frances Grissom, Leah Gitajn, Saam Morshed, Robert O'Toole, Bradley A. Petrisor, Megan Camara, Franca Mossuto, Manjari G. Joshi, Justin Fowler, Jessica Rivera, Max Talbot, Shannon Dodds, Alisha Garibaldi, Silvia Li, Uyen Nguyen, David Pogorzelski, Alejandra Rojas, Taryn Scott, Gina Del Fabbro, Olivia Page Szasz, Paula McKay, Andrea Howe, Joshua Rudnicki, Haley Demyanovich, Kelly Little, Adam Boissonneault, Michellic Medeiros, Eric Kettering, Diamond Hale, Nirmen Mahal, Andrew Eglseder, Aaron Johnson, Christopher Langhammer, Christopher Lebrun, Theodore Manson, Jason Nascone, Ebrahim Paryavi, Raymond Pensy, Andrew Pollack, Marcus Sciadini, Yasmin Degani, Katherine Joseph, Lucas S. Marchand, Heather Phipps, Eric Hempen, Herman Johal, Bill Risteyski, Dale Williams, Matthew Denkers, Krishan Rajaratnam, Jamal Al-Asiri, Jordan Leonard, Francesc A. Marcano-Fernández, Jodi Gallant, Federico Persico, Marko Gjorgjievski, Annie George, Sarah M. McGaugh, Kaitlyn Pusztai, Sarah Piekarski, Mavis Lyons, Julia Gennaccaro, Roman M. Natoli, Greg E. Gaski, Todd O. McKinley, Walter W. Virkus, Anthony T. Sorkin, Jan P. Szatkowski, Joseph R. Baele, Brian H. Mullis, Yohan Jang, Luke A. Lopas, Lauren C. Hill, Andrea Hudgins, Courteney L. Fentz, Maricela M. Diaz, Katelyn M. Garst, Emma W. Denari, Patrick Osborn, Sarah Pierrie, Eric Martinez, Joseph Kimmel, Maria Herrera, John D. Adams, Michael Beckish, Christopher Bray, Timothy R. Brown, Andrew W. Cross, Timothy Dew, Gregory Faucher, Richard W. Gurich Jr, David E. Lazarus, S. John Millon, M. Jason Palmer, Scott E. Porter, Thomas M. Schaller, Michael S. Sridhar, John L. Sanders, Edwin L. Rudisill Jr, Michael J. Garitty, Andrew S. Poole, Michael L. Sims, Clark M. Walker, Robert M. Carlisle II, Erin Adams Hofer, Brandon S. Huggins, Michael D. Hunter, William A. Marshall, Shea Bielby Ray, Cory D. Smith, Kyle M. Altman, Julia C. Bedard, Markus F. Loeffler, Erin R. Pichiotino, Austin A. Cole, Ethan J. Maltz, Wesley Parker, T. Bennett Ramsey, Alex Burnikel, Michael Colello, Russell Stewart, Jeremy Wise, M. Christian Moody, Matthew Anderson, Joshua Eskew, Benjamin Judkins, James M. Miller, Stephanie L. Tanner, Rebecca G. Snider, Christine E. Townsend, Kayla H. Pham, Abigail Martin, Emily Robertson, John Wilson Sykes, Theodore Miclau, Utku Kandemir, Meir Marmor, Amir Matityahu, R. Trigg McClellan, Eric Meinberg, David Shearer, Paul Toogood, Anthony Ding, Erin Donohue, Jothi Murali, Ashraf El Naga, Jennifer Tangtiphaiboontana, Tigist Belaye, Eleni Berhaneselase, Alexandra Paul, Kartik Garg, Dmitry Pokhvashchev, Joshua L. Gary, Stephen J. Warner, John W. Munz, Andrew M. Choo, Timothy Achor, Milton L. \\'Chip\\' Routt, Mayank Rao, Guillermo Pechero, Adam Miller, Michael Kutzler, Sterling Boutte, Ryan J. Warth, Jennifer E. Hagen, Matthew Patrick, Richard Vlasak, Thomas Krupko, Kalia Sadasivan, Michael Talerico, Marybeth Horodyski, Chris Koenig, Daniel Bailey, Daniel Wentworth, Chi Van, Justin Schwartz, Marissa Pazik, Elizabeth Lossada-Soto, Niloofar Dehghan, Clifford B. Jones, J. Tracy Watson, Michael McKee, Ammar Karim, Debra L. Sietsema, Alyse William, Tayler Dykes, William T. Obremskey, Amir Alex Jahangir, Manish Sethi, Robert Boyce, Daniel J. Stinner, Phillip Mitchell, Karen Trochez, Andres Rodriguez, Vamshi Gajari, Elsa Rodriguez, Chris Pritchett, Natalie Hogan, Fidel A. Moreno, Christina Boulton, Jason Lowe, Jason Wild, John T. Ruth, Michel Taylor, Brad Askam, Andrea Seach, Sabina Saeed, Hunter Culbert, Alejandro Crus, Thomas Knapp, Colin Hurkett, Maya Lowney, Breanna Featherston, Robin Carlson, Iliana Romero, Isaac Zarif, Michael Prayson, Indresh Venkatarayappa, Brandon Horne, Jennifer Jerele, Linda Clark, Francesc Marcano-Fernández, Montsant Jornet-Gibert, Laia Martínez-Carreres, David Martí-Garín, Jorge Serrano-Sanz, Joel Sánchez-Fernández, Matsuyama Sanz-Molero, Alejandro Carballo, Xavier Pelfort, Francesc Acerboni-Flores, Anna Alavedra-Massana, Neus Anglada-Torres, Alexandre Berenguer, Jaume Cámara-Cabrera, Ariadna Caparros-García, Ferran Fillat-Gomà, Ruben Fuentes-López, Ramona Garcia-Rodriguez, Nuria Gimeno-Clavia, Guillem Graells-Alonso, Marta Martínez-álvarez, Patricia Martínez-Grau, Raúl Pellejero-García, Ona Ràfols-Perramon, Juan Manuel Peñalver, Mònica Salomò Domènech, Albert Soler-Cano, Aldo Velasco-Barrera, Christian Yela-Verdú, Mercedes Bueno-Ruiz, Estrella Sánchez-Palomino, Vito Andriola, Matilde Molina-Corbacho, Yeray Maldonado-Sotoca, Alfons Gasset-Teixidor, Jorge Blasco-Moreu, Núria Fernández-Poch, Josep Rodoreda-Puigdemasa, Arnau Verdaguer-Figuerola, Heber Enrique Cueva-Sevieri, Santiago Garcia-Gimenez, Ernesto Guerra-Farfán, Jordi Tomas-Hernandez, Jordi Teixidor-Serra, Vicente Molero-Garcia, Jordi Selga-Marsa, Juan Antonio Porcel-Vazquez, Jose Vicente Andres-Peiro, Joan Minguell-Monyart, Jorge Nuñez-Camarena, Maria del Mar Villar-Casares, Jaume Mestre-Torres, Pilar Lalueza-Broto, Felipe Moreira-Borim, Yaiza García, Nicholas M. Romeo, Heather A. Vallier, Mary A. Breslin, Joanne Fraifogl, Eleanor S. Wilson, Leanne K Wadenpfuhl, Paul G. Halliday, Isabella Heimke, Darius G. Viskontas, Kelly L. Apostle, Dory S. Boyer, Farhad O. Moola, Bertrand H. Perey, Trevor B. Stone, H. Michael Lemke, Mauri Zomar, Ella Spicer, Chen \\'Brenda\\' Fan, Kyrsten Payne, Kevin Phelps, Michael Bosse, Madhav Karunakar, Laurence Kempton, Stephen Sims, Joseph Hsu, Rachel Seymour, Christine Churchill, Claire Bartel, Robert Miles Mayberry, Maggie Brownrigg, Cara Girardi, Ada Mayfield, Juliette Sweeney, Hannah Pollock, Robert A. Hymes, Cary C. Schwartzbach, Jeff E. Schulman, A. Stephen Malekzadeh, Michael A. Holzman, Jonathan Wills, Lolita Ramsey, James S. Ahn, Farhanaz Panjshiri, Sharmistha Das, Antoinisha D. English, Sharon M. Haaser, Jaslynn A.N. Cuff, Holly Pilson, Eben A. Carroll, Jason J. Halvorson, Sharon Babcock, J. Brett Goodman, Martha B. Holden, Debra Bullard, Wendy Williams, Taylor Hill, Ariel Brotherton, Thomas F. Higgins, Justin M. Haller, David L. Rothberg, Ashley Neese, Mark Russell, Zachary M. Olsen, Abby V. McGowan, Sophia Hill, Marcus Coe, Kevin Dwyer, Devin S. Mullin, Clifford A Reily, Peter DePalo, Amy E. Hall, Rebecca E. Dabrowski, Theresa A. Chockbengboun, Marilyn Heng, Mitchel B. Harris, R. Malcolm Smith, David W. Lhowe, John Esposito, Mira Bansal, Michael McTague, Ahmad Alnasser, Patrick F. Bergin, George V. Russell, Matthew L. Graves, John Morellato, Heather K. Champion, Leslie N. Johnson, Skeketha L. McGee, Eldrin L. Bhanat, Josny Thimothee, Jackie Serrano, Samir Mehta, Derek Donegan, Jaimo Ahn, Annamarie Horan, Mary Dooley, Ashley Kuczinski, Ashley Iwu, David Potter, Robert VanDemark II, Branden Pfaff, Troy Hollinsworth, Kristi Atkins, Michael J. Weaver, Arvind G. von Keudel, Michael F. McTague, Elizabeth M. Allen, Abigail E. Sagona, Todd Jaeblon, Robert Beer, Brent Bauer, Sean Meredith, Autumn Stone, Mark J. Gage, Rachel M. Reilly, Cindy Sparrow, Ariana Paniagua, Christopher M. Domes, Kristina P. Johnson, Steven F. Shannon, Alesha N. Scott, Bobbi Clinch, Carol A. Lin, Mark S. Vrahas, Charles N. Moon, Geoffrey S. Marecek, Denice Dubuclet, John A. Scolaro, James R. Learned, Philip K. Lim, Susan Demas, Michael J. Beltran, Michael T. Archdeacon, Henry Claude Sagi, John D. Wyrick, Theodore Toan Le, Richard T. Laughlin, and Cameron G. Thomson

Subjects
Patient Outcome Assessment, Medical education, business.industry, Stakeholder Participation, Health Policy, Patient-Centered Care, Stakeholder engagement, Medicine, Humans, Multi stakeholder, business, Patient centered
Published
2021

8. Managing work flow in high enrolling trials: The development and implementation of a sampling strategy in the PREPARE trial

Author

David Pogorzelski, Uyen Nguyen, Paula McKay, Lehana Thabane, Megan Camara, Lolita Ramsey, Rachel Seymour, J. Brett Goodman, Sheketha McGee, Joanne Fraifogl, Andrea Hudgins, Stephanie L. Tanner, Mohit Bhandari, Gerard P. Slobogean, Sheila Sprague, Jeffrey Wells, Jean-Claude D'Alleyrand, Anthony D. Harris, Daniel C. Mullins, Amber Wood, Gregory J. Della Rocca, Joan Hebden, Kyle J. Jeray, Lucas Marchand, Lyndsay M. O'Hara, Robert Zura, Michael J. Gardner, Jenna Blasman, Jonah Davies, Stephen Liang, Monica Taljaard, P.J. Devereaux, Gordon H. Guyatt, Diane Heels-Ansdell, Debra Marvel, Jana Palmer, Jeff Friedrich, Nathan N. O'Hara, Ms. Frances Grissom, I. Leah Gitajn, Saam Morshed, Robert V. O'Toole, Bradley A. Petrisor, Franca Mossuto, Manjari G. Joshi, Justin Fowler, Jessica Rivera, Max Talbot, Shannon Dodds, Alisha Garibaldi, Silvia Li, Alejandra Rojas, Taryn Scott, Gina Del Fabbro, Olivia Paige Szasz, Andrea Howe, Joshua Rudnicki, Haley Demyanovich, Kelly Little, C. Daniel Mullins, Michelle Medeiros, Eric Kettering, Diamond Hale, Andrew Eglseder, Aaron Johnson, Christopher Langhammer, Christopher Lebrun, Theodore Manson, Jason Nascone, Ebrahim Paryavi, Raymond Pensy, Andrew Pollak, Marcus Sciadini, Yasmin Degani, Haley K. Demyanovich, Katherine Joseph, Brad A. Petrisor, Herman Johal, Bill Ristevski, Dale Williams, Matthew Denkers, Krishan Rajaratnam, Jamal Al-Asiri, Jordan Leonard, Francesc A. Marcano-Fernández, Jodi Gallant, Federico Persico, Marko Gjorgjievski, Annie George, Roman M. Natoli, Greg E. Gaski, Todd O. McKinley, Walter W. Virkus, Anthony T. Sorkin, Jan P. Szatkowski, Joseph R. Baele, Brian H. Mullis, Lauren C. Hill, Patrick Osborn, Sarah Pierrie, Eric Martinez, Joseph Kimmel, John D. Adams, Michael L. Beckish, Christopher C. Bray, Timothy R. Brown, Andrew W. Cross, Timothy Dew, Gregory K. Faucher, Richard W. Gurich, David E. Lazarus, S. John Millon, M. Jason Palmer, Scott E. Porter, Thomas M. Schaller, Michael S. Sridhar, John L. Sanders, L. Edwin Rudisill, Michael J. Garitty, Andrew S. Poole, Michael L. Sims, Clark M. Walker, Robert M. Carlisle, Erin Adams Hofer, Brandon S. Huggins, Michael D. Hunter, William A. Marshall, Shea Bielby Ray, Cory D. Smith, Kyle M. Altman, Julia C. Bedard, Markus F. Loeffler, Erin R. Pichiotino, Austin A. Cole, Ethan J. Maltz, Wesley Parker, T. Bennett Ramsey, Alex Burnikel, Michael Colello, Russell Stewart, Jeremy Wise, M. Christian Moody, Rebecca G. Snider, Christine E. Townsend, Kayla H. Pham, Abigail Martin, Emily Robertson, Theodore Miclau, Utku Kandemir, Meir Marmor, Amir Matityahu, R. Trigg McClellan, Eric Meinberg, David Shearer, Paul Toogood, Anthony Ding, Erin Donohue, Tigist Belaye, Eleni Berhaneselase, Alexandra Paul, Kartik Garg, Joshua L. Gary, Stephen J. Warner, John W. Munz, Andrew M. Choo, Timothy S. Achor, Milton L. 'Chip' Routt, Mayank Rao, Guillermo Pechero, Adam Miller, Jennifer E. Hagen, Matthew Patrick, Richard Vlasak, Thomas Krupko, Kalia Sadasivan, Chris Koenig, Daniel Bailey, Daniel Wentworth, Chi Van, Justin Schwartz, Niloofar Dehghan, Clifford B. Jones, J Tracy Watson, Michael McKee, Ammar Karim, Michael Talerico, Debra L. Sietsema, Alyse Williams, Tayler Dykes, William T. Obremskey, Amir Alex Jahangir, Manish Sethi, Robert Boyce, Daniel J. Stinner, Phillip Mitchell, Karen Trochez, Andres Rodriguez, Vamshi Gajari, Elsa Rodriguez, Charles Pritchett, Christina Boulton, Jason Lowe, Jason Wild, John T. Ruth, Michel Taylor, Andrea Seach, Sabina Saeed, Hunter Culbert, Alejandro Cruz, Thomas Knapp, Colin Hurkett, Maya Lowney, Michael Prayson, Indresh Venkatarayappa, Brandon Horne, Jennifer Jerele, Linda Clark, Francesc Marcano-Fernández, Montsant Jornet-Gibert, Laia Martínez-Carreres, David Martí-Garín, Jorge Serrano-Sanz, Joel Sánchez-Fernández, Matsuyama Sanz-Molero, Alejandro Carballo, Xavier Pelfort, Francesc Acerboni-Flores, Anna Alavedra-Massana, Neus Anglada-Torres, Alexandre Berenguer, Jaume Cámara-Cabrera, Ariadna Caparros-García, Ferran Fillat-Gomà, Ruben Fuentes-López, Ramona Garcia-Rodriguez, Nuria Gimeno-Calavia, Guillem Graells-Alonso, Marta Martínez-Álvarez, Patricia Martínez-Grau, Raúl Pellejero-García, Ona Ràfols-Perramon, Juan Manuel Peñalver, Mònica Salomó Domènech, Albert Soler-Cano, Aldo Velasco-Barrera, Christian Yela-Verdú, Mercedes Bueno-Ruiz, Estrella Sánchez-Palomino, Ernesto Guerra, Yaiza García, Nicholas M. Romeo, Heather A. Vallier, Mary A. Breslin, Eleanor S. Wilson, Leanne K. Wadenpfuhl, Paul G. Halliday, Darius G. Viskontas, Kelly L. Apostle, Dory S. Boyer, Farhad O. Moola, Bertrand H. Perey, Trevor B. Stone, H. Michael Lemke, Mauri Zomar, Ella Spicer, Chen 'Brenda' Fan, Kyrsten Payne, Kevin Phelps, Michael Bosse, Madhav Karunakar, Laurence Kempton, Stephen Sims, Joseph Hsu, Christine Churchill, Claire Bartel, Robert Miles Mayberry, Maggie Brownrigg, Cara Girardi, Ada Mayfield, Robert A. Hymes, Cary C. Schwartzbach, Jeff E. Schulman, A. Stephen Malekzadeh, Michael A. Holzman, James S. Ahn, Farhanaz Panjshiri, Sharmistha Das, Antoinisha D. English, Sharon M. Haaser, Jaslynn A.N. Cuff, Holly Pilson, Eben A. Carroll, Jason J. Halvorson, Sharon Babcock, Martha B. Holden, Debra Bullard, Wendy Williams, Thomas F. Higgins, Justin M. Haller, David L. Rothberg, Ashley Neese, Mark Russell, Marcus Coe, Kevin Dwyer, Devin S. Mullin, Clifford A. Reilly, Peter DePalo, Amy E. Hall, Marilyn Heng, Mitchel B. Harris, R. Malcolm Smith, David W. Lhowe, John G. Esposito, Mira Bansal, Patrick F. Bergin, George V. Russell, Matthew L. Graves, John Morellato, Heather K. Champion, Leslie N. Johnson, Sheketha L. McGee, Eldrin L. Bhanat, Samir Mehta, Derek Donegan, Jaimo Ahn, Annamarie Horan, Mary Dooley, Ashley Kuczinski, Ashley Iwu, David Potter, Robert VanDemark, Branden Pfaff, Troy Hollinsworth, Michael J. Weaver, Arvind G. von Keudell, Michael F. McTague, Elizabeth M. Allen, Todd Jaeblon, Robert Beer, Mark J. Gage, Rachel M. Reilly, and Cindy Sparrow

Subjects
Pragmatic, medicine.medical_specialty, Comparative effectiveness research, Pharmacy, Sampling framework, Cluster crossover, Sampling strategy, Article, Odds, 03 medical and health sciences, 0302 clinical medicine, Health care, medicine, 030212 general & internal medicine, Sampling, Pharmacology, lcsh:R5-920, Descriptive statistics, business.industry, Sampling (statistics), General Medicine, Test (assessment), Work flow, Family medicine, business, lcsh:Medicine (General), 030217 neurology & neurosurgery
Abstract

Author(s): Pogorzelski, David; Nguyen, Uyen; McKay, Paula; Thabane, Lehana; Camara, Megan; Ramsey, Lolita; Seymour, Rachel; Goodman, J Brett; McGee, Sheketha; Fraifogl, Joanne; Hudgins, Andrea; Tanner, Stephanie L; Bhandari, Mohit; Slobogean, Gerard P; Sprague, Sheila; PREP-IT Investigators Executive Committee:; Steering Committee; Adjudication Committee; Data and Safety Monitoring Committee; Research Methodology Core; Patient Centred Outcomes Core; Orthopaedic Surgery Core; Operating Room Core; Infectious Disease Core; Military Core; McMaster University Methods Center; University of Maryland School of Medicine Administrative Center; University of Maryland School of Pharmacy, The PATIENTS Program; PREP-IT Clinical Sites: Lead Clinical Site (Aqueous-PREP and PREPARE); Aqueous-PREP and PREPARE; Aqueous-PREP; PREPARE; PREP-IT Investigators Executive Committee | Abstract: IntroductionPragmatic trials in comparative effectiveness research assess the effects of different treatment, therapeutic, or healthcare options in clinical practice. They are characterized by broad eligibility criteria and large sample sizes, which can lead to an unmanageable number of participants, increasing the risk of bias and affecting the integrity of the trial. We describe the development of a sampling strategy tool and its use in the PREPARE trial to circumvent the challenge of unmanageable work flow.MethodsGiven the broad eligibility criteria and high fracture volume at participating clinical sites in the PREPARE trial, a pragmatic sampling strategy was needed. Using data from PREPARE, descriptive statistics were used to describe the use of the sampling strategy across clinical sites. A Chi-square test was performed to explore whether use of the sampling strategy was associated with a reduction in the number of missed eligible patients.Results7 of 20 clinical sites (35%) elected to adopt a sampling strategy. There were 1539 patients excluded due to the use of the sampling strategy, which represents 30% of all excluded patients and 20% of all patients screened for participation. Use of the sampling strategy was associated with lower odds of missed eligible patients (297/4545 (6.5%) versus 341/3200 (10.7%) p l 0.001).ConclusionsImplementing a sampling strategy in the PREPARE trial has helped to limit the number of missed eligible patients. This sampling strategy represents a simple, easy to use tool for managing work flow at clinical sites and maintaining the integrity of a large trial.

Published
2020

9. Input connectivity reveals additional heterogeneity of dopaminergic reinforcement in Drosophila

Author

Gerald M. Rubin, Markus W. Pleijzier, Marta Costa, Konrad J. Heinz, Masayoshi Ito, Philipp Schlegel, Kei Ito, Georgia Dempsey, Nils Otto, Gregory S.X.E. Jefferis, Alexander Shakeel Bates, Ishaan Kapoor, Amelia J. Edmondson-Stait, Ildiko Stark, Davi D. Bock, Isabel C. Morgan, Joseph Hsu, Li Feng, and Scott Waddell

Subjects
0301 basic medicine, Connectomics, Biology, Article, General Biochemistry, Genetics and Molecular Biology, memory, 03 medical and health sciences, 0302 clinical medicine, Dopamine, medicine, Compartment (development), connectomics, Reinforcement, reward, 030304 developmental biology, 0303 health sciences, learning, extinction, Dopaminergic, mushroom body, 030104 developmental biology, Mushroom bodies, Drosophila, dopamine, General Agricultural and Biological Sciences, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract

Summary Different types of Drosophila dopaminergic neurons (DANs) reinforce memories of unique valence and provide state-dependent motivational control [1]. Prior studies suggest that the compartment architecture of the mushroom body (MB) is the relevant resolution for distinct DAN functions [2, 3]. Here we used a recent electron microscope volume of the fly brain [4] to reconstruct the fine anatomy of individual DANs within three MB compartments. We find the 20 DANs of the γ5 compartment, at least some of which provide reward teaching signals, can be clustered into 5 anatomical subtypes that innervate different regions within γ5. Reconstructing 821 upstream neurons reveals input selectivity, supporting the functional relevance of DAN sub-classification. Only one PAM-γ5 DAN subtype γ5(fb) receives direct recurrent feedback from γ5β′2a mushroom body output neurons (MBONs) and behavioral experiments distinguish a role for these DANs in memory revaluation from those reinforcing sugar memory. Other DAN subtypes receive major, and potentially reinforcing, inputs from putative gustatory interneurons or lateral horn neurons, which can also relay indirect feedback from MBONs. We similarly reconstructed the single aversively reinforcing PPL1-γ1pedc DAN. The γ1pedc DAN inputs mostly differ from those of γ5 DANs and they cluster onto distinct dendritic branches, presumably separating its established roles in aversive reinforcement and appetitive motivation [5, 6]. Tracing also identified neurons that provide broad input to γ5, β′2a, and γ1pedc DANs, suggesting that distributed DAN populations can be coordinately regulated. These connectomic and behavioral analyses therefore reveal further complexity of dopaminergic reinforcement circuits between and within MB compartments., Highlights • Nanoscale anatomy reveals additional subtypes of rewarding dopaminergic neurons • Connectomics reveals input specificity to subtypes of dopaminergic neurons • Axon morphology implies dopaminergic neurons provide subcompartment-level function • Unique dopaminergic subtypes serve aversive memory extinction and sugar learning, Otto et al. use electron microscope resolution connectomics to describe the structure and organization of neurons providing synaptic input to functionally discrete subtypes of dopaminergic neurons. The nanoscale anatomy reveals further anatomical and functional specialization of dopaminergic neurons, which is confirmed with behavioral experiments.

Published
2020
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10. Pushing the limits of detection for proteins secreted from single cells using quantum dots

Author

Vanessa Herrera, Jered B. Haun, Ssu-Chieh Joseph Hsu, Lisa Nguyen, Carol Chen, Wendy Liu, and Maha K. Rahim

Subjects
1.1 Normal biological development and functioning, Cell, Bioengineering, 02 engineering and technology, 01 natural sciences, Biochemistry, Article, Analytical Chemistry, Rhodamine, chemistry.chemical_compound, Single-cell analysis, Limit of Detection, Underpinning research, Quantum Dots, Electrochemistry, medicine, Environmental Chemistry, Humans, Nanotechnology, Secretion, Spectroscopy, Immunoassay, U937 cell, Tumor Necrosis Factor-alpha, Inflammatory and immune system, 010401 analytical chemistry, U937 Cells, 021001 nanoscience & nanotechnology, Orders of magnitude (mass), 0104 chemical sciences, medicine.anatomical_structure, chemistry, Quantum dot, Biophysics, Generic health relevance, Bioorthogonal chemistry, Single-Cell Analysis, 0210 nano-technology, Other Chemical Sciences, Biotechnology
Abstract

Single cell analysis methods are increasingly being utilized to investigate how individual cells process information and respond to diverse stimuli. Soluble proteins play a critical role in controlling cell populations and tissues, but directly monitoring secretion is technically challenging. Microfabricated well arrays have been developed to assess secretion at the single cell level, but these systems are limited by low detection sensitivity. Semiconductor quantum dots (QD) exhibit remarkably bright and photostable luminescence signal, but to date they have not been evaluated in single cell secretion studies using microfabricated well arrays. Here, we used QDs in a sandwich immunoassay to detect secretion of the soluble cytokine tumor necrosis factor-α (TNF-α) from single cells. To enhance detection sensitivity, we employed two different strategies. First, we used a unique single QD imaging approach, which provided a detection threshold (180 attomolar) that was >100-fold lower than previously reported results using QDs. We also amplified QD binding to each captured TNF-α molecule using the bioorthogonal cycloaddition reaction between trans-cyclooctene and tetrazine, which further lowered detection threshold to 60 attomolar. This is 6 orders of magnitude more sensitive than organic fluorophores that have been used for single cell secretion studies, and far surpasses single molecule resolution within sub-picoliter microwells that are used to assess single cell secretion. Finally, single cell secretion studies were performed using phorbol 12-myristate 13-acetate (PMA) differentiated and lipopolysaccharide (LPS) activated U-937 cells. TNF-α secretion was detected from 3-fold more single cells using the QD-based method in comparison to rhodamine, which was accomplished by extending sensitivity into the range of ∼2 to 10 000 molecules captured per microwell. In future work, we will apply this technique to assess immune cell secretion dynamics under diverse stimuli and disease settings. We will also incorporate multiplexing capabilities to evaluate the secretome at the resolution of single molecules.

Published
2019

11. The Specific Organism: Not Bacterial Gram Type: Drives the Inflammatory Response in Septic Shock

Author

Adam Linder, Malin Inghammar, James A. Russell, John H. Boyd, Joseph Hsu, Chris Fjell, and Keith R. Walley

Subjects
0301 basic medicine, Male, Vasopressin, Klebsiella pneumoniae, medicine.medical_treatment, Inflammation, medicine.disease_cause, Enterococcus faecalis, 03 medical and health sciences, 0302 clinical medicine, Streptococcus pneumoniae, medicine, Immunology and Allergy, Humans, Aged, biology, Bacteria, Septic shock, Neisseria meningitidis, Bacterial Infections, Middle Aged, biology.organism_classification, medicine.disease, Shock, Septic, 030104 developmental biology, Cytokine, 030228 respiratory system, Immunology, Cytokines, Female, medicine.symptom, Research Article
Abstract

Background and Hypothesis: The inflammatory response was targeted by unsuccessful therapies but ignored pathogen. We hypothesized that the inflammatory response differs according to organism in human septic shock. Materials and Methods: We measured 39 cytokines at baseline and 24 h in patients (n = 363) in the Vasopressin and Septic Shock Trial (VASST). We compared cytokine profiles (cytokine functional class) at baseline and at 24 h by organism and used hierarchical clustering to classify cytokines according to 28-day outcomes. Results: In 363 patients, 88 and 176 patients had at least 1 species isolated from blood and other sites, respectively. Cytokine levels differed significantly according to organism: Neisseria meningitidis and Streptococcus pneumoniae had the highest (baseline and at 24 h), while Enterococcus faecalis (blood) had the lowest mean cytokine levels. N. meningitidis and Klebsiella pneumoniae had significantly higher cytokine levels at baseline versus 24 h (p = 0.01 and 0.02, respectively); E. faecalis had significantly higher cytokine levels at 24 h versus baseline. Hierarchical clustering heat maps showed that pathogens elicited similar cytokine responses not related to the functional cytokine class. Conclusion: The organism type induces different cytokine profiles in septic shock. Specific gram-positive and gram-negative pathogens stimulated similar plasma cytokine-level patterns.

Published
2018

12. Quality, Size and Performance of Audit Firms

Author

Yahn-Shir Chen, Joseph Hsu, Mei-Ting Huang, and Ping-Sen Yang

Subjects
jel:M42, health services administration, Audit Quality, Audit Firm Size, Audit Firms
Abstract

This study examines the relations between audit quality, audit firm size, and financial performance. This study estimates audit quality of audit firms from human capital-related factors, such as educational level of auditors, work experience of auditors, and professional training. From the perspective of market segmentation, the sample is divided into three categories: national, regional, and local firms. Empirical results report a positive association between audit firm size and audit quality for the three categories of audit firms. The positive relationship of national audit firms is higher than that of regional and local audit firms. The relationship between audit quality and financial performance is positive. The positive relationship of national audit firms is higher than that of regional and local audit firms.

Published
2013

14. Studies of photoprotection against porphyrin photosensitization using dithiothreitol and glycerol

Author

Joseph Hsu, Helen Hsu, Bernard D. Goldstein, and Leonard C. Harber

Subjects
Glycerol, Male, Erythrocytes, Light, medicine.medical_treatment, Intraperitoneal injection, Radiation-Protective Agents, Dermatology, Glucosephosphate Dehydrogenase, Median lethal dose, Biochemistry, Hemolysis, Dithiothreitol, Fluorescence, chemistry.chemical_compound, Porphyrias, medicine, Humans, Erythropoiesis, Photosensitivity Disorders, Molecular Biology, Hematoporphyrin, Photolysis, Protoporphyrin IX, Lethal dose, Glutathione, Cell Biology, Molecular biology, Radiation Effects, Hematoporphyrins, chemistry, Injections, Intraperitoneal
Abstract

Although protection against ionizing radiation by compounds containing sulfhydryl (SN) groups, such as cysteine, has been reported, these agents have been unsuccessful to date in protecting mammals against non-ionizing radiation (>200nm). This study describes successful photoprotection by dithiothreitol (DTT) and glycerol against porphyrin photosensitization having an action spectrum of 400nm. Test models used were red blood cells (RBC) obtained from patients with erythropoietic protoporphyria (EPP) and mice photo-sensitized by hematoporphyrin (HP). A mortality rate approaching a lethal dose in 50% of the animals in 1 day (LD50/24 hrs) was established in 100 white mice that had received an intraperitoneal injection of 100mg HP/kg body wt., and were then irradiated with 5 × 106 ergs/cm2 from a fluorescent light source emitting 320-450nm radiation. Another 100 mice were treated in an identical manner except that they received, in addition to HP, 80mg DTT/kg body weight in a 5.5% glycerol solution. This group showed 75% reduction in mortality (p < 0.03). No lethal effects were observed in animals treated with DTT and glycerol or HP in the above concentrations without 400nm irradiation. RBC obtained from patients with EPP and exposed to 107 ergs/mm2 of 400nm radiation showed 100% hemolysis after 180min. These cells, when irradiated under identical conditions except for the addition of DTT, manifested only 19% hemolysis during this period of time. Measurements of SH groups of RBC from patients with EPP showed a progressive decrease during photohemolysis. Comparison of the rate of photohemolysis of normal and glucose-6-phosphate dehydrogenase (G6PD) deficient RBC irradiated in the presence of protoporphyrin IX revealed that G6PD deficient RBC, which have an impaired ability to produce reduced glutathione (GSH), were more susceptible to porphyrin-induced photohemolysis. These studies demonstrate that DTT and glycerol offer photoprotection in an in vivo mammalian system against porphyrin photosensitization. It is suggested that the mechanism of the photoprotective action against 320-450nm radiation has many features similar to that of radioprotection by thiols and glycerol against ionizing radiation.

Published
1972

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